WO2022063101A1 - 芳甲酰取代的三环化合物及其制法和用途 - Google Patents
芳甲酰取代的三环化合物及其制法和用途 Download PDFInfo
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- WO2022063101A1 WO2022063101A1 PCT/CN2021/119507 CN2021119507W WO2022063101A1 WO 2022063101 A1 WO2022063101 A1 WO 2022063101A1 CN 2021119507 W CN2021119507 W CN 2021119507W WO 2022063101 A1 WO2022063101 A1 WO 2022063101A1
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- alkylene
- alkyl
- alkoxy
- formula
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- 125000006413 ring segment Chemical group 0.000 claims description 143
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- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
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- 239000003623 enhancer Substances 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
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- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
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- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- BITPAXWTJXOWKL-UHFFFAOYSA-N lithium;oxolane Chemical compound [Li].C1CCOC1 BITPAXWTJXOWKL-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- OBOVZRPIWXDGEL-JEDNCBNOSA-N methyl (2s)-2-amino-3-hydroxy-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@](C)(N)CO OBOVZRPIWXDGEL-JEDNCBNOSA-N 0.000 description 1
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 1
- HMZHEECHJWHZJX-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N HMZHEECHJWHZJX-UHFFFAOYSA-N 0.000 description 1
- WFJFGIAGOSGWMT-UHFFFAOYSA-N methyl 3-aminooxolane-3-carboxylate Chemical compound COC(=O)C1(N)CCOC1 WFJFGIAGOSGWMT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 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
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035515 penetration Effects 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
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- HWYNYLXTVJYPOW-UHFFFAOYSA-N piperidine-1,3-dicarboxylic acid Chemical compound OC(=O)C1CCCN(C(O)=O)C1 HWYNYLXTVJYPOW-UHFFFAOYSA-N 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004585 polycyclic heterocycle group Chemical group 0.000 description 1
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- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- 235000013772 propylene glycol Nutrition 0.000 description 1
- PNNRZXFUPQQZSO-UHFFFAOYSA-N pyran Chemical compound [CH]1OC=CC=C1 PNNRZXFUPQQZSO-UHFFFAOYSA-N 0.000 description 1
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical compound N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 1
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 description 1
- PAQYIEZTLSDLQO-UHFFFAOYSA-N pyrido[3,4-d]pyrimidine Chemical compound N1=CN=C2C=NC=CC2=C1 PAQYIEZTLSDLQO-UHFFFAOYSA-N 0.000 description 1
- PLZDHJUUEGCXJH-UHFFFAOYSA-N pyrido[4,3-d]pyrimidine Chemical compound C1=NC=C2C=NC=CC2=N1 PLZDHJUUEGCXJH-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 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
- 230000006340 racemization Effects 0.000 description 1
- 230000004044 response Effects 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
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Definitions
- the invention belongs to the field of medicine, and particularly relates to an arylformyl-substituted tricyclic compound and a preparation method and application thereof.
- BTK B cell antigen receptor
- the present invention provides an arylformyl-substituted tricyclic compound, which, as a BTK inhibitor, has the advantages of high activity, good selectivity and low toxicity and side effects.
- the present invention provides a compound of formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
- n 0, 1, 2 or 3;
- E is NR 5 , O or N; wherein, R 5 is H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 Alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6 Monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-C(O)NR
- hydrogen atoms are simultaneously substituted by -(CH 2 ) j - to form a cycloalkyl, wherein j is 2, 3, 4, 5 or 6; the C 3-6 monocyclic cycloalkyl and the 3- to 6-membered Monocyclic heterocyclyl optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy and deuterated C 1-6 alkoxy;
- A is CR 6 or N; wherein, R 6 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- B is CR 7 or N; wherein, R 7 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- G 1 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; and the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S2 group;
- G 2 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; and the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S2 group;
- L is a bond, CR 8 R 9 , O, NH, NHC(O), C 1-2 alkylene-NHC(O) or NHC(O)-C 1-2 alkylene-; wherein, R 8 and R 9 are each independently H, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene -Cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-haloC 1-6 alkyl, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hal
- i 0 or 1
- the groups of the S1 and S2 groups are each independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl , deuterated C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 3-20 cycloalkyl (eg -C 3-6 monocyclic cycloalkane base), halogenated C 3-20 cycloalkyl (such as -halogenated C 3-6 monocyclic cycloalkyl), -OC 3-20 cycloalkyl (such as -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (eg, 3- to 6-membered monocyclic heterocyclyl), -O-3 to 20-membered heterocyclyl (eg, -O-3 to 6-membered monocyclic heterocyclyl), C 6-14
- R a and R b are each independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkane base, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered unit Cyclic heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkylene - C 6-14 aryl, -C 1 -4 alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkylene
- R a , R b and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy group, halogenated C 1-6 alkoxy and deuterated C 1-6 alkoxy ;
- R c is each independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 Alkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1 -4 alkylene-3 to 6 membered monocyclic heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8
- R d is independently H, C 1-6 alkyl or deuterated C 1-6 alkyl
- the carbon atom marked at "*" is a chiral carbon atom (eg R configuration, S configuration or a mixture thereof) or an achiral carbon atom.
- the compound of formula (C) has the structure of formula (D):
- A, B, R 1 , R 3 , R 4 , L, G 1 , G 2 , n, i and "*" are as defined in the present invention.
- the compound of formula (C) has the structure represented by formula (E) or formula (F):
- A, B, R 1 , R 3 , R 4 , L, G 1 , G 2 , n and "*" are as defined in the present invention.
- the compound of formula (C) has the structure represented by formula (II'), formula (B1'), formula (B2'), formula (C1), formula (C2) or formula (C3):
- A, B, R 1 , R 3 , R 4 , R 5 , L, G 1 , G 2 and "*" are as defined in the present invention.
- the compound of formula (C) has the structure represented by formula (IIb'), formula (B1a'), formula (B2a'), formula (C1a), formula (C2a) or formula (C3a):
- R 1 , R 3 , R 4 , R 5 , G 1 , G 2 and "*" are as defined in the present invention.
- the compound of formula (C) is of formula (C1a-1), formula (C1a-2), formula (C2a-1), formula (C2a-2), formula (C3a-1) or formula The structure shown in (C3a-2):
- R 1 , R 3 , R 4 , R 5 , G 1 and G 2 are as defined in the present invention.
- Formula C, Formula D, Formula E, Formula F, Formula C1, Formula C2, Formula C1a, Formula C2a, Formula C1a-1, Formula C1a-2, Formula C2a-1, or Formula C2a-2 , R 1 is C 1-6 alkoxy (eg methoxy) or C 1-6 alkylthio (eg methylthio or ethylthio).
- the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
- n 0, 1, 2 or 3;
- E is NR 5 or O; wherein, R 5 is H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene base-halo-C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered unit Cyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-C(O)NR
- A is CR 6 or N; wherein, R 6 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- B is CR 7 or N; wherein, R 7 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- G 1 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; and the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S2 group;
- G 2 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; and the C 6-14 aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S2 group;
- L is a bond, CR 8 R 9 , O, NH, NHC(O), C 1-2 alkylene-NHC(O) or NHC(O)-C 1-2 alkyl; wherein, R 8 , R 9 is each independently H, halogen, hydroxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy , halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano base, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1 -6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-
- i 0 or 1
- the groups of the S1 or S2 groups are each independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl , deuterated C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 3-20 cycloalkyl (eg -C 3-6 monocyclic cycloalkane base), halogenated C 3-20 cycloalkyl (such as -halogenated C 3-6 monocyclic cycloalkyl), -OC 3-20 cycloalkyl (such as -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (eg, 3- to 6-membered monocyclic heterocyclyl), -O-3 to 20-membered heterocyclyl (eg, -O-3 to 6-membered monocyclic heterocyclyl), C 6-14
- R a and R b are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkane base, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered unit Cyclic heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkylene - C 6-14 aryl, -C 1 -4 alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkylene-8
- R a , R b and the nitrogen atoms connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted with a group selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy group, halogenated C 1-6 alkoxy and deuterated C 1-6 alkoxy ;
- R c is independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 Alkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1 -4 alkylene-3 to 6 membered monocyclic heterocyclyl, C 6-14 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to
- R d is each independently H, C 1-6 alkyl or deuterated C 1-6 alkyl.
- the 3- to 20-membered heterocyclic group has 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms.
- the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.
- the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.
- the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms.
- the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms.
- the present invention provides a compound of formula (B) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
- n 0, 1, 2 or 3;
- E is NR 5 or O; wherein, R 5 is H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene base-halo-C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered unit Cyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-C(O)NR
- A is CR 6 or N; wherein, R 6 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- B is CR 7 or N; wherein, R 7 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- G 1 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; wherein, the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 options heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and
- the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are unsubstituted or independently selected from the S2 group by 1, 2, 3 or 4 group substitution;
- the groups of the S1 or S2 groups are each independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl , deuterated C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 3-20 cycloalkyl (eg -C 3-6 monocyclic cycloalkane base), halogenated C 3-20 cycloalkyl (such as -halogenated C 3-6 monocyclic cycloalkyl), -OC 3-20 cycloalkyl (such as -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (eg, 3- to 6-membered monocyclic heterocyclyl), -O-3 to 20-membered heterocyclyl (eg, -O-3 to 6-membered monocyclic heterocyclyl), C 6-14
- R a and R b are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkane base, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered unit Cyclic heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkylene - C 6-14 aryl, -C 1 -4 alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 alkylene-8
- R a , R b and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein, the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and any 1 or 2 selected heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from the group consisting of: Halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy base and deuterated C 1-6 alkoxy;
- R c is H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1- 6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene Alkyl-3- to 6-membered monocyclic heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic
- the compound of formula (B) has the structure of formula B1:
- A, B, R 3 , R 4 , R 5 , and G 1 are the same as the definitions of each group in formula B.
- the compound of formula (B) has the structure of formula B1a:
- R 3 , R 4 , R 5 and G 1 are the same as the definitions of each group in formula B.
- the compound of formula (B) has the structure represented by formula B1a-1 or formula B1a-2:
- R 3 , R 4 , R 5 and G 1 are the same as the definitions of each group in formula B.
- R 5 is H, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, - C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1-4 alkyl Alkyl-deuterated C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3- to 6-membered monocyclic heterocyclyl , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-C(O)NR a R b
- R 5 is H, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, - C 1-2 alkylene-hydroxyl, -C 1-2 alkylene-cyano, -C 1-2 alkylene-C 1-4 alkoxy, -C 1-2 alkylene-halo C 1-4 base, -C 1-2 alkylene-deuterated C 1-4 alkyl, -C 1-2 alkylene-halogenated C 1-4 alkoxy, -C 1-2 alkylene base-deuterated C 1-4 alkoxy, -C 1-2 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-2 alkylene-3- to 6-membered monocyclic heterocyclic group, -C 1-2 alkylene-NR a R b , -C 1-2 alkylene-C(O)NR a R b , -C
- formula B1a, formula B1a-1 or formula B1a-2, R 3 and R 4 are each independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 selected from N, O and S heteroatoms as ring atoms; the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-6 monocyclic cycloalkyl group and the C 3-6 monocyclic cycloalkyl group
- the 3- to 6-membered monocyclic heterocyclyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.
- formula B1a, formula B1a-1 or formula B1a-2, R 3 and R 4 are each independently selected from: C 1-6 alkyl, C 3-6 monocyclic cycloalkyl and a 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 alkane group, the C 3-6 monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or a group independently selected from the group S1 by 1, 2, 3 or 4 replace.
- formula B1a, formula B1a-1 or formula B1a-2, R 3 and R 4 are each independently selected from: C 1-6 alkyl; the C 1-6 alkyl is Unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from group S1; wherein, the group in group S1 is selected from: halogen, hydroxyl, -C 1-3 alkoxy, -deuterium Substituted C 1-3 alkoxy, -halogenated C 1-3 alkoxy, -C 3-6 monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-3 alkyl, deuterated C 1-3 alkyl or cyclopropyl; or R a , R b and the nitrogen atom to which they are attached together form a 3- to 6-membered member A nitrogen-containing heterocyclic group; wherein the 3-
- R 3 is selected from: C 1-6 alkyl and C 3-6 monocyclic cycloalkyl; the C 1- 6 alkyl is unsubstituted or substituted by deuterium or halogen;
- R 4 is selected from: C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or independently selected from 1, 2 , 3 or 4 Substituted from the group of S1 group; the group of said S1 group is selected from: hydroxyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-6 alkyl, deuterated C 1 -6 alkyl, C 3-6 monocyclic cycloalkyl;
- R 3 is methyl, trifluoromethyl, ethyl, n-propyl or cyclopropyl;
- R 4 is methyl or ethyl; the methyl group and the ethyl group are unsubstituted or substituted by a group selected from the S1 group; the S1 group is selected from: hydroxyl, methoxy, deuterated methoxy group, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, -O-cyclopropyl, -O-cyclobutyl, -N(CH 3 ) 2 , - N( CH2CH3 ) 2 , -N( CH2CH3 )( CH3 ) , -N( CH2CH2CH3 ) ( CH3 ) and -N ( CH2CH2CH3 ) ( CH2 CH3 ).
- R 3 is methyl or ethyl
- R 4 is methyl or ethyl
- the methyl and the ethyl is unsubstituted or substituted by a group selected from group S1
- R3 is methyl and the methyl group is unsubstituted or substituted with deuterium or halogen ;
- R4 is methyl and The methyl group is unsubstituted or substituted by methoxy, deuterated methoxy, halomethoxy, ethoxy, deuterated ethoxy or haloethoxy;
- R 5 is H, C 1 -6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -C 3-6 monocyclic cycloalkyl, -halogenated C 3-6 monocyclic cycloalkyl, - deuterated C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 al
- formula B1a, formula B1a-1 or formula B1a-2, R 3 and R 4 are each independently methyl; the methyl groups are each independently unsubstituted or deuterium, Halogen, hydroxy, methoxy, deuterated methoxy, halomethoxy, ethoxy, deuterated ethoxy or haloethoxy substituted.
- the cyclopropyl, the cyclobutyl, the Cyclopentyl, the cyclohexyl, the oxetanyl, the azetidine, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran, and the piperidine are each independently Unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- the cyclopropyl, the cyclobutyl, the Cyclopentyl, the cyclohexyl, the oxetanyl, the azetidine, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran, and the piperidine are each independently Unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the S1 group is selected from: cyano,
- the compound of formula (B) has the structure shown in formula B2:
- A, B, R 3 , R 4 , R 5 and G 1 are the same as the definitions of each group in formula B.
- the compound of formula (B) has the structure of formula B2a:
- R 3 , R 4 , R 5 and G 1 are the same as the definitions of each group in formula B.
- the compound formula (B) has the structure shown in formula B2a-1 or formula B2a-2:
- R 3 , R 4 , R 5 and G 1 are the same as the definitions of each group in formula B.
- formula B2a, formula B2a-1 or formula B2a-2, R 3 and R 4 are each independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 selected from N, O and S heteroatoms as ring atoms; the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-6 monocyclic cycloalkyl group and the C 3-6 monocyclic cycloalkyl group
- the 3- to 6-membered monocyclic heterocyclyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.
- formula B2a, formula B2a-1 or formula B2a-2, R 3 and R 4 are each independently selected from: C 1-6 alkyl, C 3-6 monocyclic cycloalkyl and a 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 alkane group, the C 3-6 monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or a group independently selected from the group S1 by 1, 2, 3 or 4 replace.
- formula B2a, formula B2a-1 or formula B2a-2, R 3 and R 4 are each independently selected from: C 1-6 alkyl; the C 1-6 alkyl is Unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group; wherein, the S1 group group is selected from: halogen, hydroxyl, -C 1-3 alkoxy, -deuterium Substituted C 1-3 alkoxy, -halogenated C 1-3 alkoxy, -C 3-6 monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-3 alkyl, deuterated C 1-3 alkyl or cyclopropyl; or R a , R b and the nitrogen atom to which they are attached together form a 3- to 6-membered member A nitrogen-containing heterocyclic group; wherein the 3- to
- formula B2a, formula B2a-1 or formula B2a-2, R 3 and R 4 are each independently methyl; each of said methyl groups is independently unsubstituted or deuterium, Halogen, hydroxy, methoxy, deuterated methoxy, halomethoxy, ethoxy, deuterated ethoxy or haloethoxy substituted.
- the cyclopropyl, the cyclobutyl, the Cyclopentyl, the cyclohexyl, the oxetanyl, the azetidine, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran, and the piperidine are each independently Unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the S1 group is selected from: cyano,
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
- n 0, 1, 2 or 3;
- E is NR 5 or O; wherein, R 5 is H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene base-halo-C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered unit Cyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-C(O)NR
- A is CR 6 or N; wherein, R 6 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- B is CR 7 or N; wherein, R 7 is H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -C 3-6 cycloalkyl;
- G 1 is a C 6-14 aryl group, a 5- or 6-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group; wherein, the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 options heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and
- the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are unsubstituted or independently selected from the S2 group by 1, 2, 3 or 4 group substitution;
- G 2 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; wherein, the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 options heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and
- the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are unsubstituted or independently selected from the S2 group by 1, 2, 3 or 4 group substitution;
- L is a bond, CR 8 R 9 , O, NH, NHC(O), C 1-2 alkylene-NHC(O) or NHC(O)-C 1-2 alkylene; wherein, R 8 , R 9 are each independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy , halogen Substituted C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene- Cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkyl, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4
- the groups of the S1 or S2 groups are each independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl , deuterated C 1- 6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, - halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1-6 Alkoxy, -C 1-4 alkylene-C 3-6 monocyclic cycl
- R a and R b are independently H, C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene base-C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered monocyclic heterocyclyl or C(O)C 1-6 alkyl; wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 or 2 groups selected from the group consisting of C 1-6 alkyl; or
- R a , R b and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein, the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and any 1 or 2 selected heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from the group consisting of: C 1-6 alkyl;
- R c is hydrogen, C 1-6 alkyl or halogenated C 1-6 alkyl.
- the compound of formula (I) has the structure of formula II:
- the compound of formula (I) has the structure shown in formula IIa:
- R 3 , R 4 , R 5 , L, G 1 , and G 2 have the same definitions as those of each group in formula (I).
- the compound of formula (I) has the structure of formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIg, formula IIh, formula IIi, formula IIj or formula IIk:
- R 3 , R 4 , R 5 , R 7 , R 8 , G 1 , and G 2 have the same definitions as those of each group in formula (I); m is each independently 1 or 2.
- the compound of formula (I) has formula IIb-1, formula IIc-1, formula IId-1, formula IIe-1, formula Ilf-1, formula IIg-1, formula IIh-1, formula IIi-1, formula IIj-1, formula IIk-1, formula IIb-2, formula IIc-2, formula IId-2, formula IIe-2, formula IIf-2, formula IIg-2, formula IIh-2, formula Structure shown in IIIi-2, formula IIj-2 or formula IIk-2:
- R 3 , R 4 , R 5 , R 7 , R 8 , G 1 , and G 2 have the same definitions as those of each group in formula (I); m is each independently 1 or 2.
- R 7 and R 8 are each independently selected from: H.
- R 3 and R 4 are each independently is selected from: methyl, ethyl, n-propyl, n-butyl, n-pentyl; each of said methyl, said ethyl, said n-propyl, said n-butyl, and said n-pentyl is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R 5 is H, C 1 -4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-2 alkylene-hydroxyl, -C 1-2 alkylene-cyano, -C 1-2 alkylene-C 1-2 alkoxy, -C 1-2 alkylene-halogenated C 1-2 alkyl, -C 1-2 Alkylene-deuterated C 1-2 alkyl, -C 1-2 alkylene-halo C 1-2 alkoxy, -C 1-2 alkylene-deuterated C 1-2 alkoxy , -C 1-2 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-2 alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-2 alkylene
- R 3 and R 4 are each independently is selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; the 3 to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl, the C 3-6 monocyclic cycloalkyl and the 3- to 6-membered monocyclic heterocyclyl are each independently unsubstituted or independently selected from S1 by 1, 2, 3 or 4 Group group substitution;
- R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, - C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl , -C 1-4 alkylene-halogenated C 1-6 alkane Oxygen, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene- NR a R b , -C 1-4 alkylene-C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene base-SO 2 C 1-3 alkyl, -C 1-4 alkylene-carboxy or C 3-6 monocyclic cyclo
- R 3 and R 4 are each independently is selected from: C 1-6 alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 options A heteroatom from N, O, and S is used as a ring atom; the C 1-6 alkyl group, the C 3-6 monocyclic cycloalkyl group, and the 3- to 6-membered monocyclic heterocyclic group are each independently a non-cyclic substituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 3 and R 4 are each independently is selected from: C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein, the S1 group The group is selected from: hydroxyl, -C 1-3 alkoxy, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-3 alkyl, deuterated C 1-3 alkyl or cyclopropyl; or R a , R b and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein, the 3- to 6-membered containing nitrogen heterocyclyl has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 3 is selected from: C 1 -6 alkyl and C 3-6 monocyclic cycloalkyl; the C 1-6 alkyl is unsubstituted or substituted by halogen;
- R 4 is selected from: C 1-6 alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from group S1; the group of group S1 is selected from: hydroxyl, C 1-6 alkoxy, halogenated C 1 -6 alkoxy, deuterated C 1-6 alkoxy, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-6 Alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkyl, -C 1-4 al
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 3 is methyl, tris Fluoromethyl, ethyl, n-propyl or cyclopropyl;
- R 4 is methyl or ethyl; the methyl group and the ethyl group are unsubstituted or substituted with a group selected from the S1 group;
- the group of the S1 group is selected from: hydroxyl, methoxy, deuterated methoxy, trifluoromethoxy, deuterated methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl Oxy, -O-cyclopropyl, -O-cyclobutyl, -N( CH3 ) 2 , -N( CH2CH3 ) 2 , -N( CH2CH3 ) ( CH3 ) , -N ( CH2CH2CH3
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkoxy base, -C 1-4 alkylene-halo-C 1-6 alkyl, -C 1-4 alkylene-halo-C 1-6 alkoxy, -C 1-4 alkylene-C 3 -6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-NR a R b , -C 1-4 alkylene- C(O)NR a R b , -C 1-4 alkylene-C(O)OC 1-6 alkyl, -C 1-4 alkylene-SO 2 C 1-3 alkyl, -C 1 -4 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C
- R 3 and R 4 are each independently is methyl; the methyl groups are each independently unsubstituted or deuterium, halogen, hydroxy, methoxy, deuterated methoxy, halomethoxy, ethoxy, deuterated ethoxy or Haloethoxy substituted;
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene -C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1-6 alkoxy, -C 1- 4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4
- the compound of formula (I) is of formula IIb', formula IIc', formula IId', formula IIe', formula Ilf', formula IIg', formula IIh', formula IIi', formula IIj' or The structure shown in formula IIk':
- R 5 , R 7 , R 8 , G 1 , G 2 have the same definitions as those of each group in formula (I); m is each independently 1 or 2; is C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C The 3-20 cycloalkyl and the 3- to 20-membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.
- R7 and R8 are each independently selected from: H.
- formula IIb', formula IIc', formula IId', formula IIe', formula Ilf', formula IIg', formula IIh', formula IIi', formula IIj' or formula IIk' is a C 3-6 monocyclic cycloalkyl group or a 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as Ring atom; the C 3-6 monocyclic cycloalkyl and the 3- to 6-membered monocyclic heterocyclyl are each independently unsubstituted or a group independently selected from the S1 group by 1, 2, 3 or 4 group substitution;
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1- 6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 al
- formula IIb', formula IIc', formula IId', formula IIe', formula Ilf', formula IIg', formula IIh', formula IIi', formula IIj' or formula IIk' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidine, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine; the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the
- the piperidines are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1; R 5 is H, C 1-6 alky
- formula IIb', formula IIc', formula IId', formula IIe', formula Ilf', formula IIg', formula IIh', formula IIi', formula IIj' or formula IIk' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidine, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine; the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the
- the piperidines are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein, the S1 group is selected
- the compound of formula (I) has the structure of formula III:
- A, B, R 3 , R 4 , L, G 1 , and G 2 have the same definitions as those of each group in formula (I).
- the compound of formula (I) has the structure of formula IIIa:
- R 3 , R 4 , L, G 1 and G 2 are the same as those of each group in the formula (I).
- the compound of formula (I) has the structure shown in formula IIIb, formula IIIc, formula IIId, formula IIIe, formula IIIf, formula IIIg, formula IIIh, formula IIIi, formula IIIj or formula IIIk:
- R 3 , R 4 , R 7 , R 8 , G 1 , and G 2 have the same definitions as those of each group in formula (I); m is each independently 1 or 2.
- the compound of formula (I) is of formula IIIb-1, formula IIIc-1, formula IIId-1, formula IIIe-1, formula IIIf-1, formula IIIg-1, formula IIIh-1, formula IIIi-1, formula IIIj-1, formula IIIk-1, formula IIIb-2, formula IIIc-2, formula IIId-2, formula IIIe-2, formula IIIf-2, formula IIIg-2, formula IIIh-2, formula Structure shown in IIIi-2, formula IIIj-2 or formula IIIk-2:
- R 3 , R 4 , R 7 , R 8 , G 1 , and G 2 have the same definitions as those of each group in formula (I); m is each independently 1 or 2.
- R 3 and R 4 are each independently is selected from: H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 a heteroatom selected from N, O, and S as ring atoms; the C 1-6 alkyl group, the C 3-6 monocyclic cycloalkyl group, and the 3- to 6-membered monocyclic heterocyclic group are each independently is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R 3 and R 4 are each independently is selected from: C 1-6 alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 options A heteroatom from N, O, and S is used as a ring atom; the C 1-6 alkyl group, the C 3-6 monocyclic cycloalkyl group, and the 3- to 6-membered monocyclic heterocyclic group are each independently a non-cyclic Substituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R 3 and R 4 are each independently is selected from: C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein, the S1 group The group is selected from: hydroxyl, -C 1-3 alkoxy, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-3 alkyl, deuterated C 1-3 alkyl or cyclopropyl; or R a , R b and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein, the 3- to 6-membered containing The nitrogen heterocyclyl group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O
- R 3 and R 4 are each independently is methyl; the methyl groups are each independently unsubstituted or deuterium, halogen, hydroxy, methoxy, deuterated methoxy, halomethoxy, ethoxy, deuterated ethoxy or Haloethoxy substituted.
- both G 1 and G 2 are unsubstituted.
- G1 is unsubstituted and G2 is substituted ; the substituents are as described above.
- G 1 is substituted; the substituents are as described above; G 2 is unsubstituted.
- both G1 and G2 are substituted; the substituents are as described above.
- R a and R b are each independently C 1-6 alkyl, such as C 1-4 alkyl, another example methyl.
- R c is -C 1-4 alkylene-C 1-6 alkoxy (eg -C 1-2 alkylene-C 1-3 alkoxy, another example -CH 2 CH 2 OCH 3 or -CH 2 CH 2 OCH 2 CH 3 ) or a 3- to 6-membered monocyclic heterocyclyl substituted with 1 or 2 halogens (such as the 3- to 6-membered unit substituted with 1 or 2 halogens
- the halogen in the cyclic heterocyclic group is fluorine, chlorine or bromine; for example, the 3- to 6-membered monocyclic heterocyclic group in the 3- to 6-membered monocyclic heterocyclic group substituted by 1 or 2 halogens is cyclopropyl) .
- the group of the S1 group is selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -halogenated C 3-6 monocyclic cycloalkane group, -OC 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano, -C 1-4 alkylene-C 1-6 alkane Oxygen, -C(O)C 1-6 alkyl, -C(O)C 3-6 monocyclic cycloalkyl, -C(O)NR a R b , -NHC(O)R c and -NR a R b ; wherein, R
- the group of the S1 group is selected from: deuterium, halogen, cyano, hydroxyl, -C 1-3 alkyl, -halogenated C 1-3 alkyl, -deuterated C 1-3 Alkyl, -C 1-3 alkoxy, -halogenated C 1-3 alkoxy, -deuterated C 1-3 alkoxy, -cyclopropyl, -halocyclopropyl, -O-ring Propyl, -C 1-2 alkylene-hydroxy, -C 1-2 alkylene-cyano, -C 1-2 alkylene-C 1-3 alkoxy, -C(O)C 1 -3 alkyl, -C(O) cyclopropyl, -C(O)NR a R b , -NHC(O) R c and -NR a R b ; wherein R a and R b are each independently H , C 1-3 alkyl, deuterated C 1-3 alkyl,
- the group of the S1 group is selected from: deuterium, halogen, cyano, hydroxyl, methyl, ethyl, propyl, halomethyl, deuterated methyl, methoxy, ethoxy group, halomethoxy, deuterated methoxy, -C(O)CH 3 , -C(O)cyclopropyl, -C(O)NH 2 , -C(O)N(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , - NHC(O) CH3 and -N( CH3 ) 2 .
- the group of the S1 group is selected from: deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl (eg C 1-3 alkyl), C 1-6 alkoxy (eg C 1-3 alkyl), halogenated C 1-6 alkoxy (such as halogenated C 1-3 alkyl, and for example, difluoromethoxy or trifluoromethoxy), deuterated C 1-6 alkoxy Oxygen (such as deuterated C 1-3 alkyl), -C 1-4 alkylene-hydroxy (such as -C 1-2 alkylene-hydroxy), -C(O)C 1-6 alkyl ( For example -C(O)C 1-3 alkyl), -C(O)C 3-20 cycloalkyl (for example -C(O)C 3-6 monocyclic cycloalkyl), 3 to 20 membered heterocycle group (eg 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered mono
- the group of the S1 group is selected from the group consisting of: deuterium, fluorine, cyano, hydroxyl, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, deuterated Methoxy (-OCD 3 ), -CH 2 OH, -C(O)CH 3 , -C(O)-cyclopropyl, morpholinyl -O - Cyclopropyl , -N ( CH3 ) 2 , -OCH2CH2OCH3 and -CH2CH2OCH2CH3 .
- the group of the S2 group is selected from: fluorine, chlorine, -C 1-3 alkyl, -halogenated C 1-3 alkyl and -C 3-6 monocyclic cycloalkyl.
- the group of group S2 is selected from the group consisting of: fluorine, chlorine, methyl, trifluoromethyl and cyclopropyl.
- the group of the S2 group is selected from: halogen, cyano, -C 1-6 alkyl (eg -C 1-3 alkyl), halogenated C 1-6 alkyl (eg halogen substituted C 1-3 alkyl), deuterated C 1-6 alkyl (such as deuterated C 1-3 alkyl, and for example deuterated methyl), C 1-6 alkoxy (such as C 1-3 alkane) oxy), halogenated C 1-6 alkoxy (such as halogenated C 1-3 alkoxy), deuterated C 1-6 alkoxy (such as deuterated C 1-3 alkoxy), C 3 -20 cycloalkyl (such as C 3-6 monocyclic cycloalkyl), halogenated C 3-20 cycloalkyl (such as halogenated C 3-6 monocyclic cycloalkyl, and for example, halogenated cyclopropyl), -OC 3-20 cycloalkyl (eg -OC
- the group of the S2 group is selected from: fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, deuterium Substituted methoxy, cyclopropyl, -O-cyclopropyl, -O - cyclopentyl, -N( CH3 ) 2 and -OCH2CH2OCH3 .
- the heterocyclyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R 1 and R 2 are each independently H.
- R 1 and R 2 are each independently selected from: H, C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl), C 3-6 monocyclic cycloalkyl (eg cyclopropyl, cyclobutyl), 3- to 6-membered monocyclic heterocyclyl, C 1-6 alkoxy (eg methoxy) and C 1-6 alkylthio group (eg methylthio, ethylthio); or R 1 and R 2 together with the carbon atoms to which they are attached form: C 3-6 monocyclic cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl) , cyclohexyl), 3- to 6-membered monocyclic heterocyclyl (eg, oxetanyl, azetidine, tetrahydropyrrole, te
- R 1 and R 2 are each independently selected from: methoxy, methylthio, and ethylthio.
- the heterocyclyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R3 and R4 are each independently selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and cyclobutyl; the methyl, the ethyl, the The n-propyl group, the isopropyl group, the cyclopropyl group and the cyclobutyl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S1 group.
- R 3 and R 4 are each independently selected from: C 1-6 alkyl (eg, C 1-3 alkyl, also such as methyl or ethyl) and C 3-20 cycloalkyl (eg C 3-6 monocyclic cycloalkyl, such as cyclopropyl); or R 3 and R 4 together with the carbon atoms to which they are attached constitute: C 3-20 cycloalkyl (such as C 3-6 monocyclic cycloalkane) (eg cyclopropyl, cyclopentyl, cyclohexyl) or 3 to 20 membered heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S As a ring atom (eg, a 3- to 6-membered monocyclic heterocyclyl group, wherein the 3- to 6-membered monocyclic heterocyclyl group has 1 or 2 heteroatoms selected from N and O as ring atoms, also for example, oxetine base, azetidine
- the group of the S1 group is selected from: deuterium, halogen (eg F), cyano, hydroxyl, C 1-6 alkyl (eg methyl), C 1-6 alkoxy (such as methoxy, ethoxy), deuterated C 1-6 alkoxy (eg deuterated methoxy), -C 1-4 alkylene-hydroxy (eg - CH 2 OH), -C(O ) C 1-6 alkyl (eg -C(O)CH 3 ), -C(O)C 3-20 cycloalkyl (eg -C(O)-cyclopropyl), 3- to 20-membered heterocyclyl (e.g.
- halogen eg F
- cyano hydroxyl
- C 1-6 alkyl eg methyl
- C 1-6 alkoxy such as methoxy, ethoxy
- deuterated C 1-6 alkoxy eg deuterated methoxy
- -C 1-4 alkylene-hydroxy
- morpholino ), -OC 3-6 monocyclic cycloalkyl (eg -O-cyclopropyl), -NR a R b (eg -N(CH 3 ) 2 ) and -OR c (eg -OC 1-4 alkylene) group -C 1-6 alkoxy, another example -CH 2 OCH 2 CH 2 OCH 3 ).
- R3 and R4 are each independently selected from: -CH3 , -CH2CH3 , cyclopropyl, trifluoromethyl, deuterated methyl , -CH2OH , -CH2OCH3 , -CH 2 OCF 3 , -CH 2 OCHF 2 , -CH 2 OCD 3 , -CH 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 O - cyclopropyl, -CH2N ( CH3 ) 2 , -CH(OH ) CH3 and -CH2CH3OCH3 .
- R 3 is selected from: C 1-6 alkyl and C 3-6 monocyclic cycloalkyl; each independently of said C 1-6 alkyl and said C 3-6 monocyclic cycloalkyl Ground is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.
- R 3 is selected from the group consisting of: C 1-6 alkyl and C 3-6 monocyclic cycloalkyl; said C 1-6 alkyl and said C 3-6 monocyclic cycloalkyl are not substituted or substituted by halogen.
- R3 is selected from the group consisting of: methyl, trifluoromethyl, ethyl, n-propyl and cyclopropyl.
- R 3 is selected from: C 1-6 alkyl (eg, methyl or ethyl) and C 3-6 monocyclic cycloalkyl (eg, cyclopropyl); said C 1-6 alkyl and the C 3-6 monocyclic cycloalkyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from the S1 group.
- the group of the S1 group is selected from: deuterium and halogen (eg F).
- R3 is selected from the group consisting of : -CH3 , -CH2CH3 , trifluoromethyl, deuterated methyl, and cyclopropyl.
- R 4 is selected from: C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;
- the group of the S1 group is selected from: hydroxyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -OC 3-6 monocyclic cycloalkyl and -NR a R b ; wherein, R a and R b are each independently H, C 1-6 alkyl, deuterated C 1-6 alkyl , C 3-6 monocyclic cycloalkyl, -C 1- 4 alkylene-C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered monocyclic heterocyclyl or C(O)C 1-6 wherein, the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as
- R4 is selected from: methyl and ethyl; each of said methyl and said ethyl is independently unsubstituted or substituted with 1 group selected from group S1; said group S1 The group is selected from: hydroxyl, methoxy, deuterated methoxy, trifluoromethoxy, ethoxy, deuterated ethoxy, haloethoxy, n-propoxy, isopropoxy, n-Butoxy, -O-cyclopropyl, -O-cyclobutyl, -N( CH3 ) 2 , -N( CH2CH3 ) 2 , -N( CH2CH3 ) ( CH3 ) , -N( CH2CH2CH3 )( CH3 ) and -N ( CH2CH2CH3 ) ( CH2CH3 ) .
- R 4 is selected from: C 1-6 alkyl (eg, methyl, ethyl); the C 1-6 alkyl is unsubstituted or independently selected from 1, 2, 3, or 4 Substituted from the group of S1 group; the group of said S1 group is selected from: hydroxyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -OC 3-6 monocyclic cycloalkyl, -NR a R b and -OR c (eg -OC 1-4 alkylene-C 1-6 alkoxy); wherein R a and R b are each independently H , C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 1-6 alkoxy, 3- to 6-membered monocyclic Heterocyclic group, -C 1-4 alkylene-3- to 6-membered monocyclic heterocyclic group
- R4 is selected from: methyl and ethyl; said methyl and said ethyl are unsubstituted or substituted with 1 group selected from group S1; said group of group S1 Selected from: hydroxy, methoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, deuterated ethoxy, haloethoxy, n-propoxy, isopropyl Oxy, n-butoxy, -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -N(CH 3 ) 2 , -N ( CH2CH3 ) 2 , -N( CH2CH3 )( CH3 ) , -N( CH2CH2CH3 ) ( CH3 ) and -N ( CH2CH2CH3 ) ( CH2CH 3 ).
- the group of the S1 group is selected from the group consisting of: hydroxy, methoxy, deuterated methoxy, ethoxy, -OCH 2 CH 2 OCH 3 , -O-cyclopropyl and -N (CH 3 ) 2 .
- R4 is selected from : -CH3 , -CH2OH , -CH2OCH3 , -CH2OCF3 , -CH2OCHF2 , -CH2OCF3 , -CH2OCHF2 , -CH 2 OCD 3 , -CH 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 O-cyclopropyl, -CH 2 N(CH 3 ) 2 , -CH(OH)CH 3 and -CH 2 CH 3 OCH 3 .
- the azetidine, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran, and the piperidine are each independently unsubstituted or independently selected from S by 1, 2, 3, or 4 group substitution.
- the group of the S1 group is selected from: cyano, hydroxyl, C 1-6 alkyl (eg methyl), C 1-6 alkoxy (eg methoxy), -C 1-4 alkylene-hydroxyl (eg -CH 2 OH), -C(O)C 1-6 alkyl (eg -C(O)CH 3 ), -C(O)C 3-20 cycloalkyl (eg -C(O)-cyclopropyl) and 3 to 20 membered heterocyclyl (eg morpholinyl) ).
- R3 and R4 together with the carbon atom to which they are attached constitute: E.g
- R 5 is H, C 1-3 alkyl, -C 1-2 alkylene-hydroxy, -C 1-2 alkylene-cyano, -C 1-2 alkylene- C 1-3 alkoxy, -C 1-2 alkylene-halo C 1-3 alkyl, -C 1-2 alkylene-halo C 1-3 alkoxy, -C 1-2 Alkylene-C 3-6 monocyclic cycloalkyl, -C 1-2 alkylene-3 to 6-membered monocyclic heterocyclyl, -C 1-2 alkylene-NR a R b , -C 1 -2 alkylene-C(O)NR a R b , -C 1-2 alkylene-C(O)OC 1-3 alkyl, -C 1-2 alkylene-SO 2 C 1-3 Alkyl, -C 1-2 alkylene-carboxy or C 3-6 monocyclic cycloalkyl; wherein, 1 or 2 hydrogen atoms on the "-C 1-2 alkylene
- R 5 is H, C 1-6 alkyl, -C 1-4 alkylene-NR a R b or C 3-6 monocyclic cycloalkyl; R a and R b are each the same as defined in formula (I).
- R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or -CH2CH2N ( CH3 )2 .
- R 5 is H, C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, also eg methyl, ethyl), Deuterated C 1-6 alkyl (such as deuterated C 1-3 alkyl, also such as deuterated methyl ), -C 1-4 alkylene-hydroxy (such as -C 1-2 alkylene-hydroxy, Another example is -CH 2 CH 2 OH), -C 1-4 alkylene-C 1-6 alkoxy (such as -C 1-2 alkylene-C 1-3 alkoxy, another example -CH 2 CH2OCH3 ) or -C1-4alkylene - NRaRb ( eg -C1-2alkylene - NRaRb , also eg -CH2CH2N ( CH3 )2 ) .
- C 1-6 alkyl eg methyl, ethyl,
- L is a bond
- L is CR 8 R 9 ; wherein R 8 and R 9 are each independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkylene-hydroxyl, -C 1-4 alkylene-cyano base, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-halogenated C 1 -6 alkoxy.
- L is CH2 .
- L is O.
- L is NH
- L is NHC(O).
- L is CH2NHC (O).
- L is NHC(O) CH2 .
- n is 0 or 1.
- E is NR5.
- E is O.
- E is N.
- A is CR6 ; wherein R6 is H.
- A is N.
- B is N.
- B is CR7 ; wherein R7 is H.
- G1 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, or pyrazolyl; the phenyl, the pyridyl, the pyrimidinyl, the furanyl , the pyrrolyl, the thiazolyl or the pyrazolyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.
- G1 is phenyl or pyridyl; each of said phenyl or said pyridyl is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2 .
- G1 is phenyl or pyridyl; each of said phenyl or said pyridyl is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2 ; wherein, the group in the S2 group is selected from: fluorine, chlorine, -C 1-3 alkyl, -halogenated C 1-3 alkyl, -C 3-6 monocyclic cycloalkyl.
- G 1 is C 6-14 aryl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl has 1, 2, or 3 selected from N, O, and A heteroatom of S is used as a ring atom, and the C 6-14 aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or independently selected from S2 by 1, 2, 3 or 4 group substitution.
- G1 is phenyl or pyridyl; said phenyl and said pyridyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2 ;
- group of described S2 group is selected from the following group: fluorine, chlorine, bromine, cyano, -C 1-3 alkyl, -halogenated C 1-3 alkyl, - deuterated C 1-3 alkyl base, -C 3-6 monocyclic cycloalkyl, -halogenated C 3-6 monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl, -O-halogenated C 3-6 monocyclic cycloalkane base.
- G 1 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, pyrazolyl, or thienyl; the phenyl, the pyridyl, the pyrimidinyl, the The furanyl, the pyrrolyl, the thiazolyl, the pyrazolyl and the thienyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2 .
- G 1 is phenyl, pyridyl, furyl, or thienyl; each of said phenyl, said pyridyl, said furyl, and said thienyl is independently unsubstituted or replaced by 1 , 2, 3 or 4 groups independently selected from Group S2 are substituted.
- the group of the S2 group is selected from: halogen, cyano, -C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy , Halogenated C 1-6 alkoxy, C 3-20 cycloalkyl, -OC 3-20 cycloalkyl, -NR a R b and -OR c ; for example fluorine, chlorine, bromine, iodine, cyano, methyl radical, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, -N( CH3 ) 2 and -OCH2 CH 2 OCH 3 .
- G 1 is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-6-fluorophenyl, 2-chloro-3,4 -Difluorophenyl, 2-chloro-3-fluoro-4-methoxyphenyl, 2-chloro-4-cyclopentyloxyphenyl, 2-chloro-4-(2-methoxyethyl) Phenyl, 2-chloro-4-dimethylaminophenyl, 2-chloro-4-cyclopropoxyphenyl, 2-chloro-4-methoxyphenyl, 2-chloro-4-isopropylbenzene base, 2-chloro-4-cyclopropylphenyl, 2-chloro-4-methylphenyl, 2-chlorofuryl, furyl, thienyl, 2-bromothienyl, 2-chlorothienyl, pyridine base, 3-chloropyrid
- G 2 is C 6-14 aryl or 5 or 6 membered monocyclic heteroaryl; the 5 or 6 membered monocyclic heteroaryl has 1, 2 or 3 selected from N, O and A heteroatom of S is used as a ring atom, and the C 6-14 aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or independently selected from S2 by 1, 2, 3 or 4 group substitution.
- G 2 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, or pyrazolyl; the phenyl, the pyridyl, the pyrimidinyl, the furanyl , the pyrrolyl, the thiazolyl or the pyrazolyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.
- G 2 is phenyl, pyridyl, or pyrazolyl; each of said phenyl, said pyridyl, and said pyrazolyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituted with groups independently selected from Group S2.
- G is phenyl or pyridyl; each of said phenyl or said pyridyl is independently unsubstituted or substituted with 1, 2 , 3 or 4 groups independently selected from Group S2 .
- G is phenyl or pyridyl; each of said phenyl or said pyridyl is independently unsubstituted or substituted with 1, 2 , 3 or 4 groups independently selected from Group S2 ; wherein, the group in the S2 group is selected from: fluorine, chlorine, -C 1-3 alkyl, -halogenated C 1-3 alkyl, -C 3-6 monocyclic cycloalkyl.
- G is phenyl or pyridyl; each of said phenyl or said pyridyl is independently unsubstituted or substituted with 1, 2 , 3 or 4 groups independently selected from Group S2 ; wherein, the group of the S2 group is selected from the following group: fluorine, chlorine, bromine, cyano, -C 1-3 alkyl, -C 1-3 alkoxy, -halogenated C 1-3 alkyl , -deuterated C 1-3 alkyl, -halogenated C 1-3 alkoxy, -deuterated C 1-3 alkoxy , -C 3-6 monocyclic cycloalkyl, -OC 3-6 mono Cyclocycloalkyl, -haloC 3-6 monocyclic cycloalkyl and -O-halo C 3-6 monocyclic cycloalkyl.
- the group of the S2 group is selected from: halogen, cyano, -C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy , Deuterated C 1-6 alkoxy and C 3-20 cycloalkyl groups such as fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, deuterated methoxy and cyclopropyl.
- G 2 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-trifluoromethylpyridyl, 3-methylpyridyl, 3-trifluoromethylpyridyl, 4 -Methylpyridyl, 4-cyclopropylpyridyl, 4,6-lutidine, 4-chloro-6-methylpyridyl, 2-methyl-6-chloropyridyl, 3-cyano Phenyl, 3-fluoro-4-methylpyridyl, pyridyl, 3-fluoropyridyl, 2-methoxyphenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-fluoro-6 -Methoxyphenyl, pyrazolyl, 3-methylpyrazolyl, 2-methoxy-3-fluorophenyl, 2-fluoro-3-deuterated methoxyphenyl, 2,4-di Methylpyridyl, 2-chloropyr
- G 1 is phenyl and said phenyl is substituted with fluorine or chlorine;
- G 2 is phenyl or pyridyl and said phenyl or said pyridyl is each independently unsubstituted or fluorine , chloro, methyl, trifluoromethyl or cyclopropyl substitution.
- G 1 is phenyl and said phenyl is substituted with fluorine or chlorine;
- G 2 is phenyl or pyridyl and said phenyl or said pyridyl is each independently unsubstituted or selected From fluorine, chlorine, bromine, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, halocyclopropyl, - One, two or three substitutions of O-cyclopropyl, -O-halocyclopropyl.
- G1 is phenyl and the phenyl is substituted with fluorine or chlorine ;
- G2 is phenyl and the phenyl is unsubstituted or substituted with fluorine, chlorine, methyl, trifluoromethyl or Cyclopropyl substitution.
- G1 is phenyl and the phenyl is substituted with fluorine or chlorine ;
- G2 is pyridyl and the pyridyl is unsubstituted or substituted with fluorine, chlorine, methyl, trifluoromethyl or Cyclopropyl substitution.
- G is selected from the group consisting of:
- Rg 1 and Rg 2 are each independently hydrogen or a group selected from Group S2.
- i, G 1 , L, G 2 have any of the following definitions:
- G 1 is phenyl, pyridyl, furyl or thienyl; the phenyl, the pyridyl, the furyl and the thienyl are each independently unsubstituted or 1, 2, 3 or 4 groups independently selected from Group S2 are substituted;
- i 1, L is CR 8 R 9 or O, G 1 is phenyl or pyridyl, G 2 is phenyl, pyridyl or pyrazolyl; the phenyl, the pyridyl and the The pyrazolyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2;
- i 1, L is O, G 1 is phenyl or pyridyl, and G 2 is phenyl or pyridyl; the phenyl group and the pyridyl group are each independently unsubstituted or replaced by 1, 2 , 3 or 4 groups independently selected from Group S2 are substituted.
- i 0 and G 1 is selected from:
- Rg 1 and Rg 2 are each independently hydrogen or a group selected from the S2 group.
- Rg 2 is hydrogen or is selected from the group consisting of deuterium, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, -C 3-6 monocyclic cycloalkyl, -halogenated C 3-6 monocyclic cycloalkyl.
- Rg 1 is hydrogen or is selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1 -6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 3-6 monocyclic cycloalkyl, -halogenated C 3- 6 monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl, 3 to 6 membered monocyclic heterocyclyl, -O-3 to 6 membered monocyclic heterocyclyl, -NR a R b and -OR c ;
- the 3 to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6 monocyclic cycloalkyl and the 3 to 6 The monocyclic heterocyclyl groups
- R a and R b are each independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 monocyclic cycloalkane base, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkylene-3- to 6-membered unit Cyclic heterocyclyl or C(O)C 1-6 alkyl; wherein the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
- the C 3-6 monocyclic cycloalkyl, the 3- to 6-membered monocyclic heterocyclic group are optionally substitute
- R a , R b and the nitrogen atom connected to them together form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein, the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and any 1 or 2 selected heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from the group consisting of: Halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy base and deuterated C 1-6 alkoxy;
- R c is H, -C 1-4 alkylene-halogenated C 1-6 alkyl, -C 1-4 alkylene-deuterated C 1-6 alkyl, -C 1 -4 alkylene-C 1-6 alkoxy, -C 1-4 alkylene-halo C 1-6 alkoxy, -C 1-4 alkylene-deuterated C 1-6 alkoxy base, -C 1-4 alkylene-C 3-6 monocyclic cycloalkyl, -C 1-4 alkylene-3- to 6-membered monocyclic heterocyclic group; the C 3-6 monocyclic cycloalkane group, the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, -C
- Rg 1 is hydrogen or is selected from the group consisting of halogen (eg fluorine, chlorine, bromine, iodine), cyano, C 1-6 alkyl (eg methyl), haloC 1-6 Alkyl (eg trifluoromethyl), deuterated C 1-6 alkyl (eg deuterated methyl), C 1-6 alkoxy (eg methoxy), halogenated C 1-6 alkoxy (such as trifluoromethoxy), deuterated C 1-6 alkoxy (such as deuterated methoxy), -OC 3-6 monocyclic cycloalkyl (such as -O-cyclopropyl, -O-cyclopentane) group), -NR a R b (eg -N(CH 3 ) 2 ) or -OR c (eg -O-CH 2 CH 2 OCH 3 ).
- halogen eg fluorine, chlorine, bromine, iodine
- cyano eg methyl
- Rg 2 is halogen (eg fluorine, chlorine, bromine, iodine), cyano, C 1-6 alkyl (eg methyl), halogenated C 1-6 alkyl (eg trifluoromethyl) base), deuterated C 1-6 alkyl (such as deuterated methyl), C 1-6 alkoxy (such as methoxy), halogenated C 1-6 alkoxy (such as trifluoromethoxy) , deuterated C 1-6 alkoxy (such as deuterated methoxy), -OC 3-6 monocyclic cycloalkyl (such as -O-cyclopropyl, -O-cyclopentyl), -NR a R b (eg -N( CH3 ) 2 ) or -OR c (eg -O - CH2CH2OCH3 ) .
- halogen eg fluorine, chlorine, bromine, iodine
- cyano eg fluorine, chlorine,
- the structural unit Selected from:
- R 1 , R 2 , R 3 , R 4 , n, E, A, B, G 1 , L, G 2 , i are each independently in each specific compound in the examples the corresponding group.
- R 1 , R 2 , R 3 , R 4 , n, E, A, B, G 1 , L, G, i are defined as follows:
- R 3 and R 4 are each independently selected from: C 1-6 alkyl and C 3-20 cycloalkyl; or R 3 and R 4 together with the carbon atoms to which they are attached form: C 3-20 cycloalkyl and 3- to 20-membered heterocyclyl; the C 1-6 alkyl, the C 3-20 cycloalkyl, and the 3- to 20-membered heterocyclyl are each independently unsubstituted or substituted by 1, 2, 3 Or substituted with 4 groups independently selected from the S1 group;
- n 0;
- E is NR 5 , O or N; wherein, R 5 is H, C 1-6 alkyl, deuterated C 1-6 alkyl, -C 1-4 alkylene-hydroxy, -C 1-4 alkylene base-C 1-6 alkoxy or -C 1-4 alkylene-NR a R b ;
- A is CR 6 ;
- B is CR7 ;
- G 1 is a C 6-14 aryl group or a 5- or 6-membered monocyclic heteroaryl group; and the C 6-14 aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or 2, 3 or 4 groups independently selected from Group S2 are substituted;
- G 2 is a C 6-14 aryl group or a 5- or 6-membered monocyclic heteroaryl group; and the C 6-14 aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or by 1, 2, 3 or 4 groups independently selected from Group S2 are substituted;
- L is CR 8 R 9 or O
- i 0 or 1.
- the compound of the present invention is selected from the compounds prepared in the examples of the present application. E.g,
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the above aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable vector.
- the term "pharmaceutically acceptable carrier” refers to any formulation or carrier medium representative of any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or subject , including water, oil, vegetable and mineral, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
- the pharmaceutical composition may be administered orally, by inhalation, rectally, nasally, bucally, topically, parenterally, such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
- parenterally such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
- oral, intraperitoneal or intravenous administration is preferred.
- the compounds of the present invention may be formulated in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and cornstarch, although lubricants such as magnesium stearate may also be added.
- Diluents used in capsule formulations typically include lactose and dried cornstarch.
- Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations.
- the compounds of the present invention can be prepared into different topical formulations according to different affected surfaces or organs
- the compounds of the present invention when administered topically to the eye, may be formulated as a micronized suspension or solution in the form of an isotonic, pH, sterile, isotonic carrier, with or without the addition of a preservative such as Benzyl alkoxide chloride.
- the compounds can also be formulated in the form of an ointment such as petrolatum ointment.
- the compounds of the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
- Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
- Useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
- sterile fixed oils can also be employed as a solvent or suspending medium such as mono- or diglycerides.
- the present invention provides a compound of the above aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof as a medicament.
- the present invention provides the compound of the above-mentioned aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the above-mentioned aspect in the preparation of the prevention and/or treatment of a disease or disorder Use in the medicament of ; the disease or disorder is associated with BTK and/or is associated with abnormal B cell activation.
- the disease or disorder is selected from the group consisting of xenoimmune disease, autoimmune disease, inflammatory disease, cancer.
- the xenoimmune disease, autoimmune disease, inflammatory disease may be selected from the group consisting of rheumatic disease, glomerulonephritis, Goodpasture syndrome, atherosclerosis, autoimmune blood disease, autoimmune disease Immune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allograft rejection, chronic thyroiditis, Graves' disease, Sjogren's disease, scleroderma, diabetes, hepatitis, pancreatitis, cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, Stevens-Johnson syndrome, Inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, Guillain-Barre syndrome, uve
- the cancer is leukemia or lymphoma.
- the cancer may be selected from the group consisting of small lymphocytic lymphoma (SLL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia myeloid leukemia (CML), acute promyelocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Waldenstrom's macroglobulinemia, Follicular lymphoma, multiple myeloma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin's lymphoma.
- SLL small lymphocytic lymphoma
- ALL acute lymphocytic leukemia
- CLL chronic lymphocytic leukemia
- AML acute myeloid leukemia
- CML chronic myeloid leukemia mye
- the present invention provides the use of a compound according to the above aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the above aspect, in the preparation of a BTK inhibitor.
- the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in the above aspect, or a pharmaceutically acceptable salt, stereoisomer, A solvate or prodrug, or any combination of the above, or the step of administering the pharmaceutical composition of the above aspects.
- the term "subject” refers to an animal, particularly a mammal. People are preferred.
- the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect.
- the amount of a given drug depends on factors such as the particular dosing regimen, the type of disease or condition and its severity, the subject in need of treatment or the uniqueness of the host (e.g. body weight), however, the dose to be administered may be known in the art depending on the particular surrounding circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated method is routinely determined.
- the administered dose is typically in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day.
- the desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
- the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound.
- Such salts include: acid addition salts with inorganic acids or organic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, caproic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine and the like.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
- the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
- solvent compound and “solvate” refer to substances formed by combining a compound of the present invention with a pharmaceutically acceptable solvent.
- Pharmaceutically acceptable solvents include acetic acid and the like.
- Solvent compounds include stoichiometric amounts and non-stoichiometric amounts of solvent compounds. Certain compounds of the present invention may exist in unsolvated as well as solvated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
- stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
- the compounds described in the present invention may exist in stereoisomeric forms, and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc.
- the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture.
- a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.
- Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation. And as a drug, a stereoisomer having excellent activity is preferable.
- the compounds of the present invention have optical isomers derived from asymmetric carbons and the like, and if necessary, single isomers can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.
- alkyl refers to a straight or branched chain saturated aliphatic hydrocarbyl group.
- C 1-20 alkyl refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Preferably it is a C 1-10 alkyl group. More preferred are C1-6 alkyl groups (ie straight or branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferred is C 1-4 alkyl. More preferred is C 1-3 alkyl.
- Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers, etc.
- alkoxy refers to a group having the structure -O-alkyl, wherein alkyl is as defined above.
- C 1-10 alkoxy refers to an alkoxy group having 1 to 10 carbon atoms. Preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy. More preferred is C 1-3 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.
- alkylthio refers to a group having the structure -S-alkyl, wherein alkyl is as defined above.
- C 1-10 alkylthio refers to an alkylthio group having 1 to 10 carbon atoms. Preferred is C 1-6 alkylthio. More preferred is a C 1-4 alkylthio group. More preferred is a C 1-3 alkylthio group.
- Specific examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, isobutylthio, n-pentylthio, and the like.
- alkenyl refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain
- C 2-8 alkenyl refers to having 2 to 8 carbons atom and at least one (eg, 1 to 2) carbon-carbon double bond.
- a C2-6 alkenyl group ie an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds
- a C2-4 alkenyl group ie an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds.
- Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.
- alkynyl refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain
- C 2-8 alkynyl refers to those having 2 to 8 carbons atom and at least one (eg 1 to 2) carbon-carbon triple bond alkynyl.
- a C2-6 alkynyl group ie an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds
- More preferred is a C 2-4 alkynyl group (ie an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds).
- Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
- halogen refers to fluorine, chlorine, bromine or iodine.
- halo refers to fluoro, chloro, bromo or iodo.
- haloalkyl refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein alkyl is as defined above.
- haloC 1-10 alkyl refers to a haloalkyl group having 1 to 10 carbon atoms.
- Preferred is halogenated C 1-6 alkyl. More preferred is a halogenated C 1-4 alkyl group. More preferred is a halogenated C 1-3 alkyl group.
- Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl and the like.
- haloalkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein alkoxy is as defined above.
- haloC 1-10 alkoxy refers to a haloalkoxy having 1 to 10 carbon atoms.
- Preferred is halogenated C 1-6 alkoxy. More preferred is a halogenated C 1-4 alkoxy group. More preferred is a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
- deuterated refers to the replacement of one or more hydrogen atoms in a group with deuterium atoms.
- deuterated alkyl refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by deuterium atoms, wherein alkyl is as defined above.
- deuterated C 1-10 alkyl refers to a deuterated alkyl group having 1 to 10 carbon atoms. Deuterated C 1-6 alkyl is preferred. More preferred is deuterated C 1-4 alkyl. More preferred is deuterated C 1-3 alkyl. Specific examples include, but are not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, monodeuteroethyl, 1,2-dideuteroethyl, trideuteroethyl, and the like.
- deuterated alkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein alkoxy is as defined above .
- deuterated C 1-10 alkoxy refers to a deuterated alkoxy group having 1 to 10 carbon atoms. Preferred is deuterated C 1-6 alkoxy. More preferred is deuterated C 1-4 alkoxy. More preferred is deuterated C 1-3 alkoxy.
- Specific examples include, but are not limited to, tri-deuteriomethoxy, tri-deuteroethoxy, mono-deuteromethoxy, mono-deuteroethoxy, dideuteromethoxy, dideuteroethoxy, and the like.
- cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkanes and bridged cycloalkyl groups.
- the ring carbon atoms of the cycloalkyl group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
- 3 to 20 membered cycloalkyl or "C 3-20 cycloalkyl” refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. Preferably it is C 3-12 cycloalkyl, C 5-20 spirocycloalkyl, C 5-20 fused cycloalkyl or C 5-20 bridged cycloalkyl. More preferred is a C 3-8 monocyclic cycloalkyl group.
- C 3-8 monocyclic cycloalkyl and “3- to 8-membered monocyclic cycloalkyl” refer to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms.
- it is a C 3-6 monocyclic cycloalkyl group (ie, a 3- to 6-membered monocyclic cycloalkyl group) or a C 4-6 monocyclic cycloalkyl group (ie, a 4- to 6-membered monocyclic cycloalkyl group). More preferred is a C3, C4 , C5 or C6 monocyclic cycloalkyl.
- monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
- spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, double-spirocycloalkyl groups and poly-spirocycloalkyl groups.
- spirocycloalkyl or "C 5-20 spirocycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the single rings sharing the spiro atoms are 3 to 8 membered Monocyclic cycloalkyl ring.
- it is a 6- to 14-membered (ie C6-14 ) spirocycloalkyl. More preferred is a 6- to 14-membered monospirocycloalkyl. More preferred is a 7- to 11-membered (ie C7-11 ) spirocycloalkyl.
- spirocycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
- fused cycloalkyl and “fused cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group in which two or more monocyclic rings are formed by sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl.
- the term “5 to 20 membered fused cycloalkyl” or “C 5-20 fused cycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are 3 to 20 ring carbon atoms.
- 8-membered monocyclic cycloalkyl ring Preferably it is a 6- to 14-membered (ie C6-14 ) fused cycloalkyl group. More preferred is a 6- to 14-membered di-fused cycloalkyl group. More preferred is a 7- to 10-membered (ie C 7-10 ) fused cycloalkyl group. More preferably, it is a 7- to 10-membered di-fused cycloalkyl group.
- fused cycloalkyl include, but are not limited to:
- fused cycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
- bridged cycloalkyl and “bridged cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by sharing two non-directly attached carbon atoms between two or more monocyclic rings. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
- the terms "5- to 20-membered bridged cycloalkyl” and “C 5-20 -membered bridged cycloalkyl” refer to polycyclic cyclic hydrocarbon groups having 5 to 20 ring carbon atoms, wherein any two rings share two not directly connected carbon atom.
- bridged cycloalkyl groups include, but are not limited to:
- bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.
- halocycloalkyl refers to a cycloalkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein cycloalkyl is as defined above.
- halogenated C3-8 monocyclic cycloalkyl refers to a halogenated monocyclic cycloalkyl group having 3 to 8 ring carbon atoms. Preferably it is a halogenated C 3-6 monocyclic cycloalkyl. More preferred is a haloC3 , haloC4 , haloC5 or haloC6 monocyclic cycloalkyl. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
- heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclyl and bridged heterocyclyl.
- the ring carbon atoms of the heterocyclic group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
- the 3- to 20-membered heterocyclic groups of the present invention include monocyclic heterocyclic groups (eg, 3- to 8-membered monocyclic heterocyclic groups), spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.
- monocyclic heterocyclic groups eg, 3- to 8-membered monocyclic heterocyclic groups
- spiro heterocyclic groups fused heterocyclic groups and bridged heterocyclic groups.
- Preferred is a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms.
- a 4- to 6-membered monocyclic heterocyclyl group having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 5- or 6-membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 are heteroatoms.
- the heteroatom is a nitrogen atom
- the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
- the heteroatom is a sulfur atom
- the ring carbon atoms of the monocyclic heterocyclyl may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
- monocyclic heterocyclyl groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -one, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3
- azetidinyl ie, tetrahydropyrrole
- azepinyl ie, hexahydropyridine
- morpholinyl morpholinyl
- piperazinyl oxazolidine
- 3 to 8 membered monocyclic heterocycloalkyl refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms of which 1 or 2 are heteroatoms.
- it is a 3- to 6-membered monocyclic heterocycloalkyl, ie a saturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms.
- heterocycloalkyl examples include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, Dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-dioxanyl.
- the two ring atoms connected to the above-mentioned monocyclic heterocyclyl ring, including CC and NC, can be optionally combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring.
- the 2 ring atoms attached to the monocyclic heterocyclic group forming a fused ring with other rings are preferably C-C.
- spiroheterocyclyl and “spiroheterocyclyl ring” refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (referred to as a spiro atom).
- the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
- Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
- Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
- 5- to 20-membered spiroheterocyclyl refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocycles sharing the spiro atoms is a 3- to 8-membered monocyclic heterocyclyl ring and the other
- the monocycle is a 3- to 8-membered monocyclic heterocyclyl ring or a 3- to 8-membered monocyclic cycloalkyl ring.
- 7 to 11 membered spiroheterocyclyl groups having 7 to 11 ring atoms, of which 1 or 2 are heteroatoms.
- spiroheterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
- the heteroatom is a nitrogen atom
- the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
- Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
- Shared pairs of adjacent ring atoms can be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
- the term "5- to 20-membered fused heterocyclyl” refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein the monocycles sharing adjacent pairs of ring atoms are 3- to 8-membered monocyclic heterocyclyl rings.
- Preferred is a 6- to 14-membered fused heterocyclic group having 6 to 14 ring atoms, of which 1 or 2 are heteroatoms.
- More preferred is a 6- to 10-membered fused heterocyclic group having 6 to 10 ring atoms, of which 1 or 2 are heteroatoms. More preferred is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, of which 1 or 2 are heteroatoms.
- fused heterocyclic groups include, but are not limited to:
- fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
- 5- to 20-membered bridged heterocyclyl refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected ring atoms, each monocyclic Rings can contain one or more double bonds, but no ring has a fully conjugated pi electron system.
- Preferred is a 6- to 14-membered bridged heterocyclyl group. More preferred is a 7- to 10-membered bridged heterocyclic group.
- Specific examples of bridged heterocyclyl groups include, but are not limited to:
- bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
- the above various types of heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
- aryl As used herein, the terms “aryl”, “aryl ring” and “aromatic ring” are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic ring (rings connected to rings by covalent bonds, non-fused group) or all-carbon fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups in which at least one ring is aromatic, ie, has a conjugated pi-electron system.
- C 6-14 aryl refers to an aryl group having 6 to 14 ring atoms. Preferably it is a C 6-10 aryl group.
- the C 6-14 aryl group in the present invention includes a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group, wherein examples of the monocyclic aryl group include phenyl, and examples of the non-fused polycyclic aryl group include Biphenyl, etc.
- the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings , non-limiting examples of which include naphthyl, anthracenyl, and the like.
- the aromatic condensed polycyclic ring when the C 6-14 aryl group is an aromatic condensed polycyclic ring, can also be a single aryl ring (such as phenyl) and one or more non-aromatic polycyclic rings.
- the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure).
- a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam
- the polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single aryl ring or a non-aromatic ring. ring.
- the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.
- heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaromatic ring” are used interchangeably to refer to a monocyclic or fused ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
- the heteroaryl group has 6, 10 or 14 pi electrons shared and at least one ring in the group is aromatic.
- Preferred are 5 to 10 membered heteroaryl groups having 5 to 10 ring atoms, of which 1, 2, 3 or 4 are heteroatoms.
- the 5- to 14-membered heteroaryl group in the present invention may be a monocyclic heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group.
- monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole azole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
- the fused bicyclic heteroaryl group can be either a bicyclic group formed by condensing a single aryl ring (such as phenyl) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).
- a 9- or 10-membered bicyclic heteroaryl ring is a 9- or 10-membered bicyclic heteroaryl ring), or a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic ring) ring heteroaryl ring) fused to form a bicyclic group.
- the 2 ring atoms that are arbitrarily connected on the above-mentioned monocyclic heteroaryl ring, including CC, NC, NN, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring.
- the 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably C-C, including without limitation the following forms:
- Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
- bicyclic heteroaryl groups include, but are not limited to:
- the ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.
- the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a A polycyclic group formed by condensing multiple non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.
- the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure) and the like.
- a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cycl
- the polycyclic group formed by condensing the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic heteroaromatic base ring or non-aromatic ring.
- heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
- hydroxy refers to -OH.
- hydroxymethyl refers to -CH2OH and "hydroxyethyl” refers to -CH2CH2OH or -CH(OH ) CH3 .
- cyanomethyl refers to -CH2CN and "cyanoethyl " refers to -CH2CH2CN or -CHCNCH3 .
- amino refers to -NH2 .
- cyano refers to -CN.
- nitro refers to -NO2 .
- benzyl refers to -CH2 -benzene.
- carboxylate refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).
- acetyl refers to -COCH3 .
- substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and the substituted compound is stable.
- optionally substituted or “optionally substituted” means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any or all of the hydrogens present in the compound, or in particular groups or moieties within the compound may be replaced by deuterium or tritium.
- One to the maximum number of hydrogens present in the compound can be replaced by deuterium.
- One to the maximum number of hydrogens present in any group in a compound of the general formula or in a specific compound may be deuterated.
- the ethyl group can be C2H5 or C2H5 in which x ( 1 to 5 ) hydrogens have been replaced by deuterium , such as C2DxH5- x .
- the deuterated ethyl may be C2H5 with x (1 to 5 ) hydrogens replaced by deuterium, eg, C2DxH5 -x .
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the embodiments of the present invention.
- DMSO dimethyl sulfoxide
- DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
- NH4HCO3 ammonia bicarbonate
- CAN acetonitrile
- Step 1 4-Chloro-1H-pyrrole[2,3-b]pyridine (5.0g, 32.89mmol) was suspended in dichloromethane (100mL), followed by adding triethylamine (6.9mL, 49.34mmol), 4-dichloromethane Methylaminopyridine (400 mg, 3.29 mmol) and benzenesulfonyl chloride (4.6 mL, 36.18 mmol), the reaction was stirred at room temperature for 18 hours.
- Step 2 4-Chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (5.0g, 17.12mmol) was dissolved in dichloromethane (75mL), cooled to -10°C under nitrogen protection , and tetramethylammonium nitrate (3.49 g, 25.68 mmol) was added. Trifluoroacetic anhydride (3.74 mL, 26.54 mmol) was slowly added dropwise, and the reaction was stirred at -5°C to 0°C for 30 minutes after the dropwise addition, and the reaction was slowly raised to room temperature for 18 hours.
- Step 1 (S)-2-amino-3-hydroxy-2-methylpropionic acid methyl ester hydrochloride (10.0 g, 58.96 mmol) and 4-chloro-5-nitro-1-(benzenesulfonyl) -1H-pyrrolo[2,3-b]pyridine (19.0 g, 56.26 mmol) was dissolved in N,N-dimethylacetamide (250 mL), and anhydrous N,N-diisopropylethylamine (36.36 g) was added. g, 281.29 mmol) and the reaction was stirred at 110 °C for 17 hours.
- Step 2 (S)-3-Hydroxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) methyl propionate (5.0g, 11.51mmol) was dissolved in acetonitrile (150mL), silver (II) oxide (26.67g, 115.10mmol) and methyl iodide (16.34g, 115.10mmol) were added, and the reaction was stirred at 35°C 48 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed with ethyl acetate (200 mL).
- Step 3 (S)-3-methoxy-2-methyl-2-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-4- methyl)amino)propionate (5 g, 11.15 mmol) was dissolved in acetic acid (100 mL), iron powder (6.23 g, 111.5 mmol) was added, and the reaction was stirred at 90° C. for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed with ethyl acetate (200 mL).
- Step 1 (S)-3-Hydroxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) methyl propionate (5.0g, 11.51mmol) was dissolved in acetonitrile (150mL), silver (II) oxide (26.67g, 115.10mmol) and deuterated iodomethane (16.34g, 115.10mmol) were added, and the reaction was avoided The mixture was heated to 35°C under light and stirred for 48 hours.
- Step 2 (S)-3-(methoxy-d 3 )-2-methyl-2-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b] ]pyridin-4-yl)amino)propionate methyl ester (5g, 11.07mmol) was dissolved in acetic acid (100mL), iron powder (6.23g, 111.5mmol) was added, and the reaction was stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed with ethyl acetate (200 mL).
- Step 1 (S)-methyl 2-amino-3-hydroxypropionate (10g, 64.3mmol) was dissolved in tetrahydrofuran (100mL), pivalaldehyde (6.63g, 77.1mmol), triethylamine (7.14g) were added , 70.7 mmol), reacted at 70° C. for 4 hours, cooled to room temperature, and the reaction solution was directly used for the one-step reaction without treatment.
- ES-API: [M-55] + 232.2.
- Step 4 3-(tert-butyl) 4-methyl(2R,4S)-2-(tert-butyl)-4-(methyl-d 3 )oxazolidine-3,4-dicarboxylate ( 4.5g, 14.8mmol) was dissolved in dioxane (25mL), 6N hydrochloric acid (25mL) was added, the reaction was carried out at 50°C for 2 hours, the dry solvent was concentrated, the crude product was dissolved in 1M hydrochloric acid (25mL), and back-extracted with ethyl acetate (25mL ⁇ 3) , the aqueous phase was concentrated to dryness to obtain (S)-methyl 2-amino-2(hydroxymethyl)propionate-3,3,3-d 3 hydrochloride (2.55 g, yield: 100%).
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.0 g, 2.97 mmol) and methyl 3-aminotetrahydrofuran-3-carboxylate
- the hydrochloride (806 mg, 4.45 mmol) was dissolved in N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (1.34 g, 10.40 mmol) was added, and the reaction was stirred at 95°C for 16 hours .
- Step 2 methyl (3-((5-nitro-1-(benzenesulfonyl)-1H-pyrro[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-carboxylate (635mg, 1.42 mmol) was dissolved in acetic acid (15 mL), iron powder (558 mg, 9.97 mmol) was added, and the reaction was stirred at 85 ° C for 3 hours.
- Step 3 (7'-(Benzenesulfonyl)-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrole[3',2':5,6] Pyridin[3,4-b]pyrazine]-3'(1'H)-one (200 mg, 0.52 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (146 mg, 3.64 mmol) was added, and the reaction Stir at 65 ° C for 7 hours.
- Step 4 4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine ]-3'(1'H)-one (105 mg, 0.43 mmol) and 2-chloro-4-phenoxybenzaldehyde (100 mg, 0.43 mmol) were dissolved in methanol (8 mL), the reaction was cooled to 0 °C, added Potassium hydroxide (168 mg, 3.01 mmol). The reaction was stirred at room temperature for 48 hours.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2 '-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (70 mg, 0.15 mmol) was dissolved in 6 mL of tetrahydrofuran, and Dess- Martin's oxidizer (94 mg, 0.22 mmol), the reaction was stirred at room temperature for 4 hours, then Dess-Martin oxidizer (94 mg, 0.22 mmol) was added and the reaction was stirred at room temperature for 18 hours.
- reaction solution was added with 5 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution, and extracted with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried and concentrated.
- the crude product was purified by preparative HPLC to obtain 9'-(2-chloro-4-phenoxybenzoyl)-4,4',5,7'-tetrahydro- 2H-Spiro[furan-3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (Z1, 27 mg, yield 39%), pale yellow solid.
- One isomer, arbitrarily assigned its structure as Z1-1 (4 mg, peak 1, retention time: 7.186 min, yield 28%), ES-API: [M+H] + 475.1, white solid.
- Another isomer, arbitrarily assigned its structure as Z1-2 (4 mg, peak 2, retention time: 8.731 min, yield 28%), ES-API: [M+H] + 475.1, was an off-white solid.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.0 g, 2.97 mmol) and 1-tert-butyl 3-methyl-3 -Aminopyrrolidine-1,3-dicarboxylate (1.01g, 4.16mmol) was dissolved in 15mL N,N-dimethylacetamide, N,N-diisopropylethylamine (958mg, 7.42mmol) was added , the reaction was stirred at 95°C for 16 hours.
- Step 2 1-(tert-butyl)3-methyl3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)pyrrole
- Alkane-1,3-dicarboxylate 270 mg, 0.50 mmol
- 1.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour.
- the reaction solution was concentrated, 15 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 60 mL of ethyl acetate.
- Step 3 methyl 3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylate (220mg, 0.49 mmol) was dissolved in 10 mL of acetonitrile, sodium triacetoxyborohydride (416 mg, 1.96 mmol) and 37% aqueous formaldehyde solution (159 mg, 1.96 mmol) were sequentially added under ice bath, and the reaction was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with 90 mL of ethyl acetate.
- Step 4 1-methyl-3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylic acid Methyl ester (225 mg, 0.49 mmol) was dissolved in acetic acid (7 mL), iron powder (192 mg, 3.43 mmol) was added, and the reaction was stirred at 85° C. for 2 hours.
- Step 5 1-Methyl-7'-(phenylsulfonyl)-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine [3,4-b]pyrazine]-3'(1'H)-one (195 mg, 0.49 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (98 mg, 2.45 mmol) was added, and the reaction was performed at The mixture was stirred at 65°C for 16 hours.
- Step 6 1-Methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine] -3'(1'H)-one (80 mg, 0.31 mmol) and 2-chloro-4-phenoxybenzaldehyde (108 mg, 0.46 mmol) were dissolved in methanol (8 mL), the reaction was cooled to 0 °C and hydrogen was added Potassium oxide (122 mg, 2.17 mmol) and the reaction was stirred at room temperature for 18 hours.
- reaction solution was poured into 30 mL of water, adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and extracted with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried and concentrated.
- Step 7 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-3'(1'H)-one (53 mg, 0.11 mmol) was dissolved in 6 mL of tetrahydrofuran, cooled to 0°C, Dess-Martin oxidant (92 mg, 0.22 mmol) was added and the reaction was stirred at room temperature for 18 hours.
- ES-API: [M+H] + 488.0.
- Another single isomer whose structure was arbitrarily assigned as Z2-2 (6.8 mg, peak 2, retention time 13.023 min, yield 40%), off-white solid.
- Step 1 7'-(Benzenesulfonyl)-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridine [3,4-b]pyrazine]-3'(1'H)-one (see steps 1 and 2 of Example 1 for the preparation method) (150 mg, 0.39 mmol) was dissolved in 6 mL of acetone, followed by adding anhydrous carbonic acid Potassium (118 mg, 0.86 mmol), methyl iodide (72 mg, 0.51 mmol), the reaction was stirred at room temperature for 18 hours, and anhydrous potassium carbonate (118 mg, 0.86 mmol), methyl iodide (72 mg, 0.51 mmol) were added, and the reaction was Stir at room temperature for 96 hours.
- anhydrous carbonic acid Potassium 118 mg, 0.86 mmol
- methyl iodide 72 mg, 0.51 mmol
- Step 2 4'-methyl-7'-(benzenesulfonyl)-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (155mg, 0.39mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (78mg, 1.95 mmol), the reaction was stirred at 65° C. for 16 hours.
- Step 3 4'-methyl-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridine[3, 4-b]pyrazine]-3'(1'H)-one (80 mg, 0.31 mmol) and 2-chloro-4-phenoxybenzaldehyde (108 mg, 0.47 mmol) were dissolved in methanol (8 mL) and the reaction Cool to 0°C and add potassium hydroxide (122 mg, 2.17 mmol). The reaction was stirred at room temperature for 24 hours.
- Step 4 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4'-methyl-4,4',5,7'-tetrahydro-2H-spiro [Furan-3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (75 mg, 0.15 mmol) was dissolved in 6 mL Tetrahydrofuran, cooled to 0°C, Dess-Martin oxidant (130 mg, 0.30 mmol) was added and the reaction was stirred at room temperature for 2 hours.
- the reaction solution was added with 4 mL of saturated sodium thiosulfate solution and 15 mL of saturated sodium bicarbonate solution, and extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried and concentrated. The crude product was purified by preparative HPLC to obtain the target product (Z3, 48 mg, yield 64%) as a pale yellow solid.
- Step 1 1-(tert-butyl) 3-methyl 3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)pyrrole
- Alkane-1,3-dicarboxylate (220 mg, 0.40 mmol) was dissolved in acetic acid (8 mL), iron powder (224 mg, 4.0 mmol) was added, and the reaction was stirred at 85° C. for 1 hour. The reaction solution was cooled to room temperature, poured into 30 mL of water, and extracted twice with 30 mL of ethyl acetate.
- Step 2 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2' : 5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (195mg, 0.40mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (80mg, 2.00mmol) was added ) and triethylamine (202 mg, 2.0 mmol), the reaction was stirred at 65° C. for 16 hours.
- Step 3 3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3, 4-b]pyrazine]-1-carboxylate tert-butyl ester (130 mg, 0.38 mmol) was dissolved in 2 mL of methanol, 4.0 M hydrogen chloride in methanol (5 mL, 20.0 mmol) was added, and the reaction was stirred at room temperature for 4 hours.
- Step 4 4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-3'(1 'H)-keto hydrochloride (110 mg, 0.35 mmol) was suspended in dichloromethane (15 mL), cooled to 0 °C, followed by the addition of triethylamine (177 mg, 1.75 mmol) and acetyl chloride (68 mg, 0.87 mmol) in 0.5 mL of dichloromethane solution, the reaction was stirred under an ice bath for 2 hours.
- Step 5 1-Acetyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine] -3'(1'H)-one (45 mg, 0.16 mmol) and 2-chloro-4-phenoxybenzaldehyde (74 mg, 0.32 mmol) were dissolved in methanol (6 mL), the reaction was cooled to 0 °C and hydrogen was added Potassium oxide (63 mg, 1.12 mmol) and the reaction was stirred at room temperature for 18 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 6 1-Acetyl-9'-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (43 mg, 0.083 mmol) was dissolved in 6 mL of tetrahydrofuran, cooled to 0°C, Dess-Martin oxidant (70 mg, 0.166 mmol) was added and the reaction was stirred at room temperature for 16 hours.
- a single isomer whose structure was arbitrarily assigned as Z4-1 (5 mg, peak 1, retention time 5.370 min, yield 26%), white solid.
- ES-API: [M+H] + 516.0.
- ES-API: [M+H] + 516.0.
- Step 1 Dissolve 2,4-difluorobenzaldehyde (2.84g, 20.0mmol) and phenol (1.69g, 18.0mmol) in 50mL of N,N-dimethylformamide, add cesium carbonate (8.80g, 30.0mmol) , the reaction was stirred at 75 °C for 16 h. The reaction solution was poured into 100 mL of water, and extracted with 80 mL of ethyl acetate.
- Step 2 1-Methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine] -3'(1'H)-one (50 mg, 0.19 mmol) and 2-fluoro-4-phenoxybenzaldehyde (123 mg, 0.57 mmol) were dissolved in methanol (6 mL), the reaction was cooled to 0 °C and hydrogen was added Potassium oxide (74 mg, 1.33 mmol) and the reaction was stirred at room temperature for 18 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 3 9'-((2-Fluoro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-3'(1'H)-one (37mg, 0.078mmol) was dissolved in 8mL of tetrahydrofuran, cooled to 0°C, Dess-Martin oxidant (99 mg, 0.23 mmol) was added and the reaction was stirred at room temperature for 18 hours.
- Dess-Martin oxidant 99 mg, 0.23 mmol
- the reaction solution was added with 2 mL of saturated sodium thiosulfate solution and 8 mL of saturated sodium bicarbonate solution, and extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried and concentrated. The crude product was purified by preparative HPLC to obtain the target product (Z5, 6 mg, yield 16%) as a white solid.
- Step 1 2-chloro-4-fluorobenzaldehyde (1.0g, 6.33mmol) and 2-fluorophenol (744mg, 6.65mmol) were dissolved in 15mL N,N-dimethylformamide, and cesium carbonate (2.47g, 7.60 mmol) and the reaction was stirred at 75°C for 16 hours. The reaction solution was poured into 30 mL of water, and extracted with 100 mL of ethyl acetate.
- Step 2 1-Methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine] -3'(1'H)-one (50 mg, 0.19 mmol) and 2-chloro-4-(2-fluorophenoxy)benzaldehyde (143 mg, 0.57 mmol) were dissolved in methanol (6 mL) and the reaction was cooled to At 0°C, potassium hydroxide (75 mg, 1.33 mmol) was added and the reaction was stirred at room temperature for 18 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 3 9'-((2-Chloro-4-(2-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4',7'-dihydrospiro[pyrrolidine -3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (41 mg, 0.08 mmol) was dissolved in 6 mL of tetrahydrofuran, Cooled to 0°C, Dess-Martin oxidant (51 mg, 0.12 mmol) was added and the reaction was stirred at room temperature for 3 hours, with additional Dess-Martin oxidant (51 mg, 0.12 mmol) the reaction was stirred at room temperature for 16 hours.
- Dess-Martin oxidant 51 mg, 0.12 mmol
- Step 1 2-chloro-4-fluorobenzaldehyde (1.0g, 6.33mmol) and 3-fluorophenol (744mg, 6.65mmol) were dissolved in 15mL N,N-dimethylformamide, and cesium carbonate (2.47g, 7.60 mmol) and the reaction was stirred at 75°C for 16 hours. The reaction solution was poured into 30 mL of water, and extracted with 100 mL of ethyl acetate.
- Step 2 1-Methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine] -3'(1'H)-one (50 mg, 0.19 mmol) and 2-chloro-4-(3-fluorophenoxy)benzaldehyde (143 mg, 0.57 mmol) were dissolved in methanol (6 mL) and the reaction was cooled to At 0°C, potassium hydroxide (75 mg, 1.33 mmol) was added and the reaction was stirred at room temperature for 18 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 3 9'-((2-Chloro-4-(3-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4',7'-dihydrospiro[pyrrolidine -3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (50 mg, 0.10 mmol) was dissolved in 6 mL of tetrahydrofuran, Cooled to 0°C, Dess-Martin oxidant (64 mg, 0.15 mmol) was added and the reaction was stirred at room temperature for 3 hours, with additional Dess-Martin oxidant (64 mg, 0.15 mmol) the reaction was stirred at room temperature for 16 hours.
- the reaction solution was added with 2 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution, and extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried and concentrated. The crude product was purified by preparative HPLC to obtain the target product (Z7, 5 mg, yield 10%) as a pale yellow solid.
- Step 1 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2' : 5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (225mg, 0.47mmol) was dissolved in 12mL of acetone, followed by adding anhydrous potassium carbonate (324mg, 2.35mmol), iodomethane (267 mg, 1.88 mmol) and the reaction was stirred at room temperature for 72 hours.
- anhydrous potassium carbonate 324mg, 2.35mmol
- iodomethane 267 mg, 1.88 mmol
- Step 2 4'-methyl-3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole [3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (180 mg, 0.36 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, and hydroxide was added Sodium (72 mg, 1.80 mmol), the reaction was stirred at 65°C for 16 hours.
- Step 3 4'-methyl-3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6 ]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (125 mg, 0.35 mmol) and 2-chloro-4-phenoxybenzaldehyde (244 mg, 1.05 mmol) in methanol (12 mL) , the reaction was cooled to 0 °C and potassium hydroxide (137 mg, 2.45 mmol) was added. The reaction was stirred at room temperature for 18 hours.
- Step 4 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4'-methyl-3'-oxo-1',3',4',7'-Tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (153 mg, 0.26 mmol) Dissolve in 20 mL of tetrahydrofuran, cool to 0°C, add Dess-Martin oxidant (165 mg, 0.39 mmol), and stir the reaction at room temperature for 16 hours.
- Dess-Martin oxidant 165 mg, 0.39 mmol
- Step 5 9'-(2-Chloro-4-phenoxybenzoyl)-4'-methyl-3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrole Alkane-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (150 mg, 0.25 mmol) was dissolved in 4.5 mL of dichloro Methane, cooled to 0°C, 1.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour.
- Step 6 9'-(2-Chloro-4-phenoxybenzoyl)-4'-methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-3'(1'H)-one (104mg, 0.21mmol) was dissolved in 10mL of methanol, 2mL of dichloromethane, and 37 % Aqueous formaldehyde (85 mg, 1.05 mmol), and 1 drop of acetic acid. After the reaction was stirred at room temperature for 30 minutes, sodium cyanoborohydride (26 mg, 0.42 mmol) was added and the reaction was stirred at room temperature for 2 hours.
- sodium cyanoborohydride 26 mg, 0.42 mmol
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (0.9g, 2.671mmol) and 2-amino-3-hydroxy-2-methyl Methyl propionate hydrochloride (1.0g, 5.915mmol) was dissolved in N,N-dimethylformamide (30mL), N,N-diisopropylethylamine (7.64g, 59.15mmol) was added, and the reaction Stir at 95°C for 16 hours.
- Step 2 3-Hydroxy-2-methyl-2-methyl(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) propionate (550 mg, 1.267 mmol) was dissolved in acetic acid (15 mL), iron powder (1.40 g, 25.00 mmol) was added, and the reaction was stirred at 80 ° C for 1 hour.
- Step 3 2-(Hydroxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6] Pyrido[3,4-b]pyrazin-3-one (200 mg, 0.5376 mmol) was dissolved in 12 mL of methanol, 2 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (215 mg, 5.376 mmol) was added, and the reaction was stirred at 65°C for 7 hours . 20 mL of water and 5 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 150 mL of ethyl acetate.
- Step four 2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b ] Pyrazin-3-one (300 mg, 1.293 mmol) and 2-chloro-4-phenoxybenzaldehyde (350 mg, 1.510 mmol) were dissolved in methanol (12.0 mL), the reaction was cooled to 0°C, potassium hydroxide was added (300 mg, 5.375 mmol). The reaction was stirred at room temperature for 6 hours. The reaction solution was poured into 30 mL of saturated aqueous ammonium chloride solution, adjusted to pH 8, and extracted with 100 mL of ethyl acetate.
- Step 5 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro- 3H-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin]-3-one (320 mg, 0.6896 mmol) was dissolved in 30 mL of dichloromethane, and 2,3-dichloromethane was added. -5,6-Dicyano-1,4-benzoquinone (320 mg, 1.410 mmol) and the reaction was stirred at room temperature for 2 hours.
- ES-API: [M+H] + 463.0.
- Another single isomer whose structure was arbitrarily assigned as Z9-2 6.5 mg, peak 2, retention time 11.323 min, yield 34%), pale white solid.
- ES-API: [M+H] + 463.0.
- Step 1 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2' : 5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (300mg, 0.62mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (124mg, 3.10mmol) was added ), the reaction was stirred at 60 °C for 16 hours.
- Step 2 3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3, 4-b]pyrazine]-1-carboxylate tert-butyl ester (170 mg, 0.50 mmol) and 2-chloro-4-phenoxybenzaldehyde (345 mg, 1.50 mmol) were dissolved in methanol (15 mL) and the reaction was cooled to At 0°C, potassium hydroxide (196 mg, 3.50 mmol) was added. The reaction was stirred at room temperature for 18 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 3 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrole Alkane-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylic acid tert-butyl ester (130 mg, 0.26 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled To 0°C, Dess-Martin oxidant (146 mg, 0.34 mmol) was added and the reaction was stirred at room temperature for 18 hours.
- Dess-Martin oxidant 146 mg, 0.34 mmol
- Step 5 9'-(2-Chloro-4-phenoxybenzoyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (30mg, 0.25mmol) was dissolved in 2mL methanol, 2mL 4.0M hydrogen chloride dioxygen was added Hexacyclic solution, the reaction was stirred at room temperature for 2 hours.
- Step 6 9'-(2-Chloro-4-phenoxybenzoyl)-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5, 6] Pyridin[3,4-b]pyrazine]-3'(1'H)-one hydrochloride (30mg, 0.05mmol) was dissolved in 5mL of dichloromethane, and triethylamine (27mg, 0.26 mmol), and cyclopropanoyl chloride (7 mg, 0.06 mmol) in 0.5 mL of dichloromethane, and the reaction was stirred for 15 minutes under an ice bath.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (950mg, 2.819mmol) and 1-(tert-butyl)3-ethyl3 -aminoazetidine-1,3-dicarboxylate (1.0 g, 4.096 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine ( 3.643 g, 28.19 mmol), the reaction was stirred at 95°C for 16 hours.
- Step 2 1-(tert-butyl)3-ethyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) azetidine-1,3-dicarboxylate (700 mg, 1.284 mmol) was dissolved in acetic acid (50 mL), iron powder (700 mg, 12.50 mmol) was added, and the reaction was stirred at 80° C. for 1 hour.
- Step 3 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[azetidine-3,2'-pyrrole[3', 2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (330mg, 0.7035mmol) was dissolved in 12mL methanol, 2mL tetrahydrofuran and 2mL water, sodium hydroxide (300mg, 7.50 mmol) and the reaction was stirred at 65°C for 6 hours.
- Step 4 3'-oxo-1',3',4',7'-tetrahydrospiro[azetidine-3,2'-pyrrolo[3',2':5,6]pyridine [3,4-b]pyrazine]-1-carboxylate tert-butyl ester (200 mg, 0.6079 mmol) and 2-chloro-4-phenoxybenzaldehyde (300 mg, 1.293 mmol) were dissolved in methanol (12 mL), The reaction was cooled to 0°C and potassium hydroxide (240 mg, 4.285 mmol) was added. The reaction was stirred at room temperature for 6 hours.
- Step 5 9'-(((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[ Azetidine-3,2'-pyrrolo[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (412 mg, 0.7341 mmol) dissolved in 30 mL of dichloromethane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (400 mg, 1.762 mmol) was added, and the reaction was stirred at room temperature for 3 hours.
- Step 6 9'-(2-Chloro-4-phenoxybenzoyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[azetidine-3 ,2'-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (230 mg, 0.4113 mmol) was dissolved in 8 mL of dichloromethane , and trifluoroacetic acid (469.0 mg, 4.113 mmol) was added.
- Step 7 Add 9'-(2-chloro-4-phenoxybenzoyl)-4',7'-dihydrospiro[azetidine-3,2'-pyrrolo[ to 30 mL of acetonitrile 3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (330mg, 0.7189mmol), the ice-water bath was lowered to 0-5 °C and then added with formaldehyde ( 333 mg, 4.11 mmol), and finally sodium cyanoborohydride (260 mg, 4.110 mmol) was added.
- Step 1 2-Chloro-4-hydroxybenzaldehyde (500mg, 3.20mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (686mg, 4.16mmol) were dissolved in 12mL N,N-dimethylformamide , potassium carbonate (883 mg, 6.40 mmol) was added, and the reaction was stirred at 95° C. for 20 hours. The reaction solution was poured into 40 mL of water, and extracted with 60 mL of ethyl acetate.
- Step 2 3'-oxo-1',3',4',7'-tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3, 4-b]pyrazine]-1-carboxylate tert-butyl ester (130 mg, 0.38 mmol) and 2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde ( 343 mg, 1.14 mmol) was dissolved in methanol (10 mL), the reaction was cooled to 0°C and potassium hydroxide (149 mg, 2.66 mmol) was added. The reaction was stirred at room temperature for 18 hours.
- Step 3 9'-((2-Chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-3'-oxo-1 ',3',4',7'-Tetrahydrospiro[3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylic acid tert-butyl
- the ester 122 mg, 0.19 mmol
- 10 mL of tetrahydrofuran cooled to 0°C
- Dess-Martin oxidant 104 mg, 0.25 mmol
- Step 4 9'-(2-Chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-3'-oxo-1',3',4 ',7'-Tetrahydrospiro[pyrrolidine-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (60mg , 0.093 mmol) was dissolved in 2 mL of dichloromethane, cooled to 0 °C, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour.
- Step 5 9'-(2-Chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-4',7'-dihydrospiro[pyrrolidine -3,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyrazine]-3'(1'H)-one trifluoroacetate (70mg, crude)
- 37% aqueous formaldehyde solution 50 mg, 0.61 mmol
- sodium cyanoborohydride (19 mg, 0.31 mmol) was added, and the reaction was stirred at room temperature for 30 minutes.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (0.9g, 2.671mmol) and 2-amino-3-hydroxy-2-methyl Methyl propionate hydrochloride (1.0g, 5.915mmol) was dissolved in N,N-dimethylformamide (30mL), N,N-diisopropylethylamine (7.64g, 59.15mmol) was added, and the reaction Stir at 95°C for 16 hours.
- Step 2 3-Hydroxy-2-methyl-2-methyl(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) propionate (700mg, 1.613mmol) was dissolved in acetonitrile (30mL), silver oxide (1.87g, 8.065mmol) and methyl iodide (2.29g, 16.13mmol) were added successively, and the reaction was stirred at room temperature in the dark for 48 hours under nitrogen protection.
- Step 3 3-Methoxy-2-methyl-2-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Amino) methyl propionate (700mg, 1.613mmol) was dissolved in acetic acid (30mL), iron powder (1.80g, 32.26mmol) was added. Gradually be warming up to 80 °C and stir for 1 hour.
- Step 4 2-(methoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5, 6] Pyrido[3,4-b]pyrazin-3-one (400 mg, 1.0362 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (290 mg, 7.264 mmol) was added, and the reaction was stirred at 65 °C 7 hours. 20 mL of water and 15 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 150 mL of ethyl acetate.
- Step 5 2-(Methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4 -b] Pyrazin-3-one (480 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (480 mg, 2.0724 mmol) were dissolved in methanol (20.0 mL), the reaction was cooled to 0 °C, and hydroxide was added Potassium (406 mg, 7.253 mmol). The reaction was stirred at room temperature for 6 hours. The reaction solution was poured into 30 mL of saturated aqueous ammonium chloride solution, adjusted to pH 8, and extracted with 100 mL of ethyl acetate.
- Step Six 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetra Hydrogen-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin]-3-one (620 mg, crude) was dissolved in 30 mL of dichloromethane, and 2,3- Dichloro-5,6-dicyano-1,4-benzoquinone (470 mg, 2.0724 mmol) and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with 80 mL of ethyl acetate.
- One single isomer 51.45 mg, peak 1, retention time 8.881 min, yield 40%), pale white solid.
- ES-API: [M+H] + 477.1.
- step 1 of this embodiment uses Substitute for step 1 of Example 13
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (500mg, 1.48mmol) and 4-aminotetrahydro-2H-pyran-4 -Methyl carboxylate (260 mg, 1.63 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (480 mg, 3.71 mmol) was added, and the reaction was stirred at 120°C with microwave for 1 hour .
- Step 2 4-((5-Nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)tetrahydro-2H-pyran- 4-Carboxylic acid ester (300 mg, 0.65 mmol) was dissolved in 10 mL of acetic acid, iron powder (182 mg, 3.26 mmol) was added, and the mixture was stirred at 80° C. for 3 hours.
- Step 3 7'-(Benzenesulfonyl)-2,3,4',5,6,7'-hexahydrospiro[pyran-4,2'-pyrrole[3',2':5,6] Pyridin[3,4-b]pyrazine]-3'(1'H)-one (200 mg, 0.50 mmol) was dissolved in 2 mL of methanol and 0.4 mL of water, sodium hydroxide (100 mg, 2.50 mmol) was added, and the reaction was carried out at 120 °C and microwave stirring for 1 hour.
- Step 6 2,3,4',5,6,7'-hexahydrospiro[pyran-4,2'-pyrrole[3',2':5,6]pyridine[3,4-b]pyridine Azin]-3'(1'H)-one (200 mg, 0.77 mmol) and 2-chloro-4-phenoxybenzaldehyde (360 mg, 1.55 mmol) were dissolved in methanol (10 mL) and the reaction was cooled to 0 °C, Potassium hydroxide (304 mg, 5.42 mmol) was added and the reaction was stirred at room temperature for 5 hours.
- reaction solution was poured into 30 mL of water, adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and extracted with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried and concentrated.
- Step 7 9'-(((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2,3,4',5,6,7'-hexahydrospiro[pyran-4 ,2'-pyrrole[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (70 mg, 0.14 mmol) was dissolved in 2 mL of 1,4- Dioxane and 0.2 mL of water were cooled to 0 °C, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (49 mg, 0.21 mmol) was added, and the reaction was stirred at room temperature for 2 hours The reaction solution was added with 3mL saturated sodium thiosulfate solution and 10mL saturated sodium bicarbonate solution, extracted with 40mL ethyl acetate.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.0g, 2.97mmol) and methyl 2-amino-2-methylpropanoate Ester hydrochloride (908 mg, 5.94 mmol) was dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (2.3 mL, 13.36 mmol) was added, and the reaction was stirred at 80 °C for 16 Hour.
- Step 2 methyl 2-methyl-2-((5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)propanoate (870mg, 2.08 mmol) was dissolved in acetic acid (15 mL), iron powder (466 mg, 8.32 mmol) was added, and the reaction was stirred at 85° C. for 4 hours.
- Step 3 2,2-Dimethyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrole[3',2':5,6]pyridine[3,4- b] Pyrazin-3-one (300 mg, 0.84 mmol) was dissolved in 12 mL of N,N-dimethylformamide, followed by adding anhydrous potassium carbonate (464 mg, 3.36 mmol), tert-butyl (2-iodomethoxy) ) dimethylsilane (721 mg, 2.52 mmol) and the reaction was stirred at 60°C for 24 hours. The reaction solution was poured into 40 mL of water, and extracted with 80 mL of ethyl acetate.
- Step 4 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7 -Tetrahydro-3H-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazin-3-one (350mg, 0.68mmol) was dissolved in 15mL methanol, 5mL tetrahydrofuran and 3mL water, added Sodium hydroxide (136 mg, 3.40 mmol), the reaction was stirred at 60° C.
- Step 5 4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrole[3',2':5,6]pyridine[3, 4-b]pyrazin-3-one (75 mg, 0.29 mmol) and 2-chloro-4-phenoxybenzaldehyde (135 mg, 0.58 mmol) were dissolved in methanol (7 mL), the reaction was cooled to 0 °C, hydrogen was added Potassium oxide (114 mg, 2.03 mmol). The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and extracted with 60 mL of ethyl acetate.
- Step 6 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4, 7-Tetrahydro-3H-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazin-3-one (90 mg, 0.18 mmol) was dissolved in 6 mL of dichloromethane, and 2 was added at room temperature , 3-Dichloro-5,6-dicyano-p-benzoquinone (83 mg, 0.36 mmol) and the reaction was stirred at room temperature for 16 hours.
- the reaction solution was added with 5 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution, and extracted with 50 mL of ethyl acetate.
- the organic phase was washed successively with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated brine, dried and concentrated.
- the crude product was purified by preparative HPLC to obtain the target product (Z15, 70 mg, yield 78%) as a white solid.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (0.60g, 1.7804mmol) and 3-aminotetrahydro-2H-pyran- Methyl 3-carboxylate (351.23 mg, 2.209 mmol) was dissolved in N,N-dimethylformamide (30 mL), N,N-diisopropylethylamine (7.64 g, 59.15 mmol) was added, and the reaction was carried out at 95 °C was stirred for 12 hours.
- Step 2 3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-3-carboxylate Methyl acid (320 mg, 0.6956 mmol) was dissolved in acetic acid (20 mL), iron powder (0.780 g, 13.91 mmol) was added, and the reaction was stirred at 80° C. for 1 hour.
- Step 3 7'-(benzenesulfonyl)-4',5,6,7'-tetrahydro-2H,4H-spiro[pyran-3,2'-pyrrolo[3',2':5, 6] Pyridin[3,4-b]pyrazine]-3'(1'H)-one (240 mg, 0.6030 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran and 2 mL of water, and sodium hydroxide (170 mg, 4.221 mmol) was added , the reaction was stirred at 65 °C for 7 hours.
- Step 4 4',5,6,7'-tetrahydro-2H,4H-spiro[pyran-3,2'-pyrrolo[3',2':5,6]pyridine[3,4-b ]pyrazine]-3'(1'H)-one (340 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (280 mg, 1.206 mmol) were dissolved in methanol (12.0 mL) and the reaction was cooled to 0 At °C, potassium hydroxide (236 mg, 4.221 mmol) was added. The reaction was stirred at room temperature for 6 hours.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4',5,6,7'-tetrahydro-2H,4H-spiro[pyran n- 3,2'-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (400 mg, crude) was dissolved in 20 mL of dichloromethane, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (400 mg, 1.762 mmol) was added and the reaction was stirred at room temperature for 2 hours.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (500mg, 1.49mmol) and 4-amino-1-methylpiperidine-4 -Methyl carboxylate (333 g, 1.94 mmol) was dissolved in 15 mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (577 mg, 4.47 mmol) was added, and the reaction was stirred at 95° C. for 16 hours.
- Step 2 1-methyl-4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-4-carboxyl
- the acid ester (296 mg, 0.63 mmol) was dissolved in acetic acid (7 mL), iron powder (247 mg, 4.41 mmol) was added, and the reaction was stirred at 85° C. for 2 hours.
- Step 3 1-Methyl-7'-(benzenesulfonyl)-4',7'-dihydrospiro[piperidine-4,2'-pyrrolo[3',2':5,6]pyridyl [3,4-b]pyrazine]-3'(1'1H)-one (258 mg, 0.63 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (176 mg, 4.41 mmol) was added, and the reaction was performed at The mixture was stirred at 65°C for 16 hours.
- Step 4 1-Methyl-4',7'-dihydrospiro[piperidine-4,2'-pyrrolo[3',2':5,6]pyridyl[3,4-b]pyrazine ]-3'(1'H)-one (76 mg, 0.28 mmol) and 2-chloro-4-phenoxybenzaldehyde (79 mg, 0.34 mmol) were dissolved in methanol (8 mL), the reaction was cooled to 0 °C, added Potassium hydroxide (110 mg, 1.96 mmol) and the reaction was stirred at room temperature for 18 hours.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4',7'-dihydrospiro[piperidine-4,2'- Pyrrolidin[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (56 mg, 0.11 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C , Dess-Martin oxidant (92 mg, 0.22 mmol) was added and the reaction was stirred at room temperature for 2 hours.
- Step 1 2,2-dimethyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrole[3',2':5,6]pyridine[3,4- b] Pyrazin-3-one (400mg, 1.12mmol) was dissolved in 12mL N,N-dimethylformamide, followed by adding anhydrous potassium carbonate (773mg, 5.60mmol), 2-chloro-N,N-dimethylformamide Ethane-1-amine hydrochloride (323 mg, 2.24 mmol) and the reaction was stirred at 60°C for 16 hours.
- reaction solution was cooled to room temperature, and anhydrous potassium carbonate (309 mg, 2.24 mmol), 2-chloro-N,N-dimethylethane-1-amine hydrochloride (161 mg, 1.12 mmol) were additionally added, and the reaction was carried out at 60° C. under stirring for 8 hours.
- the reaction solution was poured into 40 mL of water, and extracted twice with 40 mL of ethyl acetate.
- Step 2 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazin-3-one (250mg, 0.58mmol) was dissolved in 10mL methanol, 3mL tetrahydrofuran and 2mL water, sodium hydroxide (94mg, 2.32mmol) and Triethylamine (1.17 g, 11.60 mmol) and the reaction was stirred at 60°C for 16 hours.
- Step 3 4-(2-(Dimethylamino)ethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrole[3',2':5,6] Pyridin[3,4-b]pyrazin-3-one (75 mg, 0.26 mmol) and 2-chloro-4-phenoxybenzaldehyde (151 mg, 0.65 mmol) were dissolved in methanol (6 mL) and the reaction was cooled to 0 At °C, potassium hydroxide (102 mg, 1.82 mmol) was added. The reaction was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to 8 with 1.0M dilute hydrochloric acid.
- Step 4 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-1, 2,4,7-Tetrahydro-3H-pyrrole[3',2':5,6]pyridin[3,4-b]pyrazin-3-one (95mg, 0.18mmol) in 1,4-di Oxane (5 mL) and water (0.5 mL) were added at room temperature, and 2,3-dichloro-5,6-dicyano-p-benzoquinone (82 mg, 0.36 mmol) was added, and the reaction was stirred at room temperature for 2 hours.
- the reaction solution was added with 6 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution, and extracted with 80 mL of ethyl acetate.
- the organic phase was washed successively with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried and concentrated.
- the crude product was purified by preparative HPLC to obtain the target product (Z63, 70 mg, yield 74%) as a white solid.
- Step 1 5-Bromo-4-fluoro-1H-pyrrole[2,3-b]pyridine (950 mg, 4.42 mmol) was dissolved in 25 mL of tetrahydrofuran, cooled to 0°C under nitrogen protection, added with sodium hydride (1.01 g, 5.75 mmol, 60% dispersion in mineral oil) and the reaction was stirred at room temperature for 30 minutes. After cooling to 0°C again, a solution of benzenesulfonyl chloride (1.01 g, 5.75 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 16 hours.
- Step 2 5-bromo-4-fluoro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (500mg, 1.41mmol), (3-aminotetrahydrofuran- 3-yl)methanol (330 mg, 2.82 mmol), N,N-dimethylacetamide (7 mL), and N,N-diisopropylethylamine (546 mg, 13.36 mmol) in a microwave reactor at 160°C The reaction was carried out for 8 hours.
- Step 3 Add 3-((5-bromo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-yl) into a 5mL microwave tube in turn Methanol (115mg, 0.25mmol), Palladium acetate (12mg, 0.05mmol), [1,1"-bisnaphthalene]-2-yldi-tert-butylphosphine (30mg, 0.075mmol), Cesium carbonate (122mg, 0.375mmol) and toluene (4 mL), replaced with nitrogen for 2 minutes, and reacted in a microwave reactor at 115° C. for 1 hour.
- Step 4 7'-(Benzenesulfonyl)-1',4,5,7'-tetrahydro-2H,3'H-spiro[furan-3,2'-pyrrole[3',2':5 ,6]pyridine[3,4-b][1,4]oxazine] (180mg, crude product) was dissolved in 8mL methanol, 2mL tetrahydrofuran and 2mL water, sodium hydroxide (78mg, 1.94mmol) was added, and the reaction was carried out at 65°C Stir for 16 hours.
- Step 5 1',4,5,7'-tetrahydro-2H,3'H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridine[3,4- b][1,4]oxazine] (85 mg, 0.37 mmol) and 2-chloro-4-phenoxybenzaldehyde (256 mg, 1.10 mmol) were dissolved in methanol (8 mL), the reaction was cooled to 0 °C and hydrogen was added Potassium oxide (145 mg, 2.59 mmol). The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and extracted with 60 mL of ethyl acetate.
- Step 6 (2-Chloro-4-phenoxyphenyl)(1',4,5,7'-tetrahydro-2H,3'H-spiro[furan-3,2'-pyrrole[3',2':5,6]pyridine[3,4-b][1,4]oxazine]-9'-yl)methanol (120 mg, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (83 mg, 0.36 mmol) was added at room temperature, and the reaction was stirred at room temperature for 1 hour.
- the reaction solution was added with 5 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution, and extracted with 50 mL of ethyl acetate.
- the organic phase was washed successively with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated brine, dried and concentrated.
- the crude product was purified by preparative HPLC to obtain the target product (Z18, 40 mg, yield 33%) as a pale yellow solid.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (0.60g, 1.7804mmol) and 1-(tert-butyl)3-methyl 3-Aminopiperidine-1,3-dicarboxylate (450mg, 1.540mmol) was dissolved in N,N-dimethylformamide (20mL), N,N-diisopropylethylamine (7.64g, 59.15 mmol) and the reaction was stirred at 95°C for 12 hours.
- Step 2 1-(tert-butyl)3-methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) piperidine-1,3-dicarboxylic acid (320 mg, 0.6563 mmol) was dissolved in acetic acid (20 mL), iron powder (0.672 g, 12.0 mmol) was added, and the reaction was stirred at 80° C. for 1 hour.
- Step 3 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[piperidine-3,2'-pyrrolo[3',2' : 5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (230mg, 0.4626mmol) was dissolved in 12mL methanol, 3mL tetrahydrofuran and 2mL water, sodium hydroxide (129mg, 3.2381mmol) was added ), the reaction was stirred at 65°C for 7 hours.
- Step 4 3'-oxo-1',3',4',7'-tetrahydrospiro[piperidine-3,2'-pyrrolo[3',2':5,6]pyrido[3 ,4-b]pyrazine]-1-carboxylate tert-butyl ester (382mg, crude) and 2-chloro-4-phenoxybenzaldehyde (215mg, 0.9252mmol) were dissolved in methanol (12.0mL), the reaction was cooled To 0°C, potassium hydroxide (181 mg, 3.238 mmol) was added. The reaction was stirred at room temperature for 6 hours.
- Step 5 9'-(((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[ Piperidine-3,2'-pyrrolo[3',2':5,6]pyridine[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (500 mg, crude) was dissolved in 20 mL of dichloro Methane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (210 mg, 0.9252 mmol) was added, and the reaction was stirred at room temperature for 2 hours.
- Step 6 9'-(2-Chloro-4-phenoxybenzoyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[piperidine-3,2'-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (260 mg, 0.4429 mmol) was dissolved in dichloromethane (12 mL), Finally, trifluoroacetic acid (3.0 mL) was added, the reaction was performed at room temperature for 3 hours, and the solvent was spin-dried under reduced pressure to obtain the crude product 9'-(2-chloro-4-phenoxybenzoyl)-4',7'-dihydrospiro[ Piperidine-3,2'-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin]-3'(1'H)-one (300 mg, crude).
- Step 7 Under ice-water bath conditions, 9'-(2-chloro-4-phenoxybenzoyl)-3'-oxo-1',3',4',7'-tetrahydrospiro[piperidine -3,2'-Pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-1-carboxylate tert-butyl ester (300 mg, crude) was dissolved in acetonitrile (20 mL) , Sodium cyanoborohydride (139 mg, 2.21 mmol) was added and then aqueous formaldehyde solution (180 mg, 2.21 mmol, 37% aq) was added dropwise.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (500mg, 1.48mmol) and 4-aminotetrahydro-2H-pyran-4 -Methyl carboxylate (283mg, 1.78mmol) was dissolved in N,N-dimethylacetamide (5mL), N,N-diisopropylethylamine (573g, 4.44mmol) was added, and the microwave reaction was stirred at 120°C 1.5 hours.
- Step 2 4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-4- Methyl carboxylate (374 mg, 0.813 mmol) was dissolved in acetic acid (10 mL), iron powder (455 mg, 8.13 mmol) was added, and the reaction was stirred at 80° C. for 3 hours.
- Step 3 7'-(Benzenesulfonyl)-2,3,4',5,6,7'-hexahydrospiro[pyran-4,2'-pyrrolo[3',2':5,6 ]pyridin[3,4-b]pyrazine]-3'(1'H)-one (200 mg, 0.50 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and anhydrous potassium carbonate (414 mg, 3.0 mmol) and iodomethane (352 mg, 2.5 mmol), the reaction was stirred in a sealed tube at 40°C for 3 hours. 100 mL of ethyl acetate was added to the reaction solution for extraction.
- Step 4 4'-methyl-7'-(benzenesulfonyl)-2,3,4',5,6,7'-hexahydrospiro[pyran-4,2'-pyrrolo[3', 2':5,6]pyridin[3,4-b]pyrazine]-3'(1'H)-one (180 mg, 0.43 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, and sodium hydroxide ( 86 mg, 2.15 mmol) and the reaction was stirred at 65 °C for 15 h.
- Step six 4'-methyl-2,3,4',5,6,7'-hexahydrospiro[pyran-4,2'-pyrrolo[3',2':5,6]pyridine[ 3,4-b]pyrazine]-3'(1'H)-one (92 mg, 0.34 mmol) and 2-chloro-4-phenoxybenzaldehyde (157 mg, 0.68 mmol) were dissolved in methanol (5 mL), The reaction was cooled to 0°C and potassium hydroxide (95 mg, 1.70 mmol) was added. The reaction was stirred at room temperature for 3 hours.
- Step 7 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-4'-methyl-2,3,4',5,6,7'-hexahydrospiro [pyran-4,2'-pyrrole[3',2':5,6]pyrrolo[3,4-b]pyrazine]-3'(1'H)-one (110 mg, 0.218 mmol) dissolved in In 5 mL of 1,4-dioxane and 1 mL of water, DDQ (99 mg, 0.436 mmol) was added, the reaction was stirred at room temperature for 30 minutes, and 5 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution were added to the reaction solution.
- DDQ 99 mg, 0.436 mmol
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.0 g, 2.96 mmol) and 2-amino-3-hydroxy-2-methyl Methyl propionate (472mg, 3.56mmol) was dissolved in N,N-dimethylacetamide (10mL), N,N-diisopropylethylamine (1.14g, 8.88mmol) was added, and the microwave reaction was carried out at 95°C Stir for 15 hours.
- Step 2 3-Hydroxy-2-methyl-2-methyl(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) propionate (770 mg, 1.77 mmol) was dissolved in acetic acid (10 mL), iron powder (1.98 g, 35.4 mmol) was added, and the reaction was stirred at 80 ° C for 3 hours.
- Step 3 2-(Hydroxymethyl)-2-methyl-7-(benzenesulfonyl)-4,7-dihydro-1H-pyrrolo[3',2':5,6]pyridine[3, 4-b]pyrazin-3(2H)-one (462 mg, 1.24 mmol) was dissolved in 30 mL of methanol, 5 mL of tetrahydrofuran and 3 mL of water, sodium hydroxide (248 mg, 6.2 mmol) was added, and the reaction was stirred at 65°C for 6 hours. 15 mL of water and 4 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 100 mL of ethyl acetate.
- Step four 2-(hydroxymethyl)-2-methyl-4,7-dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine- 3(2H)-one (110 mg, 0.474 mmol) and 2-chloro-4-((3-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (286 mg, 0.95 mmol) were dissolved in methanol ( 5 mL), the reaction was cooled to 0 °C and potassium hydroxide (132 mg, 2.37 mmol) was added. The reaction was stirred at room temperature for 3 hours.
- reaction solution was poured into 60 mL of water, adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and extracted with 80 mL of ethyl acetate.
- Step Five 9-((2-Chloro-4-((3-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(hydroxymethyl)- 2-Methyl-4,7-dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3(2H)-one (110 mg, 0.206 mmol ) was dissolved in 5 mL of 1,4-dioxane and 1 mL of water, DDQ (93 mg, 0.412 mmol) was added, the reaction was stirred at room temperature for 30 minutes, and 5 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution were added to the reaction solution.
- Step 1 Under nitrogen protection, 2-chloro-4-hydroxybenzaldehyde (2.04g, 13.081mmol), 2-bromo-4-methylpyridine (1.5g, 8.721mmol), potassium phosphate (4.072g, 19.186mmol) , cuprous iodide (166mg, 0.872mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (248mg, 1.744mmol) were dissolved in 45mL of anhydrous N,N-dimethylamine The reaction solution was heated to 110 °C and stirred overnight.
- Step 2 Under ice-water bath, potassium hydroxide (113mg, 2.025mmol) was added to 2-chloro-4-((4-methylpyridin-2-yl)oxy)benzaldehyde (200mg, 0.810mmol) and 2- (Hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine-3 -ketone (94 mg, 0.405 mmol) in dichloromethane (8 mL), the reaction solution was stirred at room temperature for 3 hours. Product formation was detected by LCMS.
- Step 3 At room temperature, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (125mg, 0.551mmol) was added to 9-((2-chloro-4-((4-methyl) pyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3 ',2':5,6]pyrido[3,4-b]pyrazin-3-one (132 mg, 0.276 mmol) in dichloromethane (15 mL), and the reaction solution was stirred at room temperature for 3 hours. Product formation was detected by LCMS.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.28g, 3.79mmol) and 1-amino-3-hydroxycyclopentane Ethyl-1-carboxylate hydrochloride (662 mg, 3.16 mmol) was dissolved in N,N-dimethylacetamide (20 mL), N,N-diisopropylethylamine (1.225 g, 9.48 mmol) was added, The reaction was stirred at 95°C for 16 hours.
- Step 2 3-Hydroxy-1-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino)amino]cyclopentane -1-ethyl formate (550mg, 1.16mmol) was dissolved in acetic acid (7mL), iron powder (649mg, 11.6mmol) was added, and the reaction was stirred at 85 ° C for 3 hours.
- Step 3 3-Hydroxy-7'-(benzenesulfonyl)-4',7'-dihydrospiro[cyclopentane-1,2'-pyrrolo[3',2':5,6]pyrido [3,4-b]pyrazine]-3'(1'H)-one (410 mg, 1.03 mmol) was dissolved in 10 mL of methanol, 4 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (206 mg, 5.15 mmol) was added, and the reaction was performed at After stirring at 65°C for 6 hours, the reaction solution was concentrated under reduced pressure to obtain the crude product.
- ES-API: [M+H] + 259.1.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3-hydroxy-4',7'-dihydrospiro[cyclopentane-1,2'- Pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (180 mg, 0.367 mmol) was dissolved in 10 mL of tetrahydrofuran, 2,3 -Dichloro-5,6-dicyano-1,4-benzoquinone (166 mg, 0.733 mmol), the reaction was stirred at room temperature for 30 minutes.
- reaction solution was quenched by adding 20 mL of NaHSO 3 saturated solution, extracted with 80 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC to obtain two enantiomers.
- the other enantiomer was Z24-2 (32 mg, peak 2, retention time 7.611 min, yield 18%), white solid.
- ES-API: [M+H] + 489.1.
- ES-API: [M+H] + 489.1.
- Another single isomer whose structure was arbitrarily assigned as Z24-b 32 mg, peak 2, retention time 17.062 min, yield 41%), white solid.
- ES-API: [M+H] + 489.1.
- ES-API: [M+H] + 489.1.
- ES-API: [M+H] + 489.1.
- Step 1 3-Hydroxy-2-methyl-2-methyl ((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Propionate (550 mg, 1.16 mmol), silver oxide (5.3 g, 23 mmol) and iodomethane (3.3 g, 23 mmol) were dissolved in acetonitrile (50 mL), and the reaction was stirred at 35°C for 3 days in the dark.
- Step 2 3-methoxy-1-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)amino]pentane-
- Ethyl 1-carboxylate (354 mg, 0.72 mmol) was dissolved in acetic acid (20 mL), iron powder (286 mg, 5.11 mmol) was added, and the reaction was stirred at 85 ° C for 3 hours. The reaction solution was added with 100 mL of ethyl acetate and washed with 60 mL of water successively.
- Step 3 3-Methoxy-7'-(benzenesulfonyl)-4',7'-dihydrospiro[cyclopentane-1,2'-pyrrolo[3',2':5,6] Pyrido[3,4-b]pyrazine]-3'(1'H)-one (360 mg, 0.87 mmol) was dissolved in 10 mL methanol, 5 mL tetrahydrofuran and 2 mL water, sodium hydroxide (244 mg, 6.09 mmol) was added, The reaction was stirred at 65°C for 7 hours.
- Step 4 3-Methoxy-4',7'-dihydrospiro[cyclopentane-1,2'-pyrrolo[3',2':5,6]pyrido[3,4-b] Pyrazin]-3'(1'H)-one (100 mg, 0.37 mmol) and 2-chloro-4-phenoxybenzaldehyde (172 mg, 0.74 mmol) were dissolved in methanol (20 mL) and the reaction was cooled to 0 °C , potassium hydroxide (145 mg, 2.59 mmol) was added. The reaction was stirred at room temperature for 16 hours.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3-methoxy-4',7'-dihydrospiro[cyclopentane-1, 2'-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin]-3'(1'H)-one (121 mg, 0.24 mmol) was dissolved in 20 mL of tetrahydrofuran and 2 mL Water, 2,3-dichloro-5,6-dicyano-p-benzoquinone (109 mg, 0.48 mmol) was added, the reaction was stirred at room temperature for 1 hour, and 20 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate were added to the reaction solution.
- ES-API: [M+H] + 503.1.
- ES-API: [M+H] + 503.1.
- ES-API: [M+H] + 503.1.
- ES-API: [M+H] + 503.1.
- ES-API: [M+H] + 503.1.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.06g, 3.14mmol) and 1-amino-3-cyanocyclopentane Ethyl alkane-1-carboxylate (520mg, 2.85mmol) was dissolved in N,N-dimethylacetamide (20mL), N,N-diisopropylethylamine (11g, 8.55mmol) was added, and the reaction was carried out at 100 °C was stirred for 16 hours.
- Step 2 3-cyano-1-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)ethylpentane-
- Ethyl 1-carboxylate 973 mg, 2.01 mmol
- iron powder (1.126 g, 20.1 mmol) was added, and the reaction was stirred at 80 ° C for 3 hours.
- the reaction solution was added with 100 mL of ethyl acetate, followed by 30 mL of water.
- Step 3 3'-oxo-7'-(benzenesulfonyl)-1',3',4',7'-tetrahydrospiro[cyclopentane-1,2'-pyrrolo[3',2 ':5,6]pyrido[3,4-b]pyrazine]-3-carbonitrile (390mg, 0.96mmol) was dissolved in 10mL methanol, 4mL tetrahydrofuran and 2mL water, sodium hydroxide (192mg, 4.8mmol) was added, The reaction was stirred at 60°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product.
- ES-API: [M+H] + 268.1.
- Step 5 9'-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-3-isocyano-4',7'-dihydrospiro[cyclopentane-1,2 '-Pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (230 mg, 0.46 mmol) was dissolved in 10 mL of tetrahydrofuran, 0°C Dess-Martin oxidant (390 mg, 0.92 mmol) was added under and the reaction was stirred at room temperature for 30 minutes.
- reaction solution was quenched by adding 20 mL of saturated NaHSO 3 solution, extracted with 80 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC to obtain the target product (Z26, 148 mg, 64% yield), white solid.
- ES-API: [M+H] + 498.1.
- Mixture of two isomers P1 (15 mg, peak 1, retention time 9.094 min, yield 10%), white solid.
- a single isomer whose structure was arbitrarily assigned as Z26-3 (44.44 mg, peak 2, retention time 13.578 min, yield 31%), pale white solid ES-API: [M+H] + 498.1.
- Another single isomer whose structure was arbitrarily assigned as Z26-4 45.18 mg, peak 3, retention time 16.941 min, yield 31%), pale white solid.
- ES-API: [M+H] + 498.1.
- a single isomer whose structure was arbitrarily assigned as Z26-1 (5.25 mg, peak 1, retention time 7.995 min, yield 35%), white solid ES-API: [M+H] + 498.1.
- ES-API: [M+H] + 498.1.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (687mg, 2.03mmol) and trans-3-amino-6-((tert. Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-carboxylic acid methyl ester (580mg, 1.36mmol) was dissolved in N,N-dimethylacetamide (10mL), added N,N-Diisopropylethylamine (877 mg, 6.80 mmol) and the reaction was stirred at 95°C for 16 hours.
- Step 2 trans-6-((tert-butyldiphenylsilyl)oxy)methyl)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2, 3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-3-carboxylate methyl ester (420mg, 0.58mmol) was dissolved in acetic acid (10mL), iron powder (325mg, 5.80mmol) was added, and the reaction Stir at 85°C for 2 hours.
- Step 3 trans-6-((tert-butyldiphenylsilyl)oxy)methyl)-7'-(phenylsulfonyl)-4',5,6,7'-tetrahydro-2H, 4H spiro[pyran-3,2'-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (330 mg, 0.49 mmol) was dissolved in 10 mL of methanol, 3 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (119 mg, 2.97 mmol) was added, and the reaction was stirred at 65°C for 20 hours.
- sodium hydroxide 119 mg, 2.97 mmol
- Step 4 trans-6-(hydroxymethyl)-4',5,6,7'-tetrahydro-2H,4H-spiro[pyran-3,2'-pyrrolo[3',2': 5,6]Pyrido[3,4-b]pyrazine]-3'(1'H)-one (220 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (531 mg, 2.29 mmol) were dissolved in In methanol (12 mL), the reaction was cooled to 0 °C and potassium hydroxide (300 mg, 5.34 mmol) was added. The reaction was stirred at room temperature for 16 hours.
- Step 5 trans-9'-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-6-(hydroxymethyl)-4',5,6,7'-tetrahydro- 2H,4H-Spiro[pyran-3,2'-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazine]-3'(1'H)-one (165 mg, 0.32 mmol) was dissolved in 1,4-dioxane (7 mL) and water (0.7 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (144 mg, 0.64 mmol) was added, The reaction was stirred at room temperature for 1 hour.
- reaction solution was added with 6 mL of saturated sodium thiosulfate solution and 6 mL of saturated sodium bicarbonate solution, and extracted with 60 mL of ethyl acetate.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.967 mmol) and 2-amino-3-hydroxy-2- Methyl methylpropionate hydrochloride (0.6g, 3.550mmol) was dissolved in N,N-dimethylacetamide (30mL), N,N-diisopropylethylamine (7.64g, 59.15mmol) was added, The reaction was stirred at 95°C for 16 hours.
- Step 2 -3-Hydroxy-2-methyl-2-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Methyl propionate (600mg, 1.382mmol) was dissolved in acetonitrile (30mL), silver oxide (3.70g, 15.96mmol) and methyl iodide (1mL, 16.05mmol) were added successively, and stirred at room temperature in the dark for 48 hours under nitrogen protection.
- Step 3 3-Methoxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) methyl propionate (520 mg, 1.272 mmol) was dissolved in acetic acid (20 mL) and iron powder (1.42 g, 25.44 mmol) was added. The temperature was gradually raised to 80°C and stirred for 1 hour.
- Step 4 2-(methoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5, 6] Pyrido[3,4-b]pyrazin-3-one (260 mg, 0.69734 mmol) was dissolved in a mixed solution of acetone/N,N-dimethylformamide (10 mL: 2 mL), followed by adding iodomethane (957 mg, 6.734 mmol) and potassium carbonate (465 mg, 3.367 mmol) and stirred in a sealed tube at 40°C for 12 hours.
- Step 5 2-(methoxymethyl)-2,4-dimethyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2' : 5,6]pyrido[3,4-b]pyrazin-3-one (200mg, 0.4997mmol) was dissolved in 12mL methanol, 3mL tetrahydrofuran and 2mL water, sodium hydroxide (7140.0mg, 3.498mmol) was added, and the reaction Stir at 65°C for 7 hours. 20 mL of water and 15 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 150 mL of ethyl acetate.
- Step Six 2-(Methoxymethyl)-2,4-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[ 3,4-b]pyrazin-3-one (253 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (230 mg, 0.9913 mmol) were dissolved in methanol (20.0 mL), the reaction was cooled to 0 °C, Potassium hydroxide (200 mg, 3.5710 mmol) was added. The reaction was stirred at room temperature for 6 hours.
- Step 7 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(methoxymethyl)-2,4-dimethyl-1,2,4, 7-Tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (380 mg, crude product) was dissolved in 20 mL of tetrahydrofuran, and 2,3- Dichloro-5,6-dicyano-1,4-benzoquinone (380 mg, 1.674 mmol) and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with 80 mL of ethyl acetate.
- a single isomer whose structure was arbitrarily assigned as Z52-1 (2.52 mg, peak 1, retention time 15.908 min, yield 14%), pale white solid ES-API: [M+H] + 491.1.
- Another single isomer whose structure was arbitrarily assigned as Z52-2 (1.98 mg, peak 2, retention time 20.198 min, yield 11%), pale white solid ES-API: [M+H] + 491.1.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.5g, 13.35mmol) and 2-amino-3-hydroxy-2- Methyl methylpropionate hydrochloride (4.0g, 8.902mmol) was dissolved in N,N-dimethylacetamide (80mL), N,N-diisopropylethylamine (7.64g, 59.15mmol) was added, The reaction was stirred at 95°C for 16 hours.
- Step 2 3-Hydroxy-2-methyl-2-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propane
- Methyl acid (2.60g, 5.990mmol) was dissolved in acetonitrile (100mL), silver oxide (20.82g, 89.86mmol) and methyl iodide (21.26g, 149.5mmol) were added successively, and stirred for 48 hours at room temperature in the dark under nitrogen protection.
- Step 3 3-Methoxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) methyl propionate (1.05 g, 2.343 mmol) was dissolved in acetic acid (30 mL) and iron powder (2.62 g, 46.87 mmol) was added. The temperature was gradually raised to 80°C and stirred for 1 hour.
- Step 4 2-(methoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5, 6] Pyrido[3,4-b]pyrazin-3-one (200 mg, 0.5180 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (150 mg, 3.626 mmol) was added, and the reaction was stirred at 65 °C 7 hours. 20 mL of water and 30 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 100 mL of ethyl acetate.
- Step 5 2-(Methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4 -b] Pyrazin-3-one (246 mg, crude) and 2-chloro-4-((4-methylpyridin-2-yl)oxy)benzaldehyde (230 mg, 0.9310 mmol) were dissolved in methanol (20.0 mL) ), the reaction was cooled to 0 °C and potassium hydroxide (205 mg, 3.626 mmol) was added. The reaction was stirred at room temperature for 6 hours.
- Step Six 9-((2-Chloro-4-((4-methylpyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(methoxymethyl)-2- Methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (310 mg, crude) was dissolved in To 30 mL of tetrahydrofuran, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (310 mg, 1.3656 mmol) was added, and the reaction was stirred at room temperature for 2 hours.
- a single isomer whose structure was arbitrarily assigned as Z64-1 (7.0 mg, peak 1, retention time 18.717 min, yield 23%), pale white solid ES-API: [M+H] + 492.1.
- Another single isomer whose structure was arbitrarily assigned as Z64-2 (12 mg, peak 2, retention time 22.80 min, yield 40%), pale white solid ES-API: [M+H] + 492.1.
- Step 1 3-Hydroxy-2-methyl-2-methyl ((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Propionate (1.0 g, 2.3 mmol), silver oxide (5.3 g, 23 mmol) and deuterated iodomethane (3.34 g, 23 mmol) were dissolved in acetonitrile (50 mL), and the reaction was stirred at 35° C. for 2 days in the dark.
- acetonitrile 50 mL
- Step 2 3-(methoxy-d 3 )-2-methyl-2-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 -Methyl)amino)propionate (330 mg, 0.73 mmol) was dissolved in acetic acid (15 mL), iron powder (286 mg, 5.11 mmol) was added, and the reaction was stirred at 85° C. for 3 hours.
- Step 3 2-((methoxy-d 3 )methyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3', 2':5,6]pyrido[3,4-b]pyrazin-3-one (270 mg, 0.69 mmol) was dissolved in 10 mL methanol, 5 mL tetrahydrofuran and 2 mL water, sodium hydroxide (270 mg, 4.83 mmol) was added, The reaction was stirred at 65°C for 7 hours. 15 mL of water and 4 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 100 mL of ethyl acetate.
- Step 5 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-((methoxy-d 3 )methyl)-2-methyl-1,2, 4,7-Tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (120 mg, 0.26 mmol) was dissolved in 20 mL of tetrahydrofuran and 2 mL of water , 2,3-dichloro-5,6-dicyano-p-benzoquinone (118 mg, 0.52 mmol) was added, the reaction was stirred at room temperature for 1 hour, 20 mL of saturated sodium thiosulfate solution was added to the reaction solution, and 60 mL of ethyl acetate was used for extraction , the organic phase was washed twice with 20 mL of saturated sodium bicarbonate solution, concentrated after drying, and the crude product was preparative HPLC (column: xbridge C18 19
- Step 1 3-Hydroxy-2-methyl-2-methyl ((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Propionate (1.0 g, 2.3 mmol), silver oxide (5.3 g, 23 mmol) and iodoethane (3.6 g, 23 mmol) were dissolved in acetonitrile (50 mL) and the reaction was stirred at 35°C in the dark for 3 days.
- Step 2 3-Ethoxy-2-methyl-2-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) propionate (250 mg, 0.54 mmol) was dissolved in acetic acid (15 mL), iron powder (212 mg, 3.78 mmol) was added, and the reaction was stirred at 85 ° C for 3 hours. The reaction solution was added with 100 mL of ethyl acetate, and washed with 60 mL of water for 2 times.
- Step 3 2-(ethoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5, 6] Pyrido[3,4-b]pyrazin-3-one (170 mg, 0.43 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (119 mg, 2.98 mmol) was added, and the reaction was stirred at 65 °C 7 hours. 15 mL of water and 4 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 50 mL of ethyl acetate.
- Step four 2-(ethoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4 -b] Pyrazin-3-one (130 mg, 0.5 mmol) and 2-chloro-4-phenoxybenzaldehyde (232 mg, 1.00 mmol) were dissolved in methanol (20 mL), the reaction was cooled to 0 °C, and hydroxide was added Potassium (196 mg, 3.5 mmol). The reaction was stirred at room temperature for 16 hours.
- Step 5 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(ethoxymethyl)-2-methyl-1,2,4,7-tetra Hydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (135 mg, 0.27 mmol) was dissolved in 20 mL of tetrahydrofuran and 2 mL of water, 2,3 -Dichloro-5,6-dicyano-p-benzoquinone (123 mg, 0.56 mmol), the reaction was stirred at room temperature for 1 hour, 20 mL of saturated sodium thiosulfate solution was added to the reaction solution, and 50 mL of ethyl acetate was used for extraction.
- Step 1 Under nitrogen protection, 2-fluoro-4-hydroxybenzaldehyde (1.652g, 11.628mmol), 2-bromo-4-methylpyridine (2g, 11.628mmol), potassium phosphate (5.43g, 25.582mmol), Cuprous iodide (220 mg, 1.1.63 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (330 mg, 2.326 mmol) in N,N '-dimethylformamide (20 mL), and the reaction solution was stirred under microwave at 110°C for 1 hour.
- Step 2 (S)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido [3,4-b]pyrazin-3-one (68 mg, 0.275 mmol) and 2-fluoro-4-((4-methylpyridin-2-yl)oxy)benzaldehyde (160 mg, 0.693 mmol) were dissolved in In methanol (10 mL), the reaction solution was cooled to 0°C, and potassium hydroxide (108 mg, 1.925 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 4 hours.
- Step 3 9-((2-Fluoro-4-((4-methylpyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(methoxymethyl)-2 -Methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (62 mg, 0.130 mmol ) was dissolved in 10 mL of tetrahydrofuran, 2,3-dichloro-5,6-dicyano-p-benzoquinone (59 mg, 0.260 mmol) was added, the reaction solution was stirred at room temperature for 3 hours, and LCMS detected that the reaction was complete.
- reaction solution was added with 20 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution, and extracted with 30 mL of ethyl acetate.
- the organic phase was washed with 15 mL of saturated brine, dried and concentrated, and the crude product was subjected to preparative HPLC (column: xbridge C18 19*150 mm, 5 ⁇ m; system: 10 mmol/L, NH 4 HCO 3 aqueous solution; flow rate: 15 mL/min; gradient: 20 ⁇ 20 45% CH3CN - NH4HCO3 ; column temperature: room temperature) was purified to give 9-(2-fluoro-4-((4-methylpyridin-2-yl)oxy)benzoyl)-2 as a white solid -(Methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyridine
- a single isomer whose structure was arbitrarily assigned as Z69-1 (Peak 1, retention time: 11.371 min, 5.59 mg).
- ES-API: [M+H] + 476.1.
- Another single isomer, whose structure was arbitrarily assigned as Z69-2 peak 2, retention time: 14.824 min, 6.63 mg).
- ES-API: [M+H] + 476.1.
- Step one 2-Fluoro-4-hydroxybenzaldehyde (500mg, 3.57mmol), diphenyliodonium chloride (1.24g, 3.93mmol) and potassium carbonate (1.48g, 10.71mmol) in N,N-dimethyl
- the formamide (20 mL) mixture was stirred at 80°C overnight.
- reaction solution was dissolved in 50 mL of ethyl acetate, washed three times with 50 mL of saturated brine, the organic phase was dried and concentrated, and purified by flash silica column (0-30% ethyl acetate/petroleum ether) to obtain a white solid 2-fluoro-4 -Phenoxybenzaldehyde (600 mg), purity 100%, yield 78%.
- Step 2 To 3-methoxy-2-methyl-2-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Iron powder (1.74 g, 31.2 mmol) was added to the solution of methyl amino) propionate (700 mg, 1.56 mmol) in acetic acid (30 mL). The reaction solution was stirred at 80° C. for 2 hours. The reaction solution was filtered with celite, and 50 mL of acetic acid was used.
- Step 3 2-(methoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5 ,6]pyrido[3,4-b]pyrazin-3-one (250mg, 0.65mmol) and sodium hydroxide (130mg, 3.23mmol) were added to a mixed solvent of methanol/water (5ml/1ml), 60 °C was stirred for 2 hours.
- Step 4 To the above crude product 2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[ To a solution of 3,4-b]pyrazin-3-one (160 mg, 0.65 mmol) in methanol (5 mL) was added 2-fluoro-4-phenoxybenzaldehyde (421 mg, 1.95 mmol) and potassium hydroxide (255 mg, 4.55 mmol) and stirred at room temperature for 2 hours.
- Step 5 To 9-((2-fluoro-4-phenoxyphenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1,2,4,7- Tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (120 mg, 0.26 mmol) in 1,4-dioxane/water 2,3-Dichloro-5,6-dicyano-p-benzoquinone (118 mg, 0.52 mmol) was added to the mixed solution (5 ml/0.5 ml), and the mixture was stirred at room temperature for 30 minutes.
- a single isomer whose structure was arbitrarily assigned as Z71-1 (10 mg, peak 1, retention time 9.71 min, yield 31%, de% 100%), white solid.
- ES-API: [M+H] + 461.2.
- Another single isomer whose structure was arbitrarily assigned as Z71-2 (10 mg, peak 2, retention time 14.40 min, yield 31%, de% 100%), white solid.
- ES-API: [M+H] + 461.2.
- Step 1 Combine 2-chloro-4-hydroxybenzaldehyde (400mg, 2.6mmol), 2-chloro-4-cyclopropylpyridine (486mg, 3.12mmol), L-proline (60mg, 0.52mmol), iodine Cuprous compound (98mg, 0.52mmol), anhydrous potassium carbonate (896mg, 6.5mmol) and N,N'-dimethylacetamide (8ml) were added to a 20ml microwave tube, nitrogen was replaced, heated to 130 °C, the reaction 3 hours.
- Step 2 2-chloro-4-((4-cyclopropylpyridin-2-yl)oxy)benzaldehyde (50mg, 0.183mmol), 2-(methoxymethyl)-2-methyl- 4,7-Dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3(2H)-one (100 mg, 0.40 mmol) and potassium hydroxide (112 mg, 2 mmol) was added to 8 ml of methanol and stirred at room temperature for 5 hours.
- Step three 9-((2-chloro-4-((4-cyclopropylpyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(methoxymethyl)- 2-Methyl-4,7-dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3(2H)-one (60 mg, 0.115 mmol ) was added to the mixed solution of 1,4-dioxane/water (5ml/1ml), and then 2,3-dichloro-5,6-dicyano-p-benzoquinone (52mg, 0.231mmol) was added in portions at room temperature. After stirring for 30 minutes, the reaction was completed.
- a single isomer whose structure was arbitrarily assigned as Z73-1 (peak 1, retention time 24.62 min, 12 mg, 40% yield, 100% purity); ES-API: [M+H] + 518.1.
- Step 1 2-chloro-4-hydroxybenzaldehyde (1.23g, 7.9mmol), 2-chloro-4-trifluoromethylpyridine (870mg, 5.27mmol), L-anhydrous potassium carbonate (2.18g, 15.8 mmol) and N,N'-dimethylformamide (10ml) were added to a 50ml microwave tube, replaced with nitrogen, heated to 80°C, and reacted for 18 hours.
- Step 2 2-chloro-4-((4-trifluoromethylpyridin-2-yl)oxy)benzaldehyde (300mg, 0.99mmol), 2-(methoxymethyl)-2-methyl -4,7-Dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3(2H)-one (150 mg, 0.61 mmol) and hydroxide Potassium (170 mg, 3.04 mmol) was added to 8 ml of methanol and stirred at room temperature for 3 hours.
- Step 3 9-((2-chloro-4-((4-trifluoromethylpyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-2-(methoxymethyl) - 2-Methyl-4,7-dihydro-1H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3(2H)-one (160 mg, 0.29 mmol) was added to 1,4-dioxane/water (5ml/1ml) mixed solution, then 2,3-dichloro-5,6-dicyano-p-benzoquinone (132mg, 0.58mmol) was added in portions, After stirring at room temperature for 30 minutes, the reaction was completed.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 8.90 mmol) and 2-amino-4-methoxy- Ethyl 2-methylbutyrate hydrochloride (2.4 g, 11.57 mmol) was dissolved in N,N-dimethylacetamide (30 mL), and N,N-diisopropylethylamine (9.3 mL, 53.40 mmol) was added. ) and the reaction was stirred at 95°C for 16 hours.
- Step 2 4-Methoxy-2-methyl-2-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Ethyl butyrate (2.5 g, 5.25 mmol) was dissolved in acetic acid (40 mL), iron powder (2.06 g, 36.75 mmol) was added, and the reaction was stirred at 85° C. for 2 hours.
- Step 5 9-((2-Chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(2-methoxyethyl)-2-methyl-1,2,4,7 -Tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (800 mg, 1.63 mmol) dissolved in 1,4-dioxane (20 mL) and water (2 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (474 mg, 2.09 mmol) was added, and the reaction was stirred at room temperature for 1 hour.
- reaction solution was added with 25 mL of saturated sodium thiosulfate solution and 25 mL of saturated sodium bicarbonate solution, and extracted twice with 80 mL of ethyl acetate.
- Step 1 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.5g, 4.451mmol) and (S)-2-amino-3-hydroxyl Methyl 2-methylpropanoate hydrochloride (1.5g, 8.902mmol) was dissolved in N,N-dimethylacetamide (30mL), and N,N-diisopropylethylamine (7.64g, 59.15 g) was added. mmol) and the reaction was stirred at 95°C for 16 hours.
- Step 2 (S)-3-Hydroxy-2-methyl-2-(((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) methyl propionate (1.30g, 2.9947mmol) was dissolved in acetonitrile (40mL), silver oxide (10.41g, 44.92mmol) and methyl iodide (6.38g, 44.92mmol) were added successively, stirring at room temperature in the dark under nitrogen protection After 48 hours, the reaction was completed, celite was added for filtration, the filtrate was spin-dried under reduced pressure, and the crude product was purified with a flash silica gel column (ethyl acetate/petroleum ether: 0-50%) to obtain (S)-3-methoxy-2- Methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin
- Step 3 (S)-3-methoxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 -Methyl)amino)propionate (1.41 g, crude) was dissolved in acetic acid (40 mL) and iron powder (2.52 g, 44.99 mmol) was added. The temperature was gradually raised to 80°C and stirred for 1 hour.
- Step 4 (S)-2-(methoxymethyl)-2-methyl-7-(benzenesulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3',2 ':5,6]pyridin[3,4-b]pyrazin-3-one (1.05g, 2.7187mmol) was dissolved in 36mL methanol, 9mL tetrahydrofuran and 6mL water, sodium hydroxide (761.0mg, 19.03mmol) was added, The reaction was stirred at 65°C for 7 hours. 20 mL of water and 15 mL of saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 150 mL of ethyl acetate.
- Step 5 (S)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyridine[ 3,4-b]pyrazin-3-one (209 mg, crude) and 2-chlorobenzaldehyde (80 mg, 0.5181 mmol) were dissolved in methanol (10.0 mL), the reaction was cooled to 0 °C, potassium hydroxide (100 mg) was added , 1.785 mmol). The reaction was stirred at room temperature for 6 hours. The reaction solution was poured into 30 mL of saturated aqueous ammonium chloride solution, adjusted to pH 8, and extracted with 100 mL of ethyl acetate.
- Step 6 (2S)-9-(((2-chlorophenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro -3H-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin-3-one (80 mg, 0.2071 mmol) was dissolved in 10 mL of tetrahydrofuran, 2,3-dichloro-5 was added , 6-dicyano-1,4-benzoquinone (94 mg, 0.4142 mmol), the reaction was stirred at room temperature for 2 hours. The reaction solution was added with 60 mL of saturated sodium bicarbonate solution, and extracted with 80 mL of ethyl acetate.
- Step 1 2-Chloro-4-hydroxybenzaldehyde (500mg, 3.193mmol), bromocyclopentane (476mg, 3.193mmol) and potassium carbonate (883mg, 6.383mmol) were dissolved in N,N-dimethylformamide (15mL), the reaction was stirred at 90°C for 3 hours, LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, 30mL of ethyl acetate was added, 30mL of water was added to wash once, saturated brine (25mL ⁇ 3) was washed, organic The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2-chloro-4-(cyclopentyloxy)benzaldehyde (560 mg, 78% yield) as a pale yellow liquid.
- ES-API: [M+H] + 225.1
- Step 2 (S)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido [3,4-b]pyrazin-3-one (36.5 mg, 0.148 mmol) and 2-chloro-4-(cyclopentyloxy)benzaldehyde (83 mg, 0.371 mmol) were dissolved in methanol (6 mL) and the reaction The liquid was cooled to 0°C, and potassium hydroxide (58 mg, 1.036 mmol) was added. The reaction was stirred at room temperature for 24 hours.
- Step 3 (2S)-9-(((2-Chloro-4-(cyclopentyloxy)phenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1 ,2,4,7-tetrahydro-3H-pyrrolo[3',2':5,6]pyrido[3,4-b]pyrazin-3-one (70 mg, 0.149 mmol) was dissolved in 10 mL of tetrahydrofuran , 2,3-dichloro-5,6-dicyano-p-benzoquinone (78 mg, 0.346 mmol) was added, the reaction was stirred at room temperature for 2 hours, and 20 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution were added to the reaction solution.
Abstract
本发明公开了一种芳甲酰取代的三环化合物及其制法和用途。具体地，本发明的芳甲酰取代的三环化合物具有式(C)结构，其作为BTK抑制剂，具有活性高，选择性好且毒副作用低等优点。
Description
本申请要求申请日为2020年9月23日的中国专利申请2020110094513、申请日为2021年2月3日的中国专利申请2021101506608和申请日为2021年9月6日的中国专利申请202111038855X的优先权。本申请引用上述中国专利申请的全文。
本发明属于医药领域，具体涉及芳甲酰取代的三环化合物及其制法和用途。
布鲁顿酪氨酸激酶(BTK)是非受体酪氨酸激酶Tec家族的一个成员，是B细胞抗原受体(BCR)信号通路中的关键激酶。通过BCR发出的信号控制着一系列效应器反应，包括产生成熟抗体的细胞的激活、增殖和分化。异常的BCR介导的信号转导可引起错误调节的B细胞活化和/或病原性自身抗体的形成，从而导致多种人类疾病，包括癌症、自身免疫疾病和异种免疫性疾病。依鲁替尼(Ibrutinib，商品名Imbmvica)作为第一个进入市场的BTK抑制剂取得极大的成功。然而与许多其他抗癌药物一样，部分患者对药物表现出耐药性。研究发现，BTK激酶的C481S突变是导致耐药的主要原因，依鲁替尼是通过与BTK激酶的C481色氨酸残基的不可逆共价结合而发生药效作用的，C481S突变将色氨酸变成丝氨酸从而失去与依鲁替尼共价结合的能力。在上述背景下，本领域仍需要开发更多针对BTK的高效抑制剂。
发明内容
本发明提供了一种芳甲酰取代的三环化合物，其作为BTK抑制剂，具有活性高，选择性好且毒副作用低等优点。
一方面，本发明提供了式(C)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
式中，
R
1和R
2各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基、3至20元杂环基、C
1-6烷氧基和C
1-6烷硫基；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-
20环烷基、3至20元杂环基、羰基(C＝O)或者C＝S；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基、所述3至20元杂环基、所述C
1-6烷氧基和所述C
1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
n为0、1、2或3；
E为NR
5、O或N；其中，R
5为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
2-6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的1个或2个氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子上的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C
3-6单环环烷基和所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
当E为NR
5或O时，则与E连接的
表示单键；
当E为N时，则与E连接的
表示双键且R
2为无；
A为CR
6或N；其中，R
6为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
B为CR
7或N；其中，R
7为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
G
1为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C
6-14芳基、 所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
G
2为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
L为一根键、CR
8R
9、O、NH、NHC(O)、C
1-2亚烷基-NHC(O)或NHC(O)-C
1-2亚烷基-；其中，R
8和R
9各自独立地为H、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-SO
2C
1-3烷基或-C
1-4亚烷基-羧基；
i为0或1；
所述S1和S2组的基团各自独立地选自：氘、卤素、氰基、羟基、羧基、硝基、C
1-
6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、C
3-20环烷基(例如-C
3-6单环环烷基)、卤代C
3-20环烷基(例如-卤代C
3-6单环环烷基)、-O-C
3-
20环烷基(例如-O-C
3-6单环环烷基)、3至20元杂环基(例如3至6元单环杂环基)、-O-3至20元杂环基(例如-O-3至6元单环杂环基)、C
6-14芳基(例如苯基)、-O-C
6-14芳基(例如-O-苯基)、5或6元单环杂芳基、-O-5或6元单环杂芳基、8至10元双环杂芳基、-O-8至10元双环杂芳基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-20环烷基(例如-C
1-4亚烷基-C
3-6单环环烷基)、-C
1-4亚烷基-O-C
3-20环烷基(例如-C
1-4亚烷基-O-C
3-6单环环烷基)、-C
1-4亚烷基-3至20元杂环基(例如-C
1-4亚烷基-3至6元单环杂环基)、-C
1-4亚烷基-O-3至20元杂环基(例如-C
1-4亚烷基-O-3至6元单环杂环基)、-C
1-4亚烷基-C
6-14芳基(例如-C
1-4亚烷基-苯基)、-C
1-4亚烷基-O-C
6-14芳基(例如-C
1-4亚烷基-O-苯基)、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-O-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基、-C
1-4亚烷基-O-8至10元双环杂芳基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-NR
dC(O)R
c、-C
1-4亚烷基-NR
dC(O)NR
aR
b、-C
1-4亚烷基-SO
2R
c、-C
1-4亚烷基-NR
dSO
2R
c、-C
1-4亚烷基-SO
2NR
aR
b、-C
1-4亚烷基-NR
dSO
2NR
aR
b、-C
1-4亚烷基-羧基、-C(O)C
1-6烷基、-C(O)卤代C
1-
6烷基、-C(O)氘代C
1-6烷基、-C(O)C
3-20环烷基(例如-C(O)C
3-6单环环烷基)、-C(O)3至20元杂环基(例如-C(O)3至6元单环杂环基)、-C(O)C
6-14芳基(例如-C(O)苯基)、-C(O)5或6 元单环杂芳基、-C(O)8至10元双环杂芳基、-C(O)NR
aR
b、-NR
dC(O)R
c、-NR
dC(O)NR
aR
b、-SO
2R
c、-NR
dSO
2R
c、-SO
2NR
aR
b、-NR
dSO
2NR
aR
b、-NR
aR
b和-OR
c；所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C
3-20环烷基、所述3至20元杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
a和R
b各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-
14芳基、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基或C(O)C
1-
6烷基；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-
6烷氧基和氘代C
1-6烷氧基；或
上述各基团中，R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-
6烷氧基；
上述各基团中，R
c各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-14芳基、-C
1-4亚烷基-5或6元单环杂芳基或-C
1-4亚烷基-8至10元双环杂芳基；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-
6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
d各自独立地为H、C
1-6烷基或氘代C
1-6烷基；
“*”处标记的碳原子为手性碳原子(例如R构型、S构型或其混合)或非手性碳原子。
在一实施方案中，上述的式(C)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药里，某些基团具有如下定义，未提及的基团的定义如本发明任一方案所述(以下简称为“在一实施方案中”或“在一优选实施方案中”)。
在一实施方案中，所述式(C)化合物具有式(D)所示结构：
式中，A、B、R
1、R
3、R
4、L、G
1、G
2、n、i和“*”同本发明所定义。
在一实施方案中，所述式(C)化合物具有式(E)或式(F)所示结构：
式中，A、B、R
1、R
3、R
4、L、G
1、G
2、n和“*”同本发明所定义。
在一实施方案中，所述式(C)化合物具有式(II’)、式(B1’)、式(B2’)、式(C1)、式(C2)或式(C3)所示结构：
式中，A、B、R
1、R
3、R
4、R
5、L、G
1、G
2和“*”同本发明所定义。
在一实施方案中，所述式(C)化合物具有式(IIb’)、式(B1a’)、式(B2a’)、式(C1a)、式(C2a)或式(C3a)所示结构：
式中，R
1、R
3、R
4、R
5、G
1、G
2和“*”同本发明所定义。
在一实施方案中，所述式(C)化合物具有式(C1a-1)、式(C1a-2)、式(C2a-1)、式(C2a-2)、式(C3a-1)或式(C3a-2)所示结构：
式中，R
1、R
3、R
4、R
5、G
1、G
2同本发明所定义。
在一实施方案中，式C、式D、式E、式F、式C1、式C2、式C1a、式C2a、式C1a-1、式C1a-2、式C2a-1或式C2a-2中，R
1为C
1-6烷氧基(例如甲氧基)或C
1-6烷硫基(例如甲硫基或乙硫基)。
另一方面，本发明提供了式(A)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
式中，
R
1和R
2各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
n为0、1、2或3；
E为NR
5或O；其中，R
5为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
2-6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-
3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的1个或2个氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子上的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C
3-6单环环烷基和所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
A为CR
6或N；其中，R
6为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
B为CR
7或N；其中，R
7为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
G
1为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
G
2为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
L为一根键、CR
8R
9、O、NH、NHC(O)、C
1-2亚烷基-NHC(O)或NHC(O)-C
1-2烷基；其中，R
8、R
9各自独立地为H、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-
6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-SO
2C
1-3烷基或-C
1-4亚烷基-羧基；
i为0或1；
所述S1或S2组的基团各自独立地选自：氘、卤素、氰基、羟基、羧基、硝基、C
1-
6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、C
3-20环烷基(例如-C
3-6单环环烷基)、卤代C
3-20环烷基(例如-卤代C
3-6单环环烷基)、-O-C
3-
20环烷基(例如-O-C
3-6单环环烷基)、3至20元杂环基(例如3至6元单环杂环基)、-O-3至20元杂环基(例如-O-3至6元单环杂环基)、C
6-14芳基(例如苯基)、-O-C
6-14芳基(例如-O-苯基)、5或6元单环杂芳基、-O-5或6元单环杂芳基、8至10元双环杂芳基、-O-8至10元双环杂芳基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-20环烷基(例如-C
1-4亚烷基-C
3-6单环环烷基)、-C
1-4亚烷基-O-C
3-20环烷基(例如-C
1-4亚烷基-O-C
3-6单环环烷基)、-C
1-4亚烷基-3至20元杂环基(例如-C
1-4亚烷基-3至6元单环杂环基)、-C
1-4亚烷基-O-3至20元杂环基(例如-C
1-4亚烷基-O-3至6元单环杂环基)、-C
1-4亚烷基-C
6-14芳基(例如-C
1-4亚烷基-苯基)、-C
1-4亚烷基-O-C
6-14芳基(例如-C
1-4亚烷基-O-苯基)、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-O-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基、-C
1-4亚烷基-O-8至10元双环杂芳基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-NR
dC(O)R
c、-C
1-4亚烷基-NR
dC(O)NR
aR
b、-C
1-4亚烷基-SO
2R
c、-C
1-4亚烷基-NR
dSO
2R
c、-C
1-4亚烷基- SO
2NR
aR
b、-C
1-4亚烷基-NR
dSO
2NR
aR
b、-C
1-4亚烷基-羧基、-C(O)C
1-6烷基、-C(O)卤代C
1-
6烷基、-C(O)氘代C
1-6烷基、-C(O)C
3-20环烷基(例如-C(O)C
3-6单环环烷基)、-C(O)3至20元杂环基(例如-C(O)3至6元单环杂环基)、-C(O)C
6-14芳基(例如-C(O)苯基)、-C(O)5或6元单环杂芳基、-C(O)8至10元双环杂芳基、-C(O)NR
aR
b、-NR
dC(O)R
c、-NR
dC(O)NR
aR
b、-SO
2R
c、-NR
dSO
2R
c、-SO
2NR
aR
b、-NR
dSO
2NR
aR
b、-NR
aR
b和-OR
c；所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C
3-20环烷基、所述3至20元杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
a和R
b各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-
14芳基、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基或C(O)C
1-
6烷基；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-
6烷氧基和氘代C
1-6烷氧基；或
上述各基团中，R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-
6烷氧基；
上述各基团中，R
c各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-14芳基、-C
1-4亚烷基-5或6元单环杂芳基或-C
1-4亚烷基-8至10元双环杂 芳基；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-
6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
d各自独立地为H、C
1-6烷基或氘代C
1-6烷基。
本文中，所述3至20元杂环基具有1、2、3或4个选自N、O和S的杂原子作为环原子。
本文中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子。
本文中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子。
本文中，所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子。
本文中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子。
另一方面，本发明提供了式(B)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
R
1和R
2各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述3至20元杂环基具有1、2、3或4个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述3至20元杂环基具有1、2、3或4个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3 至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
n为0、1、2或3；
E为NR
5或O；其中，R
5为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
2-6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-
3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的1个或2个氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子上的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
A为CR
6或N；其中，R
6为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
B为CR
7或N；其中，R
7为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
G
1为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
所述S1或S2组的基团各自独立地选自：氘、卤素、氰基、羟基、羧基、硝基、C
1-
6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、C
3-20环烷基(例如-C
3-6单环环烷基)、卤代C
3-20环烷基(例如-卤代C
3-6单环环烷基)、-O-C
3-
20环烷基(例如-O-C
3-6单环环烷基)、3至20元杂环基(例如3至6元单环杂环基)、-O-3至20元杂环基(例如-O-3至6元单环杂环基)、C
6-14芳基(例如苯基)、-O-C
6-14芳基(例如-O-苯基)、5或6元单环杂芳基、-O-5或6元单环杂芳基、8至10元双环杂芳基、-O-8至10元双环杂芳基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚 烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-20环烷基(例如-C
1-4亚烷基-C
3-6单环环烷基)、-C
1-4亚烷基-O-C
3-20环烷基(例如-C
1-4亚烷基-O-C
3-6单环环烷基)、-C
1-4亚烷基-3至20元杂环基(例如-C
1-4亚烷基-3至6元单环杂环基)、-C
1-4亚烷基-O-3至20元杂环基(例如-C
1-4亚烷基-O-3至6元单环杂环基)、-C
1-4亚烷基-C
6-14芳基(例如-C
1-4亚烷基-苯基)、-C
1-4亚烷基-O-C
6-14芳基(例如-C
1-4亚烷基-O-苯基)、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-O-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基、-C
1-4亚烷基-O-8至10元双环杂芳基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-NHC(O)R
c、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-SO
2-卤代C
1-3烷基、-C
1-4亚烷基-SO
2-氘代C
1-3烷基、-C
1-
4亚烷基-SO
2C
6-14芳基、-C
1-4亚烷基-SO
2-5或6元单环杂芳基、-C
1-4亚烷基-SO
2-8至10元双环杂芳基、-C
1-4亚烷基-羧基、-C(O)C
1-6烷基、-C(O)卤代C
1-6烷基、-C(O)氘代C
1-6烷基、-C(O)C
3-20环烷基(例如-C(O)C
3-6单环环烷基)、-C(O)3至20元杂环基(例如-C(O)3至6元单环杂环基)、-C(O)C
6-14芳基(例如-C(O)苯基)、-C(O)5或6元单环杂芳基、-C(O)8至10元双环杂芳基、-C(O)NR
aR
b、-NHC(O)R
c、-NR
aR
b和-OR
c；所述3至20元杂环基具有1、2、3或4个选自N、O和S的杂原子作为环原子(例如所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子)；所述-C
1-4亚烷基-为未取代的，或者所述-C
1-4亚烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基和氘代C
1-6烷基的基团所取代，或者所述-C
1-4亚烷基-上同一个碳原子的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C
3-20环烷基、所述3至20元杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
a和R
b各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-
14芳基、-C
1-4亚烷基-5或6元单环杂芳基、-C
1-4亚烷基-8至10元双环杂芳基或C(O)C
1-
6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-
6烷氧基和氘代C
1-6烷氧基；或
上述各基团中，R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
c为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基、C
6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C
1-4亚烷基-C
6-14芳基、-C
1-4亚烷基-5或6元单环杂芳基或-C
1-4亚烷基-8至10元双环杂芳基；所述C
3-6单环环烷基、所述3至6元单环杂环基、所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基。
在一实施方案中，所述式(B)化合物具有式B1所示结构：
各式中，A、B、R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，所述式(B)化合物具有式B1a所示结构：
各式中，R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，所述式(B)化合物具有式B1a-1或式B1a-2所示结构：
各式中，R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
5为H、C
1-6烷基、C
2-
6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基、3至6元单环杂环基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基；R
a和R
b各自定义同式(B)中定义。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
5为H、C
1-4烷基、C
2-
4烯基、C
2-4炔基、-C
1-2亚烷基-羟基、-C
1-2亚烷基-氰基、-C
1-2亚烷基-C
1-4烷氧基、-C
1-2亚烷基-卤代C
1-4基、-C
1-2亚烷基-氘代C
1-4烷基、-C
1-2亚烷基-卤代C
1-4烷氧基、-C
1-2亚烷基-氘代C
1-4烷氧基、-C
1-2亚烷基-C
3-6单环环烷基、-C
1-2亚烷基-3至6元单环杂环基、-C
1-2亚烷基-NR
aR
b、-C
1-2亚烷基-C(O)NR
aR
b、-C
1-2亚烷基-C(O)OC
1-4烷基、-C
1-2亚烷基-SO
2C
1-3烷基、-C
1-2亚烷基-羧基、3至6元单环杂环基或C
3-6单环环烷基；其中，所述“-C
1-2亚烷基-”上的1个或2个氢原子可任选地被C
1-4烷基取代，或者所述“-C
1-2亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-4烷基、卤代C
1-4烷基和氘代C
1-4烷基；R
a和R
b各自定义同式(B)中定义。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-6单环环烷基和所述3至6元单环杂环基各 自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4各自独立地选自：C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4各自独立地选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：卤素、羟基、-C
1-3烷氧基、-氘代C
1-3烷氧基、-卤代C
1-3烷氧基、-C
3-6单环环烷基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-3烷基、氘代C
1-3烷基或环丙基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3选自：C
1-6烷基和C
3-
6单环环烷基；所述C
1-6烷基为未取代的或被氘或卤素取代；R
4选自：C
1-6烷基；所述C
1-
6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；所述S1组的基团选自：羟基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基或C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3为甲基、三氟甲基、乙基、正丙基或环丙基；R
4为甲基或乙基；所述甲基和所述乙基为未取代的或被1个选自S1组的基团取代；所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、-O-环丙基、-O-环丁基、-N(CH
3)
2、-N(CH
2CH
3)
2、-N(CH
2CH
3)(CH
3)、-N(CH
2CH
2CH
3)(CH
3)和-N(CH
2CH
2CH
3)(CH
2CH
3)。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3为甲基或乙基；R
4为 甲基或乙基；所述甲基和所述乙基为未取代的或被1个选自S1组的基团取代；所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、-O-环丙基、-O-环丁基、-N(CH
3)
2、-N(CH
2CH
3)
2、-N(CH
2CH
3)(CH
3)、-N(CH
2CH
2CH
3)(CH
3)和-N(CH
2CH
2CH
3)(CH
2CH
3)；R
5为H。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3为甲基且所述甲基为未取代的或被氘或卤素取代；R
4为甲基且所述甲基为未取代的或被甲氧基、氘代甲氧基、卤代甲氧基、乙氧基、氘代乙氧基或卤代乙氧基取代；R
5为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基、-氘代C
3-6单环环烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基、3至6元单环杂环基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-
4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(B)中定义。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4各自独立地为甲基；所述甲基各自独立地为未取代的或被氘、卤素、羟基、甲氧基、氘代甲氧基、卤代甲氧基、乙氧基、氘代乙氧基或卤代乙氧基取代。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B1、式B1a、式B1a-1或式B1a-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：氰基、羟基、甲基、乙基、丙基、卤代甲基、甲氧基、乙氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2。
在一实施方案中，所述式(B)化合物具有式B2所示结构：
各式中，A、B、R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，所述式(B)化合物具有式B2a所示结构：
各式中，R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，所述化合物式(B)具有式B2a-1或式B2a-2所示结构：
各式中，R
3、R
4、R
5、G
1同式B中各基团的定义。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-6单环环烷基和所述3至6元单环杂环基各 自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4各自独立地选自：C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4各自独立地选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：卤素、羟基、-C
1-3烷氧基、-氘代C
1-3烷氧基、-卤代C
1-3烷氧基、-C
3-6单环环烷基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-3烷基、氘代C
1-3烷基或环丙基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4各自独立地为甲基；所述甲基各自独立地为未取代的或被氘、卤素、羟基、甲氧基、氘代甲氧基、卤代甲氧基、乙氧基、氘代乙氧基或卤代乙氧基取代。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式B2、式B2a、式B2a-1或式B2a-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四 氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：氰基、羟基、甲基、乙基、丙基、卤代甲基、甲氧基、乙氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2。
另一方面，本发明提供了式(I)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
R
1和R
2各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-20环烷基和3至20元杂环基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基、3至20元杂环基或者羰基(C＝O)；所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
n为0、1、2或3；
E为NR
5或O；其中，R
5为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
2-6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-
3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所 取代：C
1-6烷基；
A为CR
6或N；其中，R
6为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
B为CR
7或N；其中，R
7为H、卤素、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基或-C
3-6环烷基；
G
1为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
G
2为C
6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C
6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；
L为一根键、CR
8R
9、O、NH、NHC(O)、C
1-2亚烷基-NHC(O)或NHC(O)-C
1-2亚烷基；其中，R
8、R
9各自独立地为H、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-
6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-SO
2C
1-3烷基或-C
1-4亚烷基-羧基；
所述S1或S2组的基团各自独立地选自：氘、卤素、氰基、羟基、羧基、硝基、C
1-
6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基、-O-C
3-6单环环烷基、3至6元单环杂环基、-C
1-
4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基、-C(O)C
1-6烷基、-C(O)C
3-6单环环烷基、-C(O)NR
aR
b、-NHC(O)R
c和-NR
aR
b；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；
上述各基团中，R
a和R
b各自独立地为H、C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基或 C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或
上述各基团中，R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；
上述各基团中，R
c为氢、C
1-6烷基或卤代C
1-6烷基。
在一实施方案中，所述式(I)化合物具有式II所示结构：
式中，A、B、R
3、R
4、R
5、L、G
1、G
2定义同式(I)中各基团的定义。
在一实施方案中，所述式(I)化合物具有式IIa所示结构：
式中，R
3、R
4、R
5、L、G
1、G
2定义同式(I)中各基团的定义。
在一实施方案中，所述式(I)化合物具有式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj或式IIk所示结构：
各式中，R
3、R
4、R
5、R
7、R
8、G
1、G
2定义同式(I)中各基团的定义；m各自独立地为1或2。
在一实施方案中，所述式(I)化合物具有式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2所示结构：
各式中，R
3、R
4、R
5、R
7、R
8、G
1、G
2定义同式(I)中各基团的定义；m各自独立地为1或2。
在一实施方案中，式IIk中，R
7、R
8各自独立地选自：H。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4各自独立地选自：甲基、乙基、正丙基、正丁基、正戊基；所述甲基、所述乙基、所述正丙基、所述正丁基、所述正戊基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
5为H、C
1-4烷基、卤代C
1-4烷基、氘代C
1-6烷 基、C
2-4烯基、C
2-4炔基、-C
1-2亚烷基-羟基、-C
1-2亚烷基-氰基、-C
1-2亚烷基-C
1-2烷氧基、-C
1-2亚烷基-卤代C
1-2烷基、-C
1-2亚烷基-氘代C
1-2烷基、-C
1-2亚烷基-卤代C
1-2烷氧基、-C
1-2亚烷基-氘代C
1-2烷氧基、-C
1-2亚烷基-C
3-6单环环烷基、-C
1-2亚烷基-3至6元单环杂环基、-C
1-2亚烷基-NR
aR
b、-C
1-2亚烷基-C(O)NR
aR
b、-C
1-2亚烷基-C(O)OC
1-4烷基、-C
1-2亚烷基-SO
2C
1-3烷基、-C
1-2亚烷基-羧基、3至6元单环杂环基或C
3-6单环环烷基；其中，所述-C
1-2亚烷基-为未取代的，或者-C
1-2亚烷基-上的1个或2个氢原子各自独立地被选自卤素、氰基、羟基、-C
1-2烷基、-卤代C
1-2烷基和-氘代C
1-2烷基的基团所取代，或者所述-C
1-2亚烷基-上同一个碳原子上的两个氢原子同时被-(CH
2)
j-取代进而形成环烷基，其中j为2或3；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-4烷基、-卤代C
1-4烷基、-氘代C
1-4烷基、-C
1-4烷氧基、-卤代C
1-4烷氧基和-氘代C
1-4烷氧基。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4各自独立地选自：H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
2-6烯基、所述C
2-6炔基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
5为H、C
1-6烷基、C
2-6烯基、C
2-6炔基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-
4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、 式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4各自独立地选自：C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4各自独立地选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：羟基、-C
1-3烷氧基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-3烷基、氘代C
1-3烷基或环丙基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定 义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3选自：C
1-6烷基和C
3-6单环环烷基；所述C
1-6烷基为未取代的或被卤素取代；R
4选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；所述S1组的基团选自：羟基、C
1-6烷氧基、卤代C
1-
6烷氧基、氘代C
1-6烷氧基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基和C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3为甲基、三氟甲基、乙基、正丙基或环丙基；R
4为甲基或乙基；所述甲基和所述乙基为未取代的或被1个选自S1组的基团取代；所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、三氟甲氧基、氘代甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、-O-环丙基、-O-环丁基、-N(CH
3)
2、-N(CH
2CH
3)
2、- N(CH
2CH
3)(CH
3)、-N(CH
2CH
2CH
3)(CH
3)和-N(CH
2CH
2CH
3)(CH
2CH
3)；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、 哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：氰基、羟基、甲基、乙基、丙基、卤代甲基、甲氧基、乙氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2；
R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定 义。
在一实施方案中，式II、式IIa、式IIb、式IIc、式IId、式IIe、式IIf、式IIg、式IIh、式IIi、式IIj、式IIk、式IIb-1、式IIc-1、式IId-1、式IIe-1、式IIf-1、式IIg-1、式IIh-1、式IIi-1、式IIj-1、式IIk-1、式IIb-2、式IIc-2、式IId-2、式IIe-2、式IIf-2、式IIg-2、式IIh-2、式IIi-2、式IIj-2或式IIk-2中，R
3和R
4各自独立地为甲基；所述甲基各自独立地为未取代的或被氘、卤素、羟基、甲氧基、氘代甲氧基、卤代甲氧基、乙氧基、氘代乙氧基或卤代乙氧基取代；R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，所述式(I)化合物具有式IIb’、式IIc’、式IId’、式IIe’、式IIf’、式IIg’、式IIh’、式IIi’、式IIj’或式IIk’所示结构：
各式中，R
5、R
7、R
8、G
1、G
2定义同式(I)中各基团的定义；m各自独立地为1或2；
为C
3-20环烷基或3至20元杂环基；所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式IIk’中，R
7和R
8各自独立地选自：H。
在一实施方案中，式IIb’、式IIc’、式IId’、式IIe’、式IIf’、式IIg’、式IIh’、式IIi’、式IIj’或式IIk’中，
为C
3-6单环环烷基或3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式IIb’、式IIc’、式IId’、式IIe’、式IIf’、式IIg’、式IIh’、式IIi’、式IIj’或式IIk’中，
为环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃或哌啶；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基- C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，式IIb’、式IIc’、式IId’、式IIe’、式IIf’、式IIg’、式IIh’、式IIi’、式IIj’或式IIk’中，
为环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃或哌啶；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：氰基、羟基、甲基、乙基、丙基、卤代甲基、甲氧基、乙氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2；R
5为H、C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基、-C
1-4亚烷基-NR
aR
b、-C
1-4亚烷基-C(O)NR
aR
b、-C
1-4亚烷基-C(O)OC
1-6烷基、-C
1-4亚烷基-SO
2C
1-3烷基、-C
1-4亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-4亚烷基-”上的1个或2个氢原子可任选地被C
1-6烷基取代，或者所述“-C
1-4亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，所述式(I)化合物具有式III所示结构：
式中，A、B、R
3、R
4、L、G
1、G
2定义同式(I)中各基团的定义。
在一实施方案中，所述式(I)化合物具有式IIIa所示结构：
式中，R
3、R
4、L、G
1、G
2定义同式(I)中各基团的定义。
在一实施方案中，所述式(I)化合物具有式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj或式IIIk所示结构：
各式中，R
3、R
4、R
7、R
8、G
1、G
2定义同式(I)中各基团的定义；m各自独立地为1或2。
在一实施方案中，所述式(I)化合物具有式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2所示结构：
各式中，R
3、R
4、R
7、R
8、G
1、G
2定义同式(I)中各基团的定义；m各自独立地为1或2。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式 IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4各自独立地选自：H、C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4各自独立地选自：C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4各自独立地选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：羟基、-C
1-3烷氧基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-3烷基、氘代C
1-3烷基或环丙基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；其中，所述S1组的基团选自：氰基、羟基、甲基、乙基、丙基、卤代甲基、甲氧基、乙氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2。
在一实施方案中，式III、式IIIa、式IIIb、式IIIc、式IIId、式IIIe、式IIIf、式IIIg、式IIIh、式IIIi、式IIIj、式IIIk、式IIIb-1、式IIIc-1、式IIId-1、式IIIe-1、式IIIf-1、式IIIg-1、式IIIh-1、式IIIi-1、式IIIj-1、式IIIk-1、式IIIb-2、式IIIc-2、式IIId-2、式IIIe-2、式IIIf-2、式IIIg-2、式IIIh-2、式IIIi-2、式IIIj-2或式IIIk-2中，R
3和R
4各自独立地为甲基；所述甲基各自独立地为未取代的或被氘、卤素、羟基、甲氧基、氘代甲氧基、卤代甲氧基、乙氧基、氘代乙氧基或卤代乙氧基取代。
在一实施方案中，G
1和G
2均为未取代的。
在一实施方案中，G
1为未取代的、G
2为取代的；取代基如上所述。
在一实施方案中，G
1为取代的；取代基如上所述；G
2为未取代的。
在一实施方案中，G
1和G
2均为取代的；取代基如上所述。
在一优选实施方案中，R
a和R
b各自独立地为C
1-6烷基，例如C
1-4烷基，又例如甲基。
在一优选实施方案中，R
c为-C
1-4亚烷基-C
1-6烷氧基(例如-C
1-2亚烷基-C
1-3烷氧基，又例如-CH
2CH
2OCH
3或-CH
2CH
2OCH
2CH
3)或被1或2个卤素取代的3至6元单环杂环基(例如所述被1或2个卤素取代的3至6元单环杂环基中的卤素为氟、氯或溴；例如所述被1或2个卤素取代的3至6元单环杂环基中的3至6元单环杂环基为环丙基)。
在一实施方案中，所述S1组的基团选自：氘、卤素、氰基、羟基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基、-O-C
3-6单环环烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C(O)C
1-6烷基、-C(O)C
3-6单环环烷基、-C(O)NR
aR
b、-NHC(O)R
c和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基或C(O)C
1-
6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
c为氢、C
1-6烷基或卤代C
1-6烷基。
在一实施方案中，所述S1组的基团选自：氘、卤素、氰基、羟基、-C
1-3烷基、-卤代C
1-3烷基、-氘代C
1-3烷基、-C
1-3烷氧基、-卤代C
1-3烷氧基、-氘代C
1-3烷氧基、-环丙基、-卤代环丙基、-O-环丙基、-C
1-2亚烷基-羟基、-C
1-2亚烷基-氰基、-C
1-2亚烷基-C
1-3烷氧基、-C(O)C
1-3烷基、-C(O)环丙基、-C(O)NR
aR
b、-NHC(O)R
c和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-3烷基、氘代C
1-3烷基或环丙基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；R
c为氢、C
1-3烷基或卤代C
1-3烷基。
在一实施方案中，所述S1组的基团选自：氘、卤素、氰基、羟基、甲基、乙基、丙基、卤代甲基、氘代甲基、甲氧基、乙氧基、卤代甲氧基、氘代甲氧基、-C(O)CH
3、-C(O)环丙基、-C(O)NH
2、-C(O)N(CH
3)
2、-CH
2OH、-CH
2CH
2OH、-CH
2OCH
3、-CH
2CH
2OCH
3、-CH
2N(CH
3)
2、-CH
2CH
2N(CH
3)
2、-NHC(O)CH
3和-N(CH
3)
2。
在一实施方案中，所述S1组的基团选自：氘、卤素、氰基、羟基、C
1-6烷基(例如C
1-
3烷基)、C
1-6烷氧基(例如C
1-3烷基)、卤代C
1-6烷氧基(例如卤代C
1-3烷基，又例如二氟甲氧基或三氟甲氧基)、氘代C
1-6烷氧基(例如氘代C
1-3烷基)、-C
1-4亚烷基-羟基(例如-C
1-
2亚烷基-羟基)、-C(O)C
1-6烷基(例如-C(O)C
1-3烷基)、-C(O)C
3-20环烷基(例如-C(O)C
3-6单 环环烷基)、3至20元杂环基(例如3至6元单环杂环基，其中所述3至6元单环杂环基具有1或2个选自N和O的杂原子作为环原子)、-O-C
3-6单环环烷基、-NR
aR
b和-OR
c(例如-O-C
1-4亚烷基-C
1-6烷氧基)，其中，所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子。
在一实施方案中，所述S1组的基团选自：氘、氟、氰基、羟基、甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氘代甲氧基(-OCD
3)、-CH
2OH、-C(O)CH
3、-C(O)-环丙基、吗啉基
-O-环丙基、-N(CH
3)
2、-OCH
2CH
2OCH
3和-CH
2CH
2OCH
2CH
3。
在一实施方案中，所述S2组的基团选自：氟、氯、-C
1-3烷基、-卤代C
1-3烷基和-C
3-
6单环环烷基。
在一实施方案中，所述S2组的基团选自：氟、氯、甲基、三氟甲基和环丙基。
在一实施方案中，所述S2组的基团选自：卤素、氰基、-C
1-6烷基(例如-C
1-3烷基)、卤代C
1-6烷基(例如卤代C
1-3烷基)、氘代C
1-6烷基(例如氘代C
1-3烷基，又例如氘代甲基)、C
1-6烷氧基(例如C
1-3烷氧基)、卤代C
1-6烷氧基(例如卤代C
1-3烷氧基)、氘代C
1-6烷氧基(例如氘代C
1-3烷氧基)、C
3-20环烷基(例如C
3-6单环环烷基)、卤代C
3-20环烷基(例如卤代C
3-6单环环烷基，又例如卤代环丙基)、-O-C
3-20环烷基(例如-OC
3-6单环环烷基)、-NR
aR
b和-OR
c。
在一实施方案中，所述S2组的基团选自：氟、氯、溴、碘、氰基、甲基、异丙基、三氟甲基、甲氧基、三氟甲氧基、氘代甲氧基、环丙基、-O-环丙基、-O-环戊基、-N(CH
3)
2和-OCH
2CH
2OCH
3。
在一实施方案中，R
1和R
2各自独立地选自：H、C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
1和R
2各自独立地选自：H、甲基、乙基、正丙基、异丙基、环丙基和环丁基；或者R
1和R
2与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述甲基、所述乙基、所述正丙基、所述异丙基、所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
1和R
2各自独立地为H。
在一实施方案中，R
1和R
2与同它们相连的碳原子共同构成羰基(C＝O)。
在一实施方案中，R
1和R
2各自独立地选自：H、C
1-6烷基(例如甲基、乙基、正丙基、异丙基、环丙基、环丁基)、C
3-6单环环烷基(例如环丙基、环丁基)、3至6元单环杂环基、C
1-6烷氧基(例如甲氧基)和C
1-6烷硫基(例如甲硫基、乙硫基)；或者R
1和R
2与同它们相连的碳原子共同构成：C
3-6单环环烷基(例如环丙基、环丁基、环戊基、环己基)、3至6元单环杂环基(例如氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶)、羰基(C＝O)或者C＝S；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基、所述3至6元单环杂环基、C
1-6烷氧基、C
1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
1和R
2各自独立地选自：H、C
1-6烷氧基(例如C
1-3烷氧基，又例如甲氧基)和C
1-6烷硫基(例如C
1-3烷硫基，又例如甲硫基、乙硫基)；或者R
1和R
2与同它们相连的碳原子共同构成：羰基(C＝O)或者C＝S，所述C
1-6烷氧基和所述C
1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
1和R
2各自独立地选自：甲氧基、甲硫基和乙硫基。
在一实施方案中，R
1和R
2与同它们相连的碳原子共同构成羰基(C＝O)或者C＝S。
在一实施方案中，R
1和R
2与同它们相连的碳原子共同构成C＝S。
在一实施方案中，R
3和R
4各自独立地选自：H、C
1-6烷基、C
3-6单环环烷基和3至6元单环杂环基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-6单环环烷基、3至6元单环杂环基或者羰基(C＝O)；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
3和R
4各自独立地选自：H、甲基、乙基、正丙基、异丙基、环丙基和环丁基；或者R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述甲基、所述乙基、所述正丙基、所述异丙基、所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
3和R
4各自独立地选自：甲基、乙基、正丙基、异丙基、环丙基和环丁基；所述甲基、所述乙基、所述正丙基、所述异丙基、所述环丙基和所述环丁基各 自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
3和R
4各自独立地选自：C
1-6烷基(例如C
1-3烷基，又例如甲基或乙基)和C
3-20环烷基(例如C
3-6单环环烷基，又例如环丙基)；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基(例如C
3-6单环环烷基，又例如环丙基、环戊基、环己基)或3至20元杂环基，所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子(例如3至6元单环杂环基，其中所述3至6元单环杂环基具有1或2个选自N和O的杂原子作为环原子，又例如氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃或哌啶)；所述C
1-6烷基、所述C
3-6单环环烷基和所述3至6元单环杂环各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。在一优选实施方案中，所述S1组的基团选自：氘、卤素(例如F)、氰基、羟基、C
1-6烷基(例如甲基)、C
1-6烷氧基(例如甲氧基、乙氧基)、氘代C
1-6烷氧基(例如氘代甲氧基)、-C
1-4亚烷基-羟基(例如-CH
2OH)、-C(O)C
1-6烷基(例如-C(O)CH
3)、-C(O)C
3-20环烷基(例如-C(O)-环丙基)、3至20元杂环基(例如吗啉基
)、-O-C
3-6单环环烷基(例如-O-环丙基)、-NR
aR
b(例如-N(CH
3)
2)和-OR
c(例如-OC
1-4亚烷基-C
1-6烷氧基，又例如-CH
2OCH
2CH
2OCH
3)。
在一实施方案中，R
3和R
4各自独立选自：-CH
3、-CH
2CH
3、环丙基、三氟甲基、氘代甲基、-CH
2OH、-CH
2OCH
3、-CH
2OCF
3、-CH
2OCHF
2、-CH
2OCD
3、-CH
2OCH
2CH
3、-CH
2OCH
2CH
2OCH
3、-CH
2CH
2OCH
2CH
3、-CH
2O-环丙基、-CH
2N(CH
3)
2、-CH(OH)CH
3和-CH
2CH
3OCH
3。
在一实施方案中，R
3选自：C
1-6烷基和C
3-6单环环烷基；所述C
1-6烷基和所述C
3-6单环环烷基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。
在一实施方案中，R
3选自：C
1-6烷基和C
3-6单环环烷基；所述C
1-6烷基和所述C
3-6单环环烷基为未取代的或被卤素取代。
在一实施方案中，R
3选自：甲基、三氟甲基、乙基、正丙基和环丙基。
在一实施方案中，R
3选自：C
1-6烷基(例如甲基或乙基)和C
3-6单环环烷基(例如环丙基)；所述C
1-6烷基和所述C
3-6单环环烷基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。在一优选实施方案中，所述S1组的基团选自：氘和卤素(例如F)。在一实施方案中，R
3选自：-CH
3、-CH
2CH
3、三氟甲基、氘代甲基和环丙基。
在一实施方案中，R
4选自：C
1-6烷基；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；所述S1组的基团选自：羟基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-O-C
3-6单环环烷基和-NR
aR
b；其中，R
a和R
b各自独立地为H、C
1-
6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、 -C
1-4亚烷基-3至6元单环杂环基或C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基。
在一实施方案中，R
4选自：甲基和乙基；所述甲基和所述乙基各自独立地为未取代的或被1个选自S1组的基团取代；所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、三氟甲氧基、乙氧基、氘代乙氧基、卤代乙氧基、正丙氧基、异丙氧基、正丁氧基、-O-环丙基、-O-环丁基、-N(CH
3)
2、-N(CH
2CH
3)
2、-N(CH
2CH
3)(CH
3)、-N(CH
2CH
2CH
3)(CH
3)和-N(CH
2CH
2CH
3)(CH
2CH
3)。
在一实施方案中，R
4选自：C
1-6烷基(例如甲基、乙基)；所述C
1-6烷基为未取代的或被1、2、3或4个独立选自S1组的基团取代；所述S1组的基团选自：羟基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-O-C
3-6单环环烷基、-NR
aR
b和-OR
c(例如-OC
1-4亚烷基-C
1-6烷氧基)；其中，R
a和R
b各自独立地为H、C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基或C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；或R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基。
在一实施方案中，R
4选自：甲基和乙基；所述甲基和所述乙基为未取代的或被1个选自S1组的基团取代；所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、氘代乙氧基、卤代乙氧基、正丙氧基、异丙氧基、正丁氧基、-OCH
2CH
2OCH
3、-OCH
2CH
2OCH
2CH
3、-O-环丙基、-O-环丁基、-N(CH
3)
2、-N(CH
2CH
3)
2、-N(CH
2CH
3)(CH
3)、-N(CH
2CH
2CH
3)(CH
3)和-N(CH
2CH
2CH
3)(CH
2CH
3)。在一优选实施方案中，所述S1组的基团选自：羟基、甲氧基、氘代甲氧基、乙氧基、-OCH
2CH
2OCH
3、-O-环丙基和-N(CH
3)
2。在一实施方案中，R
4选自：-CH
3、-CH
2OH、-CH
2OCH
3、-CH
2OCF
3、-CH
2OCHF
2、-CH
2OCF
3、-CH
2OCHF
2、-CH
2OCD
3、-CH
2OCH
2CH
3、-CH
2OCH
2CH
2OCH
3、-CH
2CH
2OCH
2CH
3、-CH
2O-环丙基、-CH
2N(CH
3)
2、-CH(OH)CH
3和-CH
2CH
3OCH
3。
在一实施方案中，R
3和R
4与同它们相连的碳原子共同构成：环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃、哌啶或者羰基(C＝O)；所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基、所述氮杂环丁基、所述四氢吡咯、所述四氢呋喃、所述四氢吡喃和所述哌啶各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代。在一优选实施方案中，所述S1组的基团选自：氰基、羟基、C
1-6烷基(例如甲基)、C
1-6烷氧基(例如甲氧基)、-C
1-4亚烷基-羟基(例如-CH
2OH)、-C(O)C
1-6烷基(例如-C(O)CH
3)、-C(O)C
3-20环烷基(例如-C(O)-环丙基)和3至20元杂环基(例如吗啉基
)。
在一实施方案中，R
3和R
4与同它们相连的碳原子共同构成：
例如
所述环丙基、所述环丁基、所述环戊基、所述环己基、所述氧杂环丁基(例如
)、所述氮杂环丁基(例如
)、所述四氢吡咯(例如
)、所述四氢呋喃(例如
)、所述四氢吡喃(例如
)、所述哌啶(例如
)通过任何一个环原子与分子的其余部分螺接。
在一实施方案中，R
5为H、C
1-3烷基、-C
1-2亚烷基-羟基、-C
1-2亚烷基-氰基、-C
1-2亚烷基-C
1-3烷氧基、-C
1-2亚烷基-卤代C
1-3烷基、-C
1-2亚烷基-卤代C
1-3烷氧基、-C
1-2亚烷基-C
3-6单环环烷基、-C
1-2亚烷基-3至6元单环杂环基、-C
1-2亚烷基-NR
aR
b、-C
1-2亚烷基-C(O)NR
aR
b、-C
1-2亚烷基-C(O)OC
1-3烷基、-C
1-2亚烷基-SO
2C
1-3烷基、-C
1-2亚烷基-羧基或C
3-6单环环烷基；其中，所述“-C
1-2亚烷基-”上的1个或2个氢原子可任选地被C
1-3烷基取代或者所述“-C
1-2亚烷基-”上同一个碳上的2个氢原子同时被-CH
2CH
2-取代形成环烷基；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：C
1-6烷基；R
a和R
b各 自定义同式(I)中定义。
在一实施方案中，R
5为H、C
1-6烷基、-C
1-4亚烷基-NR
aR
b或C
3-6单环环烷基；R
a和R
b各自定义同式(I)中定义。
在一实施方案中，R
5为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基或-CH
2CH
2N(CH
3)
2。
在一实施方案中，R
5为H、C
1-6烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基，又例如甲基、乙基)、氘代C
1-6烷基(例如氘代C
1-3烷基，又例如氘代甲基)、-C
1-
4亚烷基-羟基(例如-C
1-2亚烷基-羟基，又例如-CH
2CH
2OH)、-C
1-4亚烷基-C
1-6烷氧基(例如-C
1-2亚烷基-C
1-3烷氧基，又例如-CH
2CH
2OCH
3)或-C
1-4亚烷基-NR
aR
b(例如-C
1-2亚烷基-NR
aR
b，又例如-CH
2CH
2N(CH
3)
2)。
在一实施方案中，L为一根键。
在一实施方案中，L为CR
8R
9；其中，R
8、R
9各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-氰基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-卤代C
1-6烷氧基。
在一实施方案中，L为CH
2。
在一实施方案中，L为O。
在一实施方案中，L为NH。
在一实施方案中，L为NHC(O)。
在一实施方案中，L为CH
2NHC(O)。
在一实施方案中，L为NHC(O)CH
2。
在一实施方案中，n为0或1。
在一实施方案中，E为NR
5。
在一实施方案中，E为O。
在一实施方案中，E为N。
在一实施方案中，A为CR
6；其中，R
6为H。
在一实施方案中，A为N。
在一实施方案中，B为N。
在一实施方案中，B为CR
7；其中，R
7为H。
在一实施方案中，G
1为苯基、吡啶基、嘧啶基、呋喃基、吡咯基、噻唑基或吡唑基；所述苯基、所述吡啶基、所述嘧啶基、所述呋喃基、所述吡咯基、所述噻唑基或所述吡唑 基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
1为苯基或吡啶基；所述苯基或所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
1为苯基或吡啶基；所述苯基或所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；其中，所述S2组的基团选自：氟、氯、-C
1-3烷基、-卤代C
1-3烷基、-C
3-6单环环烷基。
在一实施方案中，G
1为C
6-14芳基或5或6元单环杂芳基；所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子，且所述C
6-14芳基和所述5或6元单环杂芳基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
1为苯基或吡啶基；所述苯基和所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；其中，所述S2组的基团选自下组：氟、氯、溴、氰基、-C
1-3烷基、-卤代C
1-3烷基、-氘代C
1-3烷基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基、-O-C
3-6单环环烷基、-O-卤代C
3-6单环环烷基。
在一实施方案中，G
1为苯基、吡啶基、嘧啶基、呋喃基、吡咯基、噻唑基、吡唑基或噻吩基；所述苯基、所述吡啶基、所述嘧啶基、所述呋喃基、所述吡咯基、所述噻唑基、所述吡唑基和所述噻吩基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
1为苯基、吡啶基、呋喃基或噻吩基；所述苯基、所述吡啶基、所述呋喃基和所述噻吩基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
1中，所述S2组的基团选自：卤素、氰基、-C
1-6烷基、卤代C
1-
6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-20环烷基、-O-C
3-20环烷基、-NR
aR
b和-OR
c；例如氟、氯、溴、碘、氰基、甲基、异丙基、三氟甲基、甲氧基、三氟甲氧基、环丙基、-O-环丙基、-O-环戊基、-N(CH
3)
2和-OCH
2CH
2OCH
3。
在一实施方案中，G
1为苯基、2-氯苯基、2-氟苯基、2-三氟甲基苯基、2-氯-6-氟苯基、2-氯-3,4-二氟苯基、2-氯-3-氟-4-甲氧基苯基、2-氯-4-环戊氧基苯基、2-氯-4-(2-甲氧基乙基)苯基、2-氯-4-二甲氨基苯基、2-氯-4-环丙氧基苯基、2-氯-4-甲氧基苯基、2-氯-4-异丙基苯基、2-氯-4-环丙基苯基、2-氯-4-甲基苯基、2-氯呋喃基、呋喃基、噻吩基、2-溴噻吩基、2-氯噻吩基、吡啶基、3-氯吡啶基、2-甲基苯基、2-氯-4氰基苯基、2-氯-4氟苯基、2-碘苯基、2-氯-5-氟苯基、2-氯-3氟苯基、2-氯-三氟甲氧基苯基、2-氯-4溴苯基或2,4-二氯苯基。
在一实施方案中，G
2为C
6-14芳基或5或6元单环杂芳基；所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子，且所述C
6-14芳基和所述5或6元单环杂芳基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
2为苯基、吡啶基、嘧啶基、呋喃基、吡咯基、噻唑基或吡唑基；所述苯基、所述吡啶基、所述嘧啶基、所述呋喃基、所述吡咯基、所述噻唑基或所述吡唑基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
2为苯基、吡啶基或吡唑基；所述苯基、所述吡啶基和所述吡唑基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
2为苯基或吡啶基；所述苯基或所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一实施方案中，G
2为苯基或吡啶基；所述苯基或所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；其中，所述S2组的基团选自：氟、氯、-C
1-3烷基、-卤代C
1-3烷基、-C
3-6单环环烷基。
在一实施方案中，G
2为苯基或吡啶基；所述苯基或所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；其中，所述S2组的基团选自下组：氟、氯、溴、氰基、-C
1-3烷基、-C
1-3烷氧基、-卤代C
1-3烷基、-氘代C
1-3烷基、-卤代C
1-
3烷氧基、-氘代C
1-3烷氧基、-C
3-6单环环烷基、-O-C
3-6单环环烷基、-卤代C
3-6单环环烷基和-O-卤代C
3-6单环环烷基。
在一实施方案中，G
2中，所述S2组的基团选自：卤素、氰基、-C
1-6烷基、卤代C
1-
6烷基、C
1-6烷氧基、氘代C
1-6烷氧基和C
3-20环烷基，例如氟、氯、氰基、甲基、三氟甲基、甲氧基、氘代甲氧基和环丙基。
在一实施方案中，G
2为苯基、2-氟苯基、3-氟苯基、4-三氟甲基吡啶基、3-甲基吡啶基、3-三氟甲基吡啶基、4-甲基吡啶基、4-环丙基吡啶基、4,6-二甲基吡啶基、4-氯-6-甲基吡啶基、2-甲基-6-氯吡啶基、3-氰基苯基、3-氟-4-甲基吡啶基、吡啶基、3-氟吡啶基、2-甲氧基苯基、2-氯苯基、3-甲氧基苯基、2-氟-6-甲氧基苯基、吡唑基、3-甲基吡唑基、2-甲氧基-3-氟苯基、2-氟-3-氘代甲氧基苯基、2,4-二甲基吡啶基、2-氯吡啶基、2-甲氧基-3氟苯基、2-氘代甲氧基-3-氟苯基。
在一实施方案中，G
1为苯基且所述苯基被氟或氯取代；G
2为苯基或吡啶基且所述苯基或所述吡啶基各自独立地为未取代的或被氟、氯、甲基、三氟甲基或环丙基取代。
在一实施方案中，G
1为苯基且所述苯基被氟或氯取代；G
2为苯基或吡啶基且所述苯基或所述吡啶基各自独立地为未取代的或被选自氟、氯、溴、氰基、甲基、氘代甲基、甲 氧基、氘代甲氧基、三氟甲基、三氟甲氧基、环丙基、卤代环丙基、-O-环丙基、-O-卤代环丙基中的一个、两个或三个取代。
在一实施方案中，G
1为苯基且所述苯基被氟或氯取代；G
2为苯基且所述苯基为未取代的或被氟、氯、甲基、三氟甲基或环丙基取代。
在一实施方案中，G
1为苯基且所述苯基被氟或氯取代；G
2为吡啶基且所述吡啶基为未取代的或被氟、氯、甲基、三氟甲基或环丙基取代。
在一实施方案中，式B、式B1、式B1a、式B1a-1、式B1a-2、式B2、式B2a、式B2a-1或式B2a-2中，G
1选自下组：
各式中，Rg
1、Rg
2各自独立地为氢或选自S2组的基团。
在一实施方案中，i、G
1、L、G
2具有以下任一种定义：
(1)i为0，G
1为苯基、吡啶基、呋喃基或噻吩基；所述苯基、所述吡啶基、所述呋喃 基和所述噻吩基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；
(2)i为1，L为CR
8R
9或O，G
1为苯基或吡啶基，G
2为苯基、吡啶基或吡唑基；所述苯基、所述吡啶基和所述吡唑基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；
(3)i为1，L为CR
8R
9，G
1为苯基，G
2为吡唑基；所述苯基和所述吡唑基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；
(4)i为1，L为O，G
1为苯基或吡啶基，G
2为苯基或吡啶基；所述苯基和所述吡啶基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代。
在一优选实施方案中，i为0，G
1选自：
在一实施方案中，Rg
2为氢或选自下组：氘、卤素、氰基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基。
在一实施方案中，Rg
1为氢或选自下组：氘、卤素、氰基、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基、-C
3-6单环环烷基、-卤代C
3-6单环环烷基、-O-C
3-6单环环烷基、3至6元单环杂环基、-O-3至6元单环杂环基、-NR
aR
b和-OR
c；所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基和所述3至6元单环杂环基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
a和R
b各自独立地为H、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
3-6单环环烷基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、3至6元单环杂环基、-C
1-4亚烷基-3至6元单环杂环基或C(O)C
1-6烷基；其中，所述3至6元单环杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C
3-6单环环烷基、所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；或
上述各基团中，R
a、R
b与和它们相连的氮原子共同形成3至6元含氮杂环基；其中，所述3至6元含氮杂环基具有1个氮原子和任选的1或2个选自N、O和S的杂原子作为环原子；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-6烷氧基；
上述各基团中，R
c为H、-C
1-4亚烷基-卤代C
1-6烷基、-C
1-4亚烷基-氘代C
1-6烷基、-C
1-4亚烷基-C
1-6烷氧基、-C
1-4亚烷基-卤代C
1-6烷氧基、-C
1-4亚烷基-氘代C
1-6烷氧基、-C
1-4亚烷基-C
3-6单环环烷基、-C
1-4亚烷基-3至6元单环杂环基；所述C
3-6单环环烷基、所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基和氘代C
1-
6烷氧基。
在一优选实施方案中，Rg
1为氢或选自下组：卤素(例如氟、氯、溴、碘)、氰基、C
1-
6烷基(例如甲基)、卤代C
1-6烷基(例如三氟甲基)、氘代C
1-6烷基(例如氘代甲基)、C
1-6烷氧基(例如甲氧基)、卤代C
1-6烷氧基(例如三氟甲氧基)、氘代C
1-6烷氧基(例如氘代甲氧基)、-O-C
3-6单环环烷基(例如-O-环丙基、-O-环戊基)、-NR
aR
b(例如-N(CH
3)
2)或-OR
c(例如 -O-CH
2CH
2OCH
3)。
在一优选实施方案中，Rg
2为卤素(例如氟、氯、溴、碘)、氰基、C
1-6烷基(例如甲基)、卤代C
1-6烷基(例如三氟甲基)、氘代C
1-6烷基(例如氘代甲基)、C
1-6烷氧基(例如甲氧基)、卤代C
1-6烷氧基(例如三氟甲氧基)、氘代C
1-6烷氧基(例如氘代甲氧基)、-O-C
3-6单环环烷基(例如-O-环丙基、-O-环戊基)、-NR
aR
b(例如-N(CH
3)
2)或-OR
c(例如-O-CH
2CH
2OCH
3)。
在一实施方案中，结构单元
选自：
在一实施方案中，各式中，R
1、R
2、R
3、R
4、n、E、A、B、G
1、L、G
2、i各自独立地为实施例中各具体化合物中相应的基团。
在一实施方案中，R
1、R
2、R
3、R
4、n、E、A、B、G
1、L、G、i的定义如下：
R
1和R
2各自独立地选自：H、C
1-6烷氧基、C
1-6烷硫基；或者R
1和R
2与同它们相连的碳原子共同构成：羰基(C＝O)或者C＝S；所述C
1-6烷氧基和所述C
1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
R
3和R
4各自独立地选自：C
1-6烷基和C
3-20环烷基；或者R
3和R
4与同它们相连的碳原子共同构成：C
3-20环烷基和3至20元杂环基；所述C
1-6烷基、所述C
3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；
n为0；
E为NR
5、O或N；其中，R
5为H、C
1-6烷基、氘代C
1-6烷基、-C
1-4亚烷基-羟基、-C
1-4亚烷基-C
1-6烷氧基或-C
1-4亚烷基-NR
aR
b；
当E为NR
5或O时，则与E连接的
表示单键；
当E为N时，则与E连接的
表示双键且R
2为无；
A为CR
6；
B为CR
7；
G
1为C
6-14芳基或5或6元单环杂芳基；且所述C
6-14芳基和5或6元单环杂芳基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；
G
2为C
6-14芳基或5或6元单环杂芳基；且所述C
6-14芳基和所述5或6元单环杂芳基各自独立地为未取代的或被1、2、3或4个独立选自S2组的基团取代；
L为CR
8R
9或O；
i为0或1。
在一实施方案中，本发明所述化合物选自本申请实施例所制备的化合物。例如，
另一方面，本发明提供了一种药物组合物，所述药物组合物包括上述方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。
如本文所用，术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时， 特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
另一方面，本发明提供了上述方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药作为药物。
另一方面，本发明提供了上述方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或上述方面所述药物组合物在制备预防和/或治疗疾病或病症的药物中的用途；所述疾病或病症与BTK相关和/或与B细胞活化异常相关。
在一实施方案中，所述疾病或病症选自下组：异种免疫疾病、自身免疫疾病、炎性疾病、癌症。
在一实施方案中，所述异种免疫疾病、自身免疫疾病、炎性疾病可以选自下组：风湿性疾病、肾小球肾炎、Goodpasture综合征、动脉粥样硬化、自身免疫性血液病、自身免疫性胃炎、自身免疫性炎性肠病、肠易激综合征、同种异体移植排斥、慢性甲状腺炎、格雷夫斯病、舍格伦病、硬皮病、糖尿病、肝炎、胰腺炎、原发性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮、牛皮癣、特应性皮炎、皮肌炎、接触性皮炎、湿疹、血管炎、慢性肾功能不全、Stevens-Johnson综合征、炎性疼痛、特发性腹泻、恶病质、结节病、Guillain-Barre综合征、葡萄膜炎、结膜炎、中耳炎、牙周病、帕金森氏病、阿尔茨海默氏病、败血性休克、肺间质纤维化、哮喘、支气管炎、鼻炎、鼻窦炎、尘肺、肺功能不全综合征、肺气肿、肺纤维化、慢性炎性肺病和气道上的其他炎性或阻塞性疾病。
在一实施方案中，所述癌症为白血病或淋巴瘤。
在一实施方案中，所述癌症可以选自下组：小淋巴细胞淋巴瘤(SLL)，急性淋巴细胞白血病(ALL)，慢性淋巴细胞白血病(CLL)，急性骨髓性白血病(AML)，慢性骨髓性白血 病(CML)，急性早幼粒细胞白血病，慢性粒细胞白血病，弥漫性大B细胞淋巴瘤，血管内大B细胞淋巴瘤，原发性渗出性淋巴瘤，华氏巨球蛋白血症，滤泡性淋巴瘤，多发性骨髓瘤、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)、非霍奇金淋巴癌。
另一方面，本发明提供了上述方面所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药或如上述方面所述药物组合物在制备BTK抑制剂中的用途。
另一方面，本发明提供了一种治疗癌症的方法，其包括向有此需要的受试者施用治疗有效量的上述方面所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，或上述的任意组合，或施用上述方面所述的药物组合物的步骤。
如本文所用，术语“受试者”是指动物，特别是哺乳动物。优选人。
如本文所用，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。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
如本文所用，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用，术语“溶剂化合物”和“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括乙酸等。溶剂化合物包括化学计算量的溶剂化合物和非化学计算量的溶剂化合物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
如本文所用，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。且作为药物，具有优异活性的立体异构体是优选的。本发明化合物具有源于不对称碳等的光学异构体，必要时单一异构体可通过本领域已知的方法，例如结晶或手性色谱等方法进行拆分获得。
如本文所用，术语“烷基”指直链或支链饱和脂肪族烃基基团。术语“C
1-20烷基”指具有1至20个碳原子的直链或支链烷基。优选是C
1-10烷基。更优选是C
1-6烷基(即具有1、2、3、4、5或6个碳原子的直链或支链烷基)。更优选是C
1-4烷基。更优选是C
1-3烷基。具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。
如本文所用，术语“烷氧基”指具有-O-烷基结构的基团，其中烷基的定义如上所述。术语“C
1-10烷氧基”指具有1至10个碳原子的烷氧基。优选是C
1-6烷氧基。更优选是C
1-4烷氧基。更优选是C
1-3烷氧基。具体实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、正戊氧基等。
如本文所用，术语“烷硫基”指具有-S-烷基结构的基团，其中烷基的定义如上所述。术语“C
1-10烷硫基”指具有1至10个碳原子的烷硫基。优选是C
1-6烷硫基。更优选是C
1-4烷硫基。更优选是C
1-3烷硫基。具体实例包括但不限于甲硫基、乙硫基、正丙硫基、异丙 硫基、正丁硫基、叔丁硫基、异丁硫基、正戊硫基等。
如本文所用，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基，术语“C
2-8烯基”指具有2至8个碳原子和至少一个(例如1至2个)碳-碳双键的烯基。优选为C
2-6烯基(即具有2至6个碳原子和1到2个碳-碳双键的烯基)。更优选为C
2-4烯基(即具有2到4个碳原子和1到2个碳-碳双键的烯基)。具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。
如本文所用，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基，术语“C
2-8炔基”指具有2至8个碳原子和至少一个(例如1到2个)碳-碳三键的炔基。优选为C
2-6炔基(即具有2至6个碳原子和1至2个碳-碳三键的炔基)。更优选为C
2-4炔基(即具有2到4个碳原子和1到2个碳-碳三键的炔基)。具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文所用，术语“卤素”指氟、氯、溴或碘。
如本文所用，术语“卤代”指氟代、氯代、溴代或碘代。
如本文所用，术语“卤代烷基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烷基，其中烷基的定义如上所述。术语“卤代C
1-10烷基”指具有1至10个碳原子的卤代烷基。优选为卤代C
1-6烷基。更优选为卤代C
1-4烷基。更优选为卤代C
1-3烷基。具体实例包括但不限于一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
如本文所用，术语“卤代烷氧基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烷氧基，其中烷氧基的定义如上所述。术语“卤代C
1-10烷氧基”指具有1至10个碳原子的卤代烷氧基。优选为卤代C
1-6烷氧基。更优选为卤代C
1-4烷氧基。更优选为卤代C
1-3烷氧基。具体实例包括但不限于三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
如本文所用，术语“氘代”是指某基团中一个或多个氢原子被氘原子所取代。
如本文所用，术语“氘代烷基”指一个或多个(如1、2、3、4或5个)氢原子被氘原子取代的烷基，其中烷基的定义如上所述。术语“氘代C
1-10烷基”指具有1至10个碳原子的氘代烷基。优选为氘代C
1-6烷基。更优选为氘代C
1-4烷基。更优选为氘代C
1-3烷基。具体实例包括但不限于一氘甲基、二氘甲基、三氘甲基、一氘乙基、1,2-二氘乙基、三氘乙基等。
如本文所用，术语“氘代烷氧基”指一个或多个(如1、2、3、4或5个)氢原子被氘原子取代的烷氧基，其中烷氧基的定义如上所述。术语“氘代C
1-10烷氧基”指具有1至10个 碳原子的氘代烷氧基。优选为氘代C
1-6烷氧基。更优选为氘代C
1-4烷氧基。更优选为氘代C
1-3烷氧基。具体实例包括但不限于三氘甲氧基、三氘乙氧基、一氘甲氧基、一氘乙氧基、二氘甲氧基、二氘乙氧基等。
如本文所用，术语“环烷基”和“环烷基环”可互换使用，指饱和单环或多环的环状烃基，例如包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。本发明中所述环烷基的环碳原子可任选地被1、2或3个氧代基取代形成环酮结构。术语“3至20元环烷基”或“C
3-20环烷基”指具有3至20个环碳原子的环烷基，包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。优选为C
3-12环烷基、C
5-20螺环烷基、C
5-20稠环烷基或C
5-20桥环烷基。更优选C
3-
8单环环烷基。
术语“C
3-8单环环烷基”和“3至8元单环环烷基”指具有3至8个环碳原子的饱和单环环状烃基。优选为C
3-6单环环烷基(即3至6元单环环烷基)或C
4-6单环环烷基(即4至6元单环环烷基)。更优选为C
3、C
4、C
5或C
6单环环烷基。单环环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
如本文所用，术语“螺环烷基”和“螺环烷基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基和多螺环烷基。术语“5至20元螺环烷基”或“C
5-20螺环烷基”指具有5至20个环碳原子的多环环状烃基，其中共用螺原子的单环为3至8元单环环烷基环。优选为6至14元(即C
6-14)螺环烷基。更优选为6至14元单螺环烷基。更优选为7至11元(即C
7-11)螺环烷基。更优选为7至11元单螺环烷基。最优选为7元(4元单环环烷基环/4元单环环烷基环)、8元(4元单环环烷基环/5元单环环烷基环)、9元(4元单环环烷基环/6元单环环烷基环，5元单环环烷基环/5元单环环烷基环)、10元(5元单环环烷基环/6元单环环烷基环)或11元(6元单环环烷基环/6元单环环烷基环)单螺环烷基。螺环烷基的具体实例包括但不限于：
这些螺环烷基可通过任意一个环原子与分子其余部分连接。
如本文所用，术语“稠环烷基”和“稠环烷基环”指两个或两个以上的单环通过共享毗邻的一对碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环稠环烷基。术语“5至20元稠环烷基”或“C
5-20稠环烷基”指具有5至20个环碳原子的多环环状烃基，其中共享毗邻碳原子对的单环为3至8元单环环烷基环。优选为6至 14元(即C
6-14)稠环烷基。更优选为6至14元双稠环烷基。更优选为7至10元(即C
7-10)稠环烷基。更优选为7至10元双稠环烷基。最优选为8元(5元单环环烷基环与5元单环环烷基环稠合)、9元(5元单环环烷基环与6元单环环烷基环稠合)或10元(6元单环环烷基环与6元单环环烷基环稠合)双稠环烷基。稠环烷基的具体实例包括但不限于：
这些稠环烷基可通过任意一个环原子与分子其余部分连接。
如本文所用，术语“桥环烷基”和“桥环烷基环”指两个或两个以上的单环之间通过共用两个不直接连接的碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“5至20元桥环烷基”和“C
5-20桥环烷基”指具有5至20个环碳原子的多环环状烃基，其中任意两个环共用两个不直接连接的碳原子。优选为6至14元(即C
6-14)桥环烷基。更优选为7至10元(即C
7-10)桥环烷基。桥环烷基的具体实例包括但不限于：
这些桥环烷基可通过任意一个环原子与分子其余部分连接。
如本文所用，术语“卤代环烷基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的环烷基，其中环烷基的定义如上所述。
如本文所用，术语“卤代C
3-8单环环烷基”指具有3至8个环碳原子的卤代单环环烷基。优选为卤代C
3-6单环环烷基。更优选为卤代C
3、卤代C
4、卤代C
5或卤代C
6单环环烷基。具体实例包括但不限于三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，术语“杂环基”和“杂环基环”可互换使用，指饱和或部分不饱和单环或多环的环状烃基，例如包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。术语“3至20元杂环基”指具有3至20个环原子的饱和或部分不饱和单环或多环的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中当环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。本发明所述的3至20元杂环基包括单环杂环基(例如3至8元单环杂环基)、螺杂环基、稠杂环基和桥杂环基。
如本文所用，术语“3至8元单环杂环基”和“3至8元单环杂环基环”指具有3至8个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有3至6个环原子，其中1或2个环原子为杂原子的3至6元单环杂环基。更优选为具有4至6个环原子，其中1或2个环原子为杂原子的4至6元单环杂环基。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(＝O)
m'，m'是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。
如本文所用，术语“3至6元含氮杂环基”指具有3至6个环原子，其中1个环原子为氮原子，其他1个或2个环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。具体实例包括但不限于氮杂丙环基、氮杂环丁烷基、氮杂戊环基(即四氢吡咯)、氮杂己环基(即六氢吡啶)、吗啉基、哌嗪基、噁唑烷。
如本文所用，术语“3至8元单环杂环烷基”指具有3至8个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。优选为3至6元单环杂环烷基，即具有3至6个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。杂环烷基具体实例包括但不限于氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、噁唑烷基、1,3-二氧戊环基、二氧六环基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、硫代吗啉-1,1-二氧化物基、四氢吡喃基、1,4-氧氮杂环庚烷基、1,3-氧氮杂环庚烷基、1,3-噁嗪烷基、六氢嘧啶基、1,4-二噁烷基。
上述单环杂环基环上相连的2个环原子，包括C-C、N-C均可任选地与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂环基上相连的2个环原子优选地为C-C。
如本文所用，术语“螺杂环基”和“螺杂环基环”指两个或两个以上的饱和或部分不饱和单环之间共用一个碳原子(称螺原子)形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。术语“5至20元螺杂环基”指具有5至20个环原子的螺杂环基，其中共用螺原子的单环中一个单环为3至8元单环杂环基环，另一个单环为3至8元单环杂环基环或3至8元单环环烷基环。优选为具有6至14个环原子，其中1或2个环原子为杂原子的6至14元螺杂环基。更优选为具有7至11个环原子，其中1或2个环原子为杂原子的7至11元螺杂环基。最优选为7元(4元单环杂环基环/4元单环杂环基环或4元单环杂环基环/4元单环环烷基或4元单环环烷基环/4元单环杂环基环)、8元(4元单环杂环基环/5元单环杂环基环)、9元(4元单环杂环基环/6元单环杂环基环，5元单环杂环基环/5元单环杂环基环)、10元(5元单环杂环基环/6元单环杂环基环)或11元(6元单环杂环基环/6元单环杂环基环)单螺杂环基。螺杂环基的具体实例包括但不限于：
这些螺杂环基可通过任意一个合适的环原子与分子其余部分连接。
如本文所用，术语“稠杂环基”和“稠杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共享毗邻的一对环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。共享的毗邻环原子对可以是C-C或N-C。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基。术语“5至20元稠杂环基”指具有5至20个环原子的稠杂环基，其中共享毗邻环原子对的单环为3至8元单环杂环基环。优选为具有6至14个环原子，其中1或2个环原子为杂原子的6至14元稠杂环基。更优选为具有6至10个环原子，其中1或2个环原子为杂原子的6至10元稠杂环基。更优选为具有8至10个环原子，其中1或2个环原子为杂原子的8至10元稠杂环基。最优选为8元(5元单环杂环基环与5元单环杂环基环稠合)、9元(5元单环杂环基环与6元单环杂环基环稠合)或10元(6元单环杂环基环与6元单环杂环基环稠合)双环稠杂环基。稠杂环基的具体实例包括但不限于：
这些稠杂环基可通过任意一个合适的环原子与分子其余部分连接。
如本文所用，术语“桥杂环基”和“桥杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共用两个不直接连接的环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子，其余环原子为碳。根据形成环的数目可以分为双环、三环、四环或多环桥环烷基。术语“5至20元桥杂环基”指具有5至20个环原子的饱和或部分不饱和多环杂环基团，其中任意两个环共用两个不直接连接的环原子，每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元桥杂环基。更优选为7至10元桥杂环基。桥杂环基的具体实例包括但不限于：
这些桥杂环基可通过任意一个合适的环原子与分子其余部分连接。
在本发明中，上述各类杂环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“芳基”，“芳基环”和“芳环”可互换使用，指全碳单环、全碳非稠合多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。术语“C
6-14芳基”是指具有6至14个环原子的芳基。优选为C
6-10芳基。本发明中C
6-14芳基包括单环芳基、非稠合多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，非稠合多环芳基的实例包括联苯基等。
本发明中，当C
6-14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。
在本发明的一些实施方案中，当C
6-14芳基为芳香稠合多环时，所述的芳香稠合多环也可以为单芳基环(如苯基)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为芳香环或非芳香环。所述非芳香环包括但不限于3至6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取 代，形成环内酰胺或环内酯结构)，3至6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)。上述单芳基环与一个或多个非芳香环稠合的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单芳基环或非芳香环。
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“杂芳基”，“杂芳基环”和“杂芳环”可互换使用，指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6、10或14个π电子，基团中至少一个环是芳族的。术语“5至14元杂芳基”指具有5至14个环原子，其中1、2、3或4个环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子的杂芳基。优选为具有5至10个环原子，其中1、2、3或4个环原子为杂原子的5至10元杂芳基。本发明中5至14元杂芳基可以为单环杂芳基、稠合双环杂芳基或稠合三环杂芳基。
如本文所用，术语“5或6元单环杂芳基”指具有5或6个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子的单环杂芳基。单环杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。
如本文所用，术语“8至10元双环杂芳基”指具有8至10个环原子，其中1、2、3、4或5个环原子为选自氮、氧或S(＝O)
m'(其中m'是整数0至2)的杂原子的稠合双环杂芳基。所述稠合双环杂芳基既可以是单芳基环(如苯基)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团(优选为9或10元双环杂芳基环)，也可以是单环杂芳基环(优选为5或6元单环杂芳基环)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团。
上述单环杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂芳基环上相连的2个环原子优选地为C-C，非限制性地包括如下形式：
上述基团中通过
标记的环原子与分子其他部分连接。
8至10元双环杂芳基的非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。
双环杂芳基具体实例包括但不限于：
这些基团可通过任意一个合适的环原子与分子其余部分连接。与母体结构连接的环可以为单环杂芳基环或苯环。
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单环杂芳基环(优选为5或6元单环杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单环杂芳基环或非芳香环。所述非芳香环包括但不限于3至6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3至6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单环杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单环杂芳基环或非芳香环。
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“羟基”指-OH。
如本文所用，术语“羟甲基”指-CH
2OH，“羟乙基”指-CH
2CH
2OH或-CH(OH)CH
3。
如本文所用，术语“氰基甲基”指-CH
2CN，“氰基乙基”指-CH
2CH
2CN或-CHCNCH
3。
如本文所用，术语“氨基”指-NH
2。
如本文所用，术语“氰基”指-CN。
如本文所用，术语“硝基”指-NO
2。
如本文所用，术语“苄基”指-CH
2-苯。
如本文所用，术语“氧代基”指＝O。
如本文所用，术语“羧基”指-C(O)OH。
如本文所用，术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)。
如本文所用，术语“乙酰基”指-COCH
3。
如本文所用，术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代基(即＝O)时，意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
在任何实施方案中，化合物中存在的任何或所有氢，或化合物内的特定基团或部分中的氢可以被氘或氚代替。该化合物中存在的一个至最大数目的氢可以被氘代替。通式化合物或具体化合物中的任何基团中存在的一个至最大数目的氢可以被氘代。例如，当描述某一基团为乙基时，该乙基可以是C
2H
5或其中x个(1至5个)氢被氘代替的C
2H
5，例如C
2D
xH
5-x。当描述某一基团为氘代乙基，该氘代乙基可以是x个(1至5个)氢被氘代替的C
2H
5，例如C
2D
xH
5-x。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本 文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下实施例中所用试剂缩写如下：DMSO：二甲基亚砜；DDQ：2,3-二氯-5,6-二氰对苯醌；NH
4HCO
3：碳酸氢氨；CAN：乙腈。
以下实施例中所采用的制备HPLC，若无特别说明，可采用如下条件：柱型：Waters XBridge C18,190*250mm,5μm；流动相体系:A:0.1％碳酸氢铵水溶液；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。
制备例1：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶的合成
步骤一：4-氯-1H-吡咯[2,3-b]吡啶(5.0g,32.89mmol)悬浮于二氯甲烷(100mL)，依次加入三乙胺(6.9mL,49.34mmol)，4-二甲基氨基吡啶(400mg,3.29mmol)和苯磺酰氯(4.6mL,36.18mmol)，反应在室温下搅拌18小时。反应液中加入200mL二氯甲烷，依次用1.0M 60mL稀盐酸洗涤2次，80mL饱和碳酸氢钠,50mL水，60mL饱和食盐水洗涤，干燥浓缩得到4-氯-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(9.5g,收率99％)，棕色固体。ES-API:[M+H]
+＝293.0。
步骤二：4-氯-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(5.0g,17.12mmol)溶于二氯甲烷(75mL)，氮气保护下冷却到-10℃，加入四甲基硝酸铵(3.49g,25.68mmol)。缓慢滴加三氟乙酸酐(3.74mL,26.54mmol)，滴加完反应在-5℃-0℃搅拌30分钟，缓慢升到室温反应18小时。反应液中加入200mL二氯甲烷，依次用100mL水洗涤2次，100mL饱和碳酸钠,100mL饱和碳酸氢钠，100mL水，100mL饱和食盐水洗涤，无水硫酸钠干燥，用硅胶过滤，滤液浓缩得到4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(4.05g,收率70％)，白色固体。ES-API:[M+H]
+＝338.0。
制备例2 (S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮的合成
步骤一：(S)-2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(10.0g，58.96mmol)和4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(19.0g,56.26mmol)溶于N,N-二甲基乙酰胺(250mL)，加入无水N,N-二异丙基乙胺(36.36g,281.29mmol)，反应在110℃搅拌17小时。反应液中加入1000mL乙酸乙酯，用500mL水洗涤2次，500mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(S)-3-羟基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(16.0g,收率65.5％)，黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：(S)-3-羟基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5.0g，11.51mmol)溶于乙腈(150mL),加入氧化银(II)(26.67g,115.10mmol)和碘甲烷(16.34g,115.10mmol),反应在35℃搅拌48小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(200mL)洗涤。所得滤液经真空浓缩得到(S)-3-甲氧基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5g,收率97％),黄色固体。ES-API:[M+H]
+＝449.1。
步骤三：(S)-3-甲氧基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5g,11.15mmol)溶于乙酸(100mL)，加入铁粉(6.23g,111.5mmol),反应在90℃搅拌2小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(200mL)洗涤。滤液真空浓缩,所得粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(4g,收率93％)，浅黄色固体。ES-API:[M+H]
+＝387.2。
制备例3 (S)-2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮的合成
步骤一：(S)-3-羟基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5.0g，11.51mmol)溶于乙腈(150mL),加入氧化银(II)(26.67g,115.10mmol)和氘代碘甲烷(16.34g,115.10mmol),反应在避光条件下加热至35℃搅拌48小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(200mL)洗涤。所得滤液经真空浓缩得到(S)-3-(甲氧基-d
3)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5g,收率96％),黄色固体。ES-API:[M+H]
+＝452.1。
步骤二：(S)-3-(甲氧基-d
3)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(5g,11.07mmol)溶于乙酸(100mL)，加入铁粉(6.23g,111.5mmol),反应在90℃搅拌2小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(200mL)洗涤。滤液真空浓缩,所得粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到(S)-2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(4g,收率93％)，浅黄色固体。ES-API:[M+H]
+＝390.2。
制备例4 (S)-2-氨基-2(羟甲基)丙酸甲酯-3,3,3-d
3盐酸盐的合成
步骤一：(S)-2-氨基-3-羟基丙酸甲酯(10g,64.3mmol)溶于四氢呋喃(100mL)中，加入特戊醛(6.63g,77.1mmol)、三乙胺(7.14g,70.7mmol)，70℃反应4小时，冷至室温，反应液不处理直接用于一步反应。
步骤二：前一步反应液，加入碳酸钾溶液(13.3g,96.5mmol)，二碳酸二叔丁酯(15.4g,70.7mmol)，室温反应16小时，加入水、乙酸乙酯分液，有机相食盐水洗涤，干燥，浓缩，过柱纯化(石油醚/乙酸乙酯＝5/1)得到3-(叔丁基)4-甲基(2R,4S)-2-(叔丁基)恶唑烷-3,4-二羧酸酯(7.5g,收率:40.7％)。ES-API:[M-55]
+＝232.2。
步骤三：3-(叔丁基)4-甲基(2R,4S)-2-(叔丁基)恶唑烷-3,4-二羧酸酯(5.1g,17.7mmol)溶于四氢呋喃(50mL)，降温至-78℃，加入1M双三甲基硅基胺基锂四氢呋喃溶液(53mL)，反应0.5小时，加入氘代碘甲烷(12.83g,88.5mmol)，-78℃反应1小时，氯化铵淬灭反应(50 mL)，乙酸乙酯萃取(50mLX1)，有机相食盐水洗涤(50mLX1)，无水硫酸钠干燥，浓缩，粗品经柱层析纯化(石油醚/乙酸乙酯＝5/1)得到3-(叔丁基)4-甲基(2R,4S)-2-(叔丁基)-4-(甲基-d
3)恶唑烷-3,4-二羧酸酯(4.5g,收率:80.6％)。ES-API:[M-55]
+＝260.2。
步骤四：3-(叔丁基)4-甲基(2R,4S)-2-(叔丁基)-4-(甲基-d
3)恶唑烷-3,4-二羧酸酯(4.5g,14.8mmol)溶于二氧六环(25mL)，加入6N盐酸(25mL)，50℃反应2小时，浓缩干溶剂，粗品溶于1M盐酸(25mL)，乙酸乙酯反萃取(25mLX3)，水相浓缩干，得到(S)-2-氨基-2(羟甲基)丙酸甲酯-3,3,3-d
3盐酸盐(2.55g,收率:100％)。ES-API:[M+H]
+＝137.1。
1H NMR(400MHz,CDCl
3)δ8.68(s,2H),7.53-7.27(m,1H),3.7(s,3H),3.63-3.60(m,1H)。
实施例1：Z1、Z1-1、Z1-2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.0g,2.97mmol)和3-氨基四氢呋喃-3-羧酸甲酯盐酸盐(806mg,4.45mmol)溶于N,N-二甲基甲酰胺(15mL)，加入N,N-二异丙基乙胺(1.34g,10.40mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢呋喃-3-羧酸甲酯(660mg,收率:50％)，黄色固体。ES-API:[M+H]
+＝447.1。
步骤二：(3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢呋喃-3-羧酸甲酯(635mg,1.42mmol)溶于乙酸(15mL)，加入铁粉(558mg,9.97mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到7'-(苯磺酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(530mg,收率97％)，黄色固体。ES-API:[M+H]
+＝385.1
步骤三：(7'-(苯磺酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡 嗪]-3'(1'H)-酮(200mg，0.52mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水中，加入氢氧化钠(146mg，3.64mmol)，反应在65℃搅拌7小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(105mg,收率82％)，灰白色固体。ES-API:[M+H]
+＝245.1。
步骤四：4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(105mg，0.43mmol)和2-氯-4-苯氧基苯甲醛(100mg，0.43mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(168mg，3.01mmol)。反应在室温下搅拌48小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(70mg,收率34％)，淡黄色固体。ES-API:[M+H]
+＝477.1。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(70mg,0.15mmol)溶于6mL四氢呋喃，加入戴斯-马丁氧化剂(94mg，0.22mmol)，反应在室温下搅拌4小时，再加入戴斯-马丁氧化剂(94mg，0.22mmol)，反应在室温下搅拌18小时。反应液加入5mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(Z1，27mg，收率39％)，淡黄色固体。
1H NMR(500MHz,DMSO-d
6)δ12.56(s,1H),10.70(s,1H),8.51(s,1H),7.78(s,1H),7.67(s,1H),7.57(d,J＝8.5Hz,1H),7.51–7.43(m,2H),7.26(t,J＝7.5Hz,1H),7.21–7.15(m,3H),7.02(dd,J＝8.5,2.0Hz,1H),4.06–3.96(m,2H),3.94-3.89(m 1H),3.80(d,J＝9.0Hz,1H),2.55-2.50(m,2H),2.11–1.98(m,1H).ES-API:[M+H]
+＝475.0。
步骤六：将上述步骤得到的化合物Z1(14mg,0.03mmol)用手性制备拆分(柱:AB,250mm*4.6mm*5um；流动相:己烷:EtOH＝50:50；流速:1ml/min；柱温：30℃)得到两个单一异构体化合物。一个异构体，任意指定其结构为Z1-1(4mg,峰1，保留时间：7.186min，收率28％)，ES-API:[M+H]
+＝475.1，为白色固体。另一个异构体，任意指定其结构为Z1-2(4mg,峰2，保留时间：8.731min，收率28％)，ES-API:[M+H]
+＝475.1，为灰白色固体。
实施例2：Z2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.0g,2.97mmol)和1-叔丁基3-甲基-3-氨基吡咯烷-1,3-二羧酸酯(1.01g,4.16mmol)溶于15mL N,N-二甲基乙酰胺，加入N,N-二异丙基乙胺(958mg,7.42mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，依次用30mL稀食盐水洗涤3次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到1-(叔丁基)3-甲基3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-1,3-二羧酸酯(660mg,收率40％)，黄色固体。ES-API:[M+H]
+＝546.1。
步骤二：1-(叔丁基)3-甲基3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-1,3-二羧酸酯(270mg,0.50mmol)溶于3mL二氯甲烷，加入1.5mL三氟乙酸，反应在室温下搅拌1小时。反应液浓缩，加入15mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩得到3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-3-羧酸甲酯(220mg,收率100％)，黄色固体。ES-API:[M+H]
+＝446.2。
步骤三：3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-3-羧酸甲酯(220mg,0.49mmol)溶于10mL乙腈，冰浴下依次加入三乙酰氧基硼氢化钠(416mg,1.96mmol)，和37％甲醛水溶液(159mg,1.96mmol)，反应在室温下搅拌2小时。反应液加入20mL饱和碳酸氢钠溶液，用90mL乙酸乙酯萃取。有机相用30mL饱和食盐水洗涤，干燥后浓缩得到1-甲基-3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-3-羧酸甲酯(225mg,收率99％)，黄色固体。ES-API:[M+H]
+＝460.1。
步骤四：1-甲基-3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-3-羧酸甲酯(225mg,0.49mmol)溶于乙酸(7mL)，加入铁粉(192mg,3.43mmol),反应在85℃搅拌2小时。反应液浓缩，加入20mL饱和碳酸氢钠溶液和100mL二氯甲烷/甲醇＝10：1，悬浮液用硅藻土过滤，滤饼用二氯甲烷/甲醇＝10：1洗涤，有机相分离，用25mL饱和食 盐水洗涤，干燥浓缩得到1-甲基-7'-(苯基磺酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(195mg,收率100％)，灰白色固体。ES-API:[M+H]
+＝398.1
步骤五：1-甲基-7'-(苯基磺酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(195mg，0.49mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(98mg，2.45mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和食盐水洗涤，干燥后浓缩得到1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(80mg,收率63％)，淡棕色固体。ES-API:[M+H]
+＝258.1。
步骤六：1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(80mg，0.31mmol)和2-氯-4-苯氧基苯甲醛(108mg，0.46mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(122mg，2.17mmol)，反应在室温下搅拌18小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(53mg,收率35％)，黄色固体。ES-API:[M+H]
+＝490.1。
步骤七：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(53mg,0.11mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(92mg，0.22mmol)，反应在室温下搅拌18小时。反应液加入3mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用10mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z2，11mg,收率20％)，淡黄色固体。ES-API:[M+H]
+＝488.1。
步骤八：将上述步骤制得的化合物Z2(17mg,0.035mmol)用手性制备拆分(柱:IF,250mm*4.6mm*5um,流动相:正己烷:乙醇:二乙胺＝70:30:2,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z2-1(7.0mg,峰1，保留时间10.161min，收率41％)，白色固体。ES-API:[M+H]
+＝488.0。另一个单一异构体，其结构任意指定为Z2-2(6.8mg,峰2，保留时间13.023min，收率40％)，灰白色固 体。
1H NMR(500MHz,DMSO-d
6)δ12.65(s,1H),10.74(s,1H),8.67(s,1H),7.77(s,1H),7.68(s,1H),7.57(d,J＝8.5Hz,1H),7.48(t,J＝7.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.21-7.15(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),4.05–3.97(m,2H),3.95-3.88(m,1H),3.82(d,J＝9.0Hz,1H),2.58–2.52(m,1H),2.11–2.01(m,1H).ES-API:[M+H]
+＝488.0。
实施例3：Z3的合成
步骤一：7'-(苯磺酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(制备方法参见实施例1的步骤一和步骤二)(150mg，0.39mmol)溶于6mL丙酮，依次加入无水碳酸钾(118mg,0.86mmol)，碘甲烷(72mg，0.51mmol)，反应在室温下搅拌18小时，另外补加无水碳酸钾(118mg,0.86mmol)，碘甲烷(72mg，0.51mmol)，反应在室温下搅拌96小时。反应液倒入15mL水中，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥浓缩得到4'-甲基-7'-(苯磺酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(155mg,收率100％)，黄色固体。ES-API:[M+H]
+＝399.1。
步骤二：4'-甲基-7'-(苯磺酰基)-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(155mg，0.39mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(78mg，1.95mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃取。有机相用20mL饱和食盐水洗涤，干燥后浓缩得到4'-甲基-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(95mg,收率94％)，淡棕色固体。ES-API:[M+H]
+＝259.1。
步骤三：4'-甲基-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(80mg，0.31mmol)和2-氯-4-苯氧基苯甲醛(108mg，0.47mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(122mg，2.17mmol)。反应在室温下搅拌24小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡 啶[3,4-b]吡嗪]-3'(1'H)-酮(80mg,收率52％)，灰白色固体。ES-API:[M+H]
+＝491.1。
步骤四：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-4,4',5,7'-四氢-2H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(75mg,0.15mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(130mg，0.30mmol)，反应在室温下搅拌2小时。反应液加入4mL饱和硫代硫酸钠溶液和15mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z3，48mg,收率64％)，淡黄色固体。
1H NMR(500MHz,DMSO-d
6)δ8.74(s,1H),8.03(s,1H),7.70(s,1H),7.56(d,J＝8.5Hz,1H),7.48(t,J＝8.0Hz,2H),7.25(t,J＝7.5Hz,1H),7.22–7.14(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),4.04-4.00(m,2H),3.94-3.89(m,1H),3.78(d,J＝9.0Hz,1H),3.42(s,3H),2.54-2.48(m,1H),2.07–1.98(m,1H).ES-API:[M+H]
+＝489.1。
实施例4：Z4、Z4-1和Z4-2的合成
步骤一：1-(叔丁基)3-甲基3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)吡咯烷-1,3-二羧酸酯(220mg,0.40mmol)溶于乙酸(8mL)，加入铁粉(224mg,4.0mmol),反应在85℃搅拌1小时。反应液冷却到室温，倒入30mL水中，用30mL乙酸乙酯萃取2次。合并有机相依次用25mL水洗涤，30mL饱和碳酸氢钠溶液洗涤3次，30mL饱和食盐水洗涤，干燥浓缩得到3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(195mg,收率100％)，淡棕色固体。ES-API:[M+H]
+＝484.1
步骤二：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(195mg,0.40mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(80mg，2.00mmol)和三乙胺(202mg，2.0mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙 酯萃取。有机相用20mL饱和食盐水洗涤，干燥后浓缩得到3'-氧代-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(130mg,收率94％)，淡棕色固体。ES-API:[M+H]
+＝344.2。
步骤三：3'-氧代-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(130mg，0.38mmol)，溶于2mL甲醇，加入4.0M氯化氢甲醇溶液(5mL,20.0mmol)，反应在室温下搅拌4小时。反应液浓缩得到4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮盐酸盐(110mg,收率92％)，淡绿色固体。ES-API:[M+H]
+＝244.1(free base)。
步骤四：4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮盐酸盐(110mg,0.35mmol)悬浮于二氯甲烷(15mL)，冷却至0℃，依次加入三乙胺(177mg,1.75mmol)和乙酰氯(68mg,0.87mmol)的0.5mL二氯甲烷溶液，反应在冰浴下搅拌2小时。反应液加入2mL甲醇，浓缩后粗品用薄层制备板(二氯甲烷/甲醇＝8:1)纯化得到1-乙酰基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg,收率50％)，淡棕色固体。ES-API:[M+H]
+＝286.1
步骤五：1-乙酰基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(45mg，0.16mmol)和2-氯-4-苯氧基苯甲醛(74mg，0.32mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(63mg，1.12mmol)，反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到1-乙酰基-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(48mg,收率58％)，灰白色固体。ES-API:[M+H]
+＝518.2。
步骤六：1-乙酰基-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(43mg,0.083mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(70mg，0.166mmol)，反应在室温下搅拌16小时。反应液加入3mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用20mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z4，20mg,收率51％)，白色固体。ES-API:[M+H]
+＝516.0。
步骤七：将上述步骤制得的化合物Z4(19mg,0.037mmol)用手性制备拆分(柱:IC250mm*4.6mm*5um,流动相:甲醇:乙醇＝50:50,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z4-1(5mg,峰1，保留时间5.370min，收率26％)，白色固体。ES-API:[M+H]
+＝516.0。另一个单一异构体，其结构任意指定为Z4-2(7mg,峰2，保留时间8.524min，收率37％)，白色固体。ES-API:[M+H]
+＝516.0。
实施例5：Z5的合成
步骤一：2,4-二氟苯甲醛(2.84g,20.0mmol)和苯酚(1.69g,18.0mmol)溶于50mL N,N-二甲基甲酰胺，加入碳酸铯(8.80g,30.0mmol)，反应在75℃搅拌16小时。反应液倒入100mL水中，80mL乙酸乙酯萃取。有机相用40mL饱和食盐水洗涤4次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-3％)得到2-氟-4-苯氧基苯甲醛(1.4g,收率36％)，无色液体。
1H NMR(500MHz,DMSO-d
6)δ10.11(s,1H),7.85(t,J＝8.5Hz,1H),7.54–7.44(m,2H),7.34–7.29(m,1H),7.22–7.16(m,2H),6.95(dd,J＝12.5,2.5Hz,1H),6.89(dd,J＝8.5,2.5Hz,1H).ES-API:[M+H]
+＝217.1。
步骤二：1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg，0.19mmol)和2-氟-4-苯氧基苯甲醛(123mg，0.57mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(74mg，1.33mmol)，反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到9'-((2-氟-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(37mg,收率40％)，淡黄色固体。ES-API:[M+H]
+＝474.1。
步骤三：9'-((2-氟-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(37mg,0.078mmol)溶于8mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(99mg，0.23mmol)，反应在室温下搅拌18小时。反应液加入2mL饱和硫代硫酸钠溶液和8mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z5，6mg,收率16％)，白色固体。
1H NMR(500MHz,CDCl
3)δ13.13(s,1H),12.13(s,1H),7.89(s,1H),7.52–7.46(m,2H),7.43(t,J＝8.0Hz,2H),7.23(t,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,2H),6.86(dd,J＝8.5,2.5Hz,1H),6.79(dd,J＝11.0,2.0Hz,1H),3.37(s,1H),2.96–2.63(m,4H),2.46(s,3H),2.20-2.11(m,1H).ES-API:[M+H]
+＝472.1。
实施例6：Z6的合成
步骤一：2-氯-4-氟苯甲醛(1.0g,6.33mmol)和2-氟苯酚(744mg,6.65mmol)溶于15mL N,N-二甲基甲酰胺，加入碳酸铯(2.47g,7.60mmol)，反应在75℃搅拌16小时。反应液倒入30mL水中，100mL乙酸乙酯萃取。有机相用30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-4％)得到2-氯-4-(2-氟苯氧基)苯甲醛(1.15g,收率72％)，白色固体。ES-API:[M+H]
+＝251.1。
步骤二：1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg，0.19mmol)和2-氯-4-(2-氟苯氧基)苯甲醛(143mg，0.57mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(75mg，1.33mmol)，反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到9'-((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(41mg,收率41％)，黄色固体。ES-API:[M+H]
+＝508.1。
步骤三：9'-((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(41mg,0.08mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(51mg，0.12mmol)，反应在室温下搅拌3小时，额外戴斯-马丁氧化剂(51mg，0.12mmol)，反应在室温下搅拌16小时。反应液加入2mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z6，2.5mg,收率6％)，淡黄色固体。ES-API:[M+H]
+＝506.0。
实施例7：Z7的合成
步骤一：2-氯-4-氟苯甲醛(1.0g,6.33mmol)和3-氟苯酚(744mg,6.65mmol)溶于15mL N,N-二甲基甲酰胺，加入碳酸铯(2.47g,7.60mmol)，反应在75℃搅拌16小时。反应液倒 入30mL水中，100mL乙酸乙酯萃取。有机相用30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-4％)得到2-氯-4-(3-氟苯氧基)苯甲醛(930mg,收率59％)，白色固体。ES-API:[M+H]
+＝251.1。
步骤二：1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg，0.19mmol)和2-氯-4-(3-氟苯氧基)苯甲醛(143mg，0.57mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(75mg，1.33mmol)，反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到9'-((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg,收率50％)，黄色固体。ES-API:[M+H]
+＝508.0。
步骤三：9'-((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(50mg,0.10mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(64mg，0.15mmol)，反应在室温下搅拌3小时，额外戴斯-马丁氧化剂(64mg，0.15mmol)，反应在室温下搅拌16小时。反应液加入2mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z7，5mg,收率10％)，淡黄色固体。
1H NMR(500MHz,CDCl
3)δ13.12(s,1H),12.15(s,1H),7.42-7.35(m,2H),7.30(dd,J＝15.0,8.0Hz,1H),7.06(d,J＝2.5Hz,1H),6.93(dd,J＝8.5,2.5Hz,1H),6.88–6.71(m,3H),3.37(s,1H),3.05-2.58(m,4H),2.48(s,3H),2.20-2.10(m,1H).ES-API:[M+H]
+＝506.0。
实施例8：Z8的合成
步骤一：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(225mg，0.47mmol)溶于12mL丙酮，依次加入无水碳酸钾(324mg,2.35mmol)，碘甲烷(267mg，1.88mmol)，反应在室温下搅拌72小时。反应液倒入15mL水中，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥浓缩，粗品 用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到4'-甲基-3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(180mg,收率78％)，淡黄色固体。ES-API:[M+H]
+＝498.1。
步骤二：4'-甲基-3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(180mg，0.36mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(72mg，1.80mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩得到4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(125mg,收率97％)，淡棕色固体。ES-API:[M+H]
+＝358.2。
步骤三：4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(125mg，0.35mmol)和2-氯-4-苯氧基苯甲醛(244mg，1.05mmol)溶于甲醇(12mL)，将反应冷至0℃，加入氢氧化钾(137mg，2.45mmol)。反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，加入80mL乙酸乙酯。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(168mg,收率81％)，白色固体。ES-API:[M+H]
+＝590.2。
步骤四：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(153mg,0.26mmol)溶于20mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(165mg，0.39mmol)，反应在室温下搅拌16小时。反应液加入4mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液和20mL饱和食盐水洗涤，干燥后浓缩得到9'-(2-氯-4-苯氧基苯甲酰基)-4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(150mg,收率100％)，黄色固体。ES-API:[M+H]
+＝588.1。
步骤五：9'-(2-氯-4-苯氧基苯甲酰基)-4'-甲基-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(150mg,0.25mmol)溶于4.5mL二氯甲烷，冷却至0℃，加入1.5mL三氟乙酸，反应在室温下搅拌1小时。反应液浓缩，加入10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取2次。有机相用25mL饱和食盐水洗涤，干燥后浓缩得到9'-(2-氯-4-苯氧基苯甲酰基)-4'-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(124mg,收率100％)，淡棕色固体。ES-API:[M+H]
+＝488.0。
步骤六：9'-(2-氯-4-苯氧基苯甲酰基)-4'-甲基-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(104mg,0.21mmol)溶于10mL甲醇，2mL二氯甲烷，室温下依次加入37％甲醛水溶液(85mg,1.05mmol)，和1滴乙酸，反应在室温下搅拌30分钟后，加入氰基硼氢化钠(26mg,0.42mmol)，反应在室温下搅拌2小时。反应液浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到粗品58mg，然后用制备HPLC纯化得到目标产物(Z8，8mg,收率7％)，黄色固体。ES-API:[M+H]
+＝502.1。
实施例9：Z9、Z9-1和Z9-2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(0.9g,2.671mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(1.0g,5.915mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(620mg,收率53％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(550mg,1.267mmol)溶于乙酸(15mL)，加入铁粉(1.40g,25.00mmol),反应在80℃搅拌1小时。溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(羟甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(380mg,收率80.6％)，黄色固体。ES-API:[M+H]
+＝373.1
步骤三：2-(羟甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.5376mmol)溶于12mL甲醇，2mL四氢呋喃和2mL水，加入氢氧化钠(215mg，5.376mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和5mL 饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,粗品)，灰白色固体。ES-API:[M+H]
+＝233.0。
步骤四：2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，1.293mmol)和2-氯-4-苯氧基苯甲醛(350mg，1.510mmol)溶于甲醇(12.0mL)，将反应冷至0℃，加入氢氧化钾(300mg，5.375mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH为8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3-酮(320mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝465.1。
步骤五：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3-酮(320mg,0.6896mmol)溶于30mL二氯甲烷，加入2,3-二氯-5,6-二氰基-1,4-苯醌(320mg，1.410mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(Z9，26mg,收率8％)，淡黄色固体，ES-API:[M+H]
+＝463.0。
1H NMR(500MHz,DMSO-d
6)δ12.39(s,1H),10.39(s,1H),8.23(s,1H),7.67(s,1H),7.57(s,1H),7.54(d,J＝8.4Hz,1H),7.48(t,J＝8.0Hz,2H),7.25(t,J＝7.4Hz,1H),7.22–7.13(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),5.21(t,J＝5.4Hz,1H),3.69(dd,J＝10.6,6.0Hz,1H),3.48(dd,J＝10.7,4.8Hz,1H),1.36(s,3H)。
步骤六：将上述步骤制得的化合物Z9(20mg,0.0433mmol)用手性制备拆分(柱：IC150mm*4.6mm*5um,流动相:正己烷:乙醇：二乙胺＝70:30:0.2,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z9-1(7mg,峰1，保留时间10.019min，收率35％)，淡白色固体。ES-API:[M+H]
+＝463.0。另一个单一异构体，其结构任意指定为Z9-2(6.5mg,峰2，保留时间11.323min，收率34％)，淡白色固体。ES-API:[M+H]
+＝463.0。
实施例10：Z10的合成
步骤一：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(300mg，0.62mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(124mg，3.10mmol)，反应在60℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩得到3'-氧代-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(170mg,收率80％)，淡棕色固体。ES-API:[M+H]
+＝344.2。
步骤二：3'-氧代-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(170mg，0.50mmol)和2-氯-4-苯氧基苯甲醛(345mg，1.50mmol)溶于甲醇(15mL)，将反应冷至0℃，加入氢氧化钾(196mg，3.50mmol)。反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(145mg,收率51％)，黄色固体。ES-API:[M+H]
+＝576.1。
步骤三：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(130mg,0.26mmol)溶于10mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(146mg，0.34mmol)，反应在室温下搅拌18小时。反应液加入4mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相依次用10mL饱和碳酸氢钠溶液和10mL饱和食盐水洗涤，干燥后浓缩得到9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(129mg,收率100％)，黄色固体。S-API:[M+H]
+＝574.2。
步骤五：9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(30mg,0.25mmol)溶于2mL甲醇，加入2mL4.0M氯化氢二氧六环溶液，反应在室温下搅拌2小时。反应液浓缩得到9'-(2-氯-4-苯氧基苯甲酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮盐酸盐 (30mg,收率100％)，黄色固体。ES-API:[M+H]
+＝474.0(free base)。
步骤六：9'-(2-氯-4-苯氧基苯甲酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮盐酸盐(30mg,0.05mmol)溶于5mL二氯甲烷，冰浴下依次加入三乙胺(27mg,0.26mmol)，和环丙烷酰氯(7mg,0.06mmol)的0.5mL二氯甲烷溶液，反应在冰浴下搅拌15分钟后。反应液加入2mL甲醇，浓缩，粗品用制备HPLC纯化得到目标产物(Z10，15mg,收率54％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.58(s,1H),10.78-10.74(m,1H),8.58-8.51(m,1H),7.83-7.80(m,1H),7.70-7.66(m,1H),7.58-7.52(m,1H),7.50–7.42(m,2H),7.25(t,J＝6.9Hz,1H),7.21–7.13(m,3H),7.02(dd,J＝8.5,1.5Hz,1H),4.17–3.80(m,2H),3.75–3.48(m,2H),2.57-2.33(m,1H),2.21-2.00(m,1H),1.85–1.72(m,1H),0.80–0.60(m,4H).ES-API:[M+H]
+＝542.1。
实施例11：Z11的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(950mg,2.819mmol)和1-(叔丁基)3-乙基3-氨基氮杂环丁烷-1,3-二羧酸酯(1.0g,4.096mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N,N-二异丙基乙胺(3.643g,28.19mmol)，反应在95℃搅拌16小时。反应液冷却到室温后加入100mL乙酸乙酯，用80mL水洗涤2次，60mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到1-(叔丁基)3-乙基3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)氮杂环丁烷-1,3-二羧酸酯(860mg,收率56％)，淡黄色固体。ES-API:[M+H]
+＝546.1。
步骤二：1-(叔丁基)3-乙基3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)氮杂环丁烷-1,3-二羧酸酯(700mg,1.284mmol)溶于乙酸(50mL)，加入铁粉(700mg, 12.50mmol),反应在80℃搅拌1小时。减压旋干溶剂后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,60mL饱和碳酸氢钠洗涤2次，60mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(530mg,收率88％)，淡黄色固体。ES-API:[M+H]
+＝470.1
步骤三：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(330mg，0.7035mmol)溶于12mL甲醇，2mL四氢呋喃和2mL水，加入氢氧化钠(300mg，7.50mmol)，反应在65℃搅拌6小时。向反应液中加入15mL水和10mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用40mL饱和碳酸氢钠溶液，60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(200mg,收率86％)，灰白色固体。ES-API:[M+H]
+＝330.1。
步骤四：3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(200mg，0.6079mmol)和2-氯-4-苯氧基苯甲醛(300mg，1.293mmol)溶于甲醇(12mL)，将反应冷至0℃，加入氢氧化钾(240mg，4.285mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH为8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(412mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝562.2。
步骤五：9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(412mg,0.7341mmol)溶于30mL二氯甲烷，加入2,3-二氯-5,6-二氰基-1,4-苯醌(400mg，1.762mmol)，反应在室温下搅拌3小时。反应液加入60mL饱和碳酸氢钠溶液，用150mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-20％)得到9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(230mg,收率67％)，淡黄色固体。ES-API:[M+H]
+＝560.2。
步骤六：9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(230mg,0.4113mmol)溶于8mL二氯甲烷中，加入三氟乙酸(469.0mg,4.113mmol)。室温反应2小时，反应完毕，减压旋干溶剂得到粗品目标化合物9'-(2-氯-4-苯氧基苯甲酰基)-4',7'-二氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(330mg,粗品)。褐色油状液体。ES-API:[M+H]
+＝460.1。
步骤七：向30mL乙腈中加入9'-(2-氯-4-苯氧基苯甲酰基)-4',7'-二氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(330mg,0.7189mmol)，冰水浴降至0～5℃后加入甲醛(333mg,4.11mmol),最后加入氰基硼氢化钠(260mg,4.110mmol)。室温反应2小时后加入50mL饱和碳酸氢钠和80mL乙酸乙酯。有机相用无水硫酸钠干燥后减压旋干，粗品经制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-1-甲基-4',7'-二氢螺[氮杂环丁烷-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(Z11，10.0mg,收率5％)。淡黄色固体。ES-API:[M+H]
+＝474.1。
实施例12：Z12的合成
步骤一：2-氯-4-羟基苯甲醛(500mg,3.20mmol)和2-氟-4-(三氟甲基)吡啶(686mg,4.16mmol)溶于12mL N,N-二甲基甲酰胺，加入碳酸钾(883mg,6.40mmol)，反应在95℃搅拌20小时。反应液倒入40mL水中，60mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-5％)得到2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲醛(720mg,收率75％)，无色液体。ES-API:[M+H]
+＝302.0。
步骤二：3'-氧代-1',3',4',7'-四氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(130mg，0.38mmol)和2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲醛(343mg，1.14mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(149mg，2.66mmol)。反应在室温下搅拌18小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9'-((2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(135mg,收率55％)，淡棕色固体。ES-API:[M+H]
+＝645.1。
步骤三：9'-((2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(122mg,0.19mmol)溶于10mL 四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(104mg，0.25mmol)，反应在室温下搅拌18小时。反应液加入4mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相依次用10mL饱和碳酸氢钠溶液和10mL饱和食盐水洗涤，干燥后浓缩得到9'-(2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(121mg,收率100％)，黄色固体。ES-API:[M+H]
+＝643.2。
步骤四：9'-(2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(60mg,0.093mmol)溶于2mL二氯甲烷，冷却至0℃，加入0.5mL三氟乙酸，反应在室温下搅拌1小时。反应液浓缩得到9'-(2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮三氟乙酸盐(75mg,粗品)。ES-API:[M+H]
+＝543.1(游离碱)。
步骤五：9'-(2-氯-4-((4-(三氟甲基)吡啶-2-基)氧基)苯甲酰基)-4',7'-二氢螺环[吡咯烷-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮三氟乙酸盐(70mg,粗品)溶于3mL乙腈，室温下依次加入37％甲醛水溶液(50mg,0.61mmol)，反应在室温下搅拌30分钟后，加入氰基硼氢化钠(19mg,0.31mmol)，反应在室温下搅拌30分钟。反应液浓缩，粗品用制备HPLC纯化得到目标产物(Z12，8mg,收率15％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.56(s,1H),10.58(s,1H),8.48(d,J＝5.0Hz,1H),8.45(s,1H),8.33(s,1H),7.76(s,1H),7.64(d,J＝8.5Hz,1H),7.62–7.56(m,3H),7.54(d,J＝2.0Hz,1H),7.31(dd,J＝8.5,2.0Hz,1H),2.99-2.91(m,1H),2.82(d,J＝9.5Hz,1H),2.70(d,J＝9.5Hz,1H),2.55-2.50(m,1H),2.34–2.22(m,4H),1.90–1.80(m,1H).ES-API:[M+H]
+＝557.0。
实施例13：Z13、Z13-1和Z13-2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(0.9g,2.671mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(1.0g,5.915mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(620mg,收率53％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(700mg,1.613mmol)溶于乙腈(30mL)，依次加入氧化银(1.87g,8.065mmol)和碘甲烷(2.29g,16.13mmol),氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-甲氧基-2-甲基-2-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(570mg,收率78％)，黄色固体。ES-API:[M+H]
+＝449.0。
步骤三：3-甲氧基-2-甲基-2-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(700mg,1.613mmol)溶于乙酸(30mL)中，加入铁粉(1.80g,32.26mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg,收率64％)，黄色固体。ES-API:[M+H]
+＝387.1
步骤四：2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg，1.0362mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(290mg，7.264mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(480mg,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤五：2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(480mg，粗品)和2-氯-4-苯氧基苯甲醛(480mg，2.0724mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(406mg，7.253mmol)。反应在室温下搅拌6小时。将反应液 倒入30mL饱和氯化铵水溶液中，调pH为8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3-酮(620mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝479.0。
步骤六：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3-酮(620mg,粗品)溶于30mL二氯甲烷，加入2,3-二氯-5,6-二氰基-1,4-苯醌(470mg，2.0724mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(Z13，126mg,三步收率25％)，淡黄色固体，ES-API:[M+H]
+＝477.1。
1H NMR(500MHz,DMSO-d
6)δ12.45(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.5Hz,1H),7.48(dd,J＝8.5,7.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.22–7.11(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.39(s,3H)。
步骤七：将上述步骤制得化合物Z13(126mg,0.2646mmol)用手性制备拆分(柱：IC150mm*4.6mm*5um,流动相：正己烷:乙醇:二乙胺＝70:30:0.2,流速：1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体(51.45mg,峰1，保留时间8.881min，收率40％)，淡白色固体。ES-API:[M+H]
+＝477.1。
1H NMR(500MHz,DMSO-d
6)δ12.46(s,1H),10.49(s,1H),8.28(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.5Hz,1H),7.48(t,J＝8.0Hz,2H),7.25(t,J＝7.5Hz,1H),7.21–7.16(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.65(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.39(s,3H)。另一个单一异构体(53.0mg,峰2，保留时间11.86min，收率42％)，淡白色固体。ES-API:[M+H]
+＝477.1。
1H NMR(400MHz,DMSO-d
6)δ12.46(s,1H),10.49(s,1H),8.28(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.4Hz,1H),7.52–7.44(m,2H),7.29–7.23(m,1H),7.22–7.16(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.65(d,J＝9.6Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,3H),1.39(s,3H)。
实施例13A：Z13-1的合成
本实施例参照实施例13的步骤，不同点在于本实施例步骤一用
代替实施例13步骤一的
得到的最终产物经手性分析(柱：IC 150mm*4.6mm*5um,流动相：正己烷:乙醇:二乙胺＝70:30:0.2,流速：1ml/min,柱温：30℃)后确定未发生消旋，因此确定该最终产物为Z13-1。将实施例13步骤七拆分得到的两个单一异构体与实施例13A制得的产物Z13-1比较确定：保留时间8.881min的异构体的结构为化合物Z13-1；保留时间11.86min的异构体的结构为化合物Z13-2。
实施例14：Z14的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(500mg,1.48mmol)和4-氨基四氢-2H-吡喃-4-羧酸甲酯(260mg,1.63mmol)溶于5mL N,N-二甲基乙酰胺，加入N,N-二异丙基乙胺(480mg,3.71mmol)，反应在120℃微波搅拌1小时。反应液中加入100mL乙酸乙酯，依次用30mL稀食盐水洗涤3次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3- b]吡啶-4-基)氨基)甲基)四氢-2H-吡喃-4-羧酸酯(300mg,收率44％)，黄色固体。ES-API:[M+H]
+＝461.0。
步骤二：4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)甲基)四氢-2H-吡喃-4-羧酸酯(300mg,0.65mmol)溶于10mL醋酸，加入铁粉(182mg,3.26mmol)，80℃下搅拌3小时。反应液浓缩，加入60mL乙酸乙酯，过滤浓缩，残留物用快速硅胶柱(0-100％乙酸乙酯/石油醚)纯化得到7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg,收率77％)，黄色固体。ES-API:[M+H]
+＝399.1。
步骤三：7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg，0.50mmol)溶于2mL甲醇和0.4mL水，加入氢氧化钠(100mg，2.50mmol)，反应在120℃微波搅拌1小时.反应液干燥后浓缩得到粗品2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg)，黑色固体。ES-API:[M+H]
+＝259.1。
步骤六：2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg，0.77mmol)和2-氯-4-苯氧基苯甲醛(360mg，1.55mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(304mg，5.42mmol)，反应在室温下搅拌5小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用快速硅胶柱(0-20％甲醇/二氯甲烷)纯化得到9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(70mg,收率18％)，黄色固体。ES-API:[M+H]
+＝491.0。
步骤七：9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(70mg,0.14mmol)溶于2mL1,4-二氧六环和0.2mL水中，冷却到0℃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(49mg，0.21mmol)，反应在室温下搅拌2小时。反应液加入3mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用10mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z14，24mg，收率34％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ12.58(s,1H),10.54(s,1H),8.86(s,1H),7.78(s,1H),7.70(s,1H),7.60(d,J＝8.4Hz,1H),7.53–7.44(m,2H),7.29–7.23(m,1H),7.21–7.19(m,2H),7.19–7.17(m,1H),7.04(dd,J＝8.4,2.0Hz,1H),3.89–3.80(m,2H),3.80–3.69(m,2H),2.14–2.02(m,2H),1.61(d,J＝12.8Hz,2H).ES-API:[M+H]
+＝489.1。
实施例15：Z15的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.0g,2.97mmol)和2-氨基-2-甲基丙酸甲酯盐酸盐(908mg,5.94mmol)溶于N,N-二甲基甲酰胺(10mL)，加入N,N-二异丙基乙胺(2.3mL,13.36mmol)，反应在80℃搅拌16小时。反应液中加入100mL乙酸乙酯，用40mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)丙酸甲酯(870mg,收率70％)，黄色固体。ES-API:[M+H]
+＝419.0。
步骤二：2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)丙酸甲酯(870mg,2.08mmol)溶于乙酸(15mL)，加入铁粉(466mg,8.32mmol),反应在85℃搅拌4小时。反应液倒入45mL水中，不溶的固体过滤，滤饼用少量水洗涤，真空干燥得到2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(670mg,收率90％)，类白色固体。ES-API:[M+H]
+＝357.1
步骤三：2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(300mg，0.84mmol)溶于12mL N,N-二甲基甲酰胺，依次加入无水碳酸钾(464mg,3.36mmol)，叔丁基(2-碘甲氧基)二甲基硅烷(721mg，2.52mmol)，反应在60℃下搅拌24小时。反应液倒入40mL水中，用80mL乙酸乙酯萃取。有机相用30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到4-(2-((叔丁基二甲基硅烷基)氧基)乙基)-2,2-二甲基-7-(苯基磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(400mg,收率92％)，白色固体。ES-API:[M+H]
+＝515.2。
步骤四：4-(2-((叔丁基二甲基硅烷基)氧基)乙基)-2,2-二甲基-7-(苯基磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(350mg，0.68mmol)溶于15mL甲醇，5mL四氢呋喃和3mL水，加入氢氧化钠(136mg，3.40mmol)，反应在60℃搅拌16小时，反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃 取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到4-(2-羟乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(177mg,收率100％)，白色固体。ES-API:[M+H]
+＝261.1。
步骤五：4-(2-羟乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(75mg，0.29mmol)和2-氯-4-苯氧基苯甲醛(135mg，0.58mmol)溶于甲醇(7mL)，将反应冷至0℃，加入氢氧化钾(114mg，2.03mmol)。反应在室温下搅拌16小时。反应液用1.0M稀盐酸调pH为8，60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-羟乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(95mg,收率67％)，淡黄色固体。ES-API:[M+H]
+＝493.1。
步骤六：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-羟乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(90mg,0.18mmol)溶于6mL二氯甲烷，室温下加入2,3-二氯-5,6-二氰对苯醌(83mg，0.36mmol)，反应在室温下搅拌16小时。反应液加入5mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用50mL乙酸乙酯萃取。有机相依次用15mL饱和碳酸氢钠溶液，15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z15，70mg,收率78％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ12.61(s,1H),8.33(s,1H),8.15(s,1H),7.68(s,1H),7.57(d,J＝8.4Hz,1H),7.51–7.44(m,2H),7.28–7.22(m,1H),7.21–7.15(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),4.89(s,1H),4.04(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),1.38(s,6H).ES-API:[M+H]
+＝491.1。
实施例16：Z16、Z16-1和Z16-2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(0.60g,1.7804mmol)和3-氨基四氢-2H-吡喃-3-羧酸甲酯(351.23mg,2.209mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌12小时。反应液中加入100mL 乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(320mg,收率39％)，淡黄色固体。ES-API:[M+H]
+＝461.0。
步骤二：3-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(320mg,0.6956mmol)溶于乙酸(20mL)，加入铁粉(0.780g,13.91mmol),反应在80℃搅拌1小时。溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到7'-(苯磺酰基)-4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(240mg,收率85.0％)，淡黄色固体。ES-API:[M+H]
+＝399.1
步骤三：7'-(苯磺酰基)-4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(240mg，0.6030mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(170mg，4.221mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和5mL饱和氯化铵溶液，用160mL乙酸乙酯萃取。有机相依次用40mL饱和碳酸氢钠溶液，60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(340mg,粗品)，灰白色固体。ES-API:[M+H]
+＝259.1。
步骤四：4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(340mg，粗品)和2-氯-4-苯氧基苯甲醛(280mg，1.206mmol)溶于甲醇(12.0mL)，将反应冷至0℃，加入氢氧化钾(236mg，4.221mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH为8，120mL乙酸乙酯萃取。有机相用63mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(400mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝491.2。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4',5,6,7'-四氢-2H,4H-螺[吡喃n-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(400mg,粗品)溶于20mL二氯甲烷，加入2,3-二氯-5,6-二氰基-1,4-苯醌(400mg，1.762mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-4',5,6,7'-四氢-2H,4H-螺[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z16，65mg,三步总收率20％)，淡黄色固体，ES-API:[M+H]
+＝489.1。
步骤六：将上述步骤制得的化合物Z16(65mg,0.1332mmol)用手性制备拆分(柱：IC150mm*4.6mm*5um,流动相:正己烷:乙醇＝50:50,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z16-1(15.15mg,峰1，保留时间8.132min，收率23％)，淡白色固体。ES-API:[M+H]
+＝489.1；
1H NMR(400MHz,DMSO-d
6)δ12.52(s,1H),10.54(s,1H),8.79(s,1H),7.75(s,1H),7.66(s,1H),7.58(d,J＝8.4Hz,1H),7.52–7.43(m,2H),7.22(dt,J＝9.4,7.4Hz,4H),7.03(dd,J＝8.4,2.3Hz,1H),3.92(d,J＝9.2Hz,1H),3.80(q,J＝11.6Hz,2H),3.40(d,J＝8.4Hz,1H),1.97–1.80(m,3H),1.51(d,J＝6.7Hz,1H)。另一个单一异构体，其结构任意指定为Z16-2(15.30mg,峰2，保留时间11.960min，收率23.5％)，淡白色固体。ES-API:[M+H]
+＝489.1；
1H NMR(400MHz,DMSO-d
6)δ12.52(s,1H),10.54(s,1H),8.79(s,1H),7.75(s,1H),7.66(s,1H),7.58(d,J＝8.4Hz,1H),7.52–7.43(m,2H),7.21(ddd,J＝11.6,9.7,4.1Hz,4H),7.03(dd,J＝8.4,2.4Hz,1H),3.92(d,J＝8.3Hz,1H),3.80(q,J＝11.4Hz,2H),3.42(t,J＝9.8Hz,1H),1.98–1.81(m,3H),1.51(d,J＝7.1Hz,1H).
实施例17：Z17的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(500mg,1.49mmol)和4-氨基-1-甲基哌啶-4-羧酸甲酯(333g,1.94mmol)溶于15mL N,N-二甲基乙酰胺，加入N,N-二异丙基乙胺(577mg,4.47mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，依次用30mL稀食盐水洗涤3次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到1-甲基-4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)哌啶-4-羧酸酯(296mg,收率42％)，黄色固体。ES-API:[M+H]
+＝474.1。
步骤二：1-甲基-4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)哌啶-4-羧酸酯(296mg,0.63mmol)溶于乙酸(7mL)，加入铁粉(247mg,4.41mmol),反应在85℃搅 拌2小时。反应液浓缩，加入20mL饱和碳酸氢钠溶液和100mL二氯甲烷/甲醇＝10：1，悬浮液用硅藻土过滤，滤饼用二氯甲烷/甲醇＝10：1洗涤，有机相分离，用25mL饱和食盐水洗涤，干燥浓缩得到1-甲基-7'-(苯磺酰基)-4',7'-二氢螺[哌啶-4,2'-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪]-3'(1'1H)-酮(258mg,收率100％，粗品)，灰白色固体，直接进行下一步反应。ES-API:[M+H]
+＝412.3。
步骤三：1-甲基-7'-(苯磺酰基)-4',7'-二氢螺[哌啶-4,2'-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪]-3'(1'1H)-酮(258mg，0.63mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(176mg，4.41mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和食盐水洗涤，干燥后浓缩得到1-甲基-4',7'-二氢螺[哌啶-4,2'-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪]-3'(1'H)-酮(76mg,收率45％)，淡棕色固体。ES-API:[M+H]
+＝272.2。
步骤四：1-甲基-4',7'-二氢螺[哌啶-4,2'-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪]-3'(1'H)-酮(76mg，0.28mmol)和2-氯-4-苯氧基苯甲醛(79mg，0.34mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(110mg，1.96mmol)，反应在室温下搅拌18小时。将反应液用1.0M稀盐酸调pH为8，直接浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺[哌啶-4,2'-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(56mg,收率33％)，黄色固体。ES-API:[M+H]
+＝504.2。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-1-甲基-4',7'-二氢螺[哌啶-4,2'-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(56mg,0.11mmol)溶于6mL四氢呋喃，冷却到0℃，加入戴斯-马丁氧化剂(92mg，0.22mmol)，反应在室温下搅拌2小时。反应液加入3mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用40mL乙酸乙酯萃取。有机相用10mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-1-甲基-4',7'-二氢螺[哌啶-4,2'-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪]-3'(1'H)-酮(Z17，0.61mg,收率1.1％)，淡黄色固体。ES-API:[M+H]
+＝502.2。
实施例18：Z63的合成
步骤一：2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(400mg，1.12mmol)溶于12mL N,N-二甲基甲酰胺，依次加入无水碳酸钾(773mg,5.60mmol)，2-氯-N，N-二甲基乙烷-1-胺盐酸盐(323mg，2.24mmol)，反应在60℃下搅拌16小时。反应液冷却到室温，另外加入无水碳酸钾(309mg,2.24mmol)，2-氯-N，N-二甲基乙烷-1-胺盐酸盐(161mg，1.12mmol)，反应在60℃下搅拌8小时。反应液倒入40mL水中，用40mL乙酸乙酯萃取2次。合并有机相用25mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-7％)得到4-(2-(二甲氨基)乙基)-2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(300mg,收率62％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ8.10-8.05(m,2H),7.94(s,1H),7.74-7.69(m 1H),7.65–7.58(m,3H),7.34(s,1H),6.93(d,J＝4.0Hz,1H),4.00(t,J＝7.2Hz,2H),2.41(t,J＝7.2Hz,2H),2.20(s,6H),1.29(s,6H).ES-API:[M+H]
+＝428.1。
步骤二：4-(2-(二甲氨基)乙基)-2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(250mg，0.58mmol)溶于10mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(94mg，2.32mmol)和三乙胺(1.17g，11.60mmol)，反应在60℃搅拌16小时。反应液用1.0M稀盐酸调pH为8，加入100mL乙酸乙酯，依次用30mL饱和碳酸氢钠溶液洗涤2次，30mL饱和食盐水洗涤，干燥后浓缩得到4-(2-(二甲氨基)乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(150mg,收率89％)，白色固体。ES-API:[M+H]
+＝288.3。
步骤三：4-(2-(二甲氨基)乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(75mg，0.26mmol)和2-氯-4-苯氧基苯甲醛(151mg，0.65mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(102mg，1.82mmol)。反应在室温下搅拌16小时。反应液用1.0M稀盐酸调pH为8，浓缩后粗品用薄层制备板(二氯甲烷/7.0M氨甲醇溶液＝10:1) 纯化得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-(二甲氨基)乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(100mg,收率74％)，淡黄色固体。ES-API:[M+H]
+＝520.2。
步骤四：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-(二甲氨基)乙基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(95mg,0.18mmol)溶于1，4-二氧六环(5mL)和水(0.5mL)，室温下加入2,3-二氯-5,6-二氰对苯醌(82mg，0.36mmol)，反应在室温下搅拌2小时。反应液加入6mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z63，70mg，收率74％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ12.60(s,1H),8.33(s,1H),8.03(s,1H),7.68(s,1H),7.57(d,J＝8.4Hz,1H),7.52–7.43(m,2H),7.25(t,J＝7.2Hz,1H),7.23–7.14(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),4.09(t,J＝7.2Hz,2H),2.44(t,J＝7.2Hz,2H),2.21(s,6H),1.38(s,6H).ES-API:[M+H]
+＝518.2。
实施例19：Z18的合成
步骤一：5-溴-4-氟-1H-吡咯[2,3-b]吡啶(950mg,4.42mmol)溶于25mL四氢呋喃，在氮气保护下冷却至0℃，加入氢化钠(1.01g,5.75mmol，60％分散在矿物油)，反应在室温下搅拌30分钟。再次冷却至0℃，缓慢滴加苯磺酰氯(1.01g,5.75mmol)的四氢呋喃溶液(2mL)，反应在室温下搅拌16小时。反应液中加入40mL水，用80mL乙酸乙酯萃取。有机相用30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到5-溴-4-氟-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.5g,收率95％)，白色固体。ES-API:[M+H]
+＝355.0，357.0。
步骤二：向20mL微波管中依次加入5-溴-4-氟-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(500mg,1.41mmol)，(3-氨基四氢呋喃-3-基)甲醇(330mg,2.82mmol)，N,N-二甲基乙酰胺(7mL)， 和N,N-二异丙基乙胺(546mg,13.36mmol)，在微波反应器中160℃反应8小时。反应液中加入100mL乙酸乙酯，用30mL稀食盐水洗涤3次，30mL饱和食盐水洗涤，干燥浓缩，粗品用乙酸乙酯/石油醚＝1：1打浆得到(3-((5-溴-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢呋喃-3-基)甲醇(240mg,收率38％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ8.16(s,1H),8.08(d,J＝7.6Hz,2H),7.77-7.69(m,2H),7.62(t,J＝7.6Hz,2H),6.81(d,J＝4.0Hz,1H),5.67(s,1H),5.44(t,J＝5.2Hz,1H),3.95–3.59(m,6H),2.30-2.10(m,2H).ES-API:[M+H]
+＝452.0，454.0。
步骤三：向5mL微波管中依次加入3-((5-溴-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢呋喃-3-基)甲醇(115mg,0.25mmol)，醋酸钯(12mg,0.05mmol),[1,1”-双萘]-2-基二叔丁基膦(30mg,0.075mmol),碳酸铯(122mg,0.375mmol)和甲苯(4mL)，氮气置换2分钟，在微波反应器中115℃反应1小时。反应液过滤，用二氯甲烷洗涤，滤液浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-3％)得到7'-(苯磺酰基)-1',4,5,7'-四氢-2H，3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪](105mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝372.1
步骤四：7'-(苯磺酰基)-1',4,5,7'-四氢-2H,3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪](180mg，粗品)溶于8mL甲醇，2mL四氢呋喃和2mL水，加入氢氧化钠(78mg，1.94mmol)，反应在65℃搅拌16小时.反应液用1.0M稀盐酸调pH为8，加入10mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)得到1',4,5,7'-四氢-2H,3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪](90mg,两步收率82％)，淡黄色固体。ES-API:[M+H]
+＝232.1。
步骤五：1',4,5,7'-四氢-2H，3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪](85mg，0.37mmol)和2-氯-4-苯氧基苯甲醛(256mg，1.10mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(145mg，2.59mmol)。反应在室温下搅拌16小时。反应液用1.0M稀盐酸调pH为8，60mL乙酸乙酯萃取。有机相用20mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到(2-氯-4-苯氧基苯基)(1',4,5,7'-四氢-2H，3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪]-9'-基)甲醇(120mg,收率70％)，淡黄色固体。ES-API:[M+H]
+＝464.1。
步骤六：(2-氯-4-苯氧基苯基)(1',4,5,7'-四氢-2H，3'H-螺环[呋喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b][1,4]恶嗪]-9'-基)甲醇(120mg,0.26mmol)溶于1，4-二氧六环(5mL)和水(0.5mL)，室温下加入2,3-二氯-5,6-二氰对苯醌(83mg，0.36mmol)，反应在室温下搅拌1小时。反 应液加入5mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用50mL乙酸乙酯萃取。有机相依次用15mL饱和碳酸氢钠溶液，15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z18，40mg,收率33％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ8.39(s,1H),7.75(s,1H),7.57-7.52(m,2H),7.47(t,J＝8.0Hz,2H),7.25(t,J＝7.6Hz,1H),7.21-7.15(m,3H),7.01(dd,J＝8.4,2.4Hz,1H),6.06(s,1H),4.11(d,J＝10.6Hz,1H),4.04–3.89(m,3H),3.76(d,J＝8.8Hz,1H),3.56(d,J＝8.8Hz,1H),2.18–2.08(m,1H),1.99–1.89(m,1H).ES-API:[M+H]
+＝462.0。
实施例20：Z19的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(0.60g,1.7804mmol)和1-(叔丁基)3-甲基3-氨基哌啶-1,3-二羧酸酯(450mg,1.540mmol)溶于N,N-二甲基甲酰胺(20mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌12小时。反应液中加入120mL乙酸乙酯，用80mL水洗涤2次，60mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到1-(叔丁基)3-甲基3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)哌啶-1,3-二羧酸(367mg,收率36％)，淡黄色固体。ES-API:[M+H]
+＝560.2。
步骤二：1-(叔丁基)3-甲基3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)哌啶-1,3-二羧酸(320mg,0.6563mmol)溶于乙酸(20mL)，加入铁粉(0.672g,12.0mmol),反应在80℃搅拌1小时。溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(230mg,收率70％)，淡黄色固体。ES-API:[M+H]
+＝498.2。
步骤三：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(230mg，0.4626mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(129mg，3.2381mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和5mL饱和氯化铵溶液，用160mL乙酸乙酯萃取。有机相依次用40mL饱和碳酸氢钠溶液，60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(382mg,粗品)，灰白色固体。ES-API:[M+H]
+＝358.3。
步骤四：3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(382mg，粗品)和2-氯-4-苯氧基苯甲醛(215mg，0.9252mmol)溶于甲醇(12.0mL)，将反应冷至0℃，加入氢氧化钾(181mg，3.238mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH为8，120mL乙酸乙酯萃取。有机相用63mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(500mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝590.2。
步骤五：9'-(((2-氯-4-苯氧基苯基)(羟基)甲基)-3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-1-羧酸叔丁酯(500mg,粗品)溶于20mL二氯甲烷，加入2,3-二氯-5,6-二氰基-1,4-苯醌(210mg，0.9252mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-30％)得到9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(260mg,三步总收率95％)，淡黄色固体，ES-API:[M+H]
+＝588.2。
步骤六：9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(260mg,0.4429mmol)溶于二氯甲烷(12mL)中，最后加入三氟乙酸(3.0mL)，室温反应3小时后减压旋干溶剂得到粗品9'-(2-氯-4-苯氧基苯甲酰基)-4',7'-二氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(300mg,粗品)。ES-API:[M+H]
+＝488.1。粗品直接用于下一步反应。
步骤七：冰水浴条件下，9'-(2-氯-4-苯氧基苯甲酰基)-3'-氧代-1',3',4',7'-四氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-1-羧酸叔丁酯(300mg,粗品)溶于乙腈(20mL)，加入氰基硼氢化钠(139mg,2.21mmol)后再滴加入甲醛水溶液(180mg,2.21mmol,37％a.q.)。将体系缓慢升温至室温并搅拌2小时。反应完毕，向体系中加入饱和碳酸氢钠(30mL)和乙酸乙酯(60mL)，将乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干，粗品经制备HPLC 纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-1-甲基-4',7'-二氢螺[哌啶-3,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(Z19,13mg,2步总收率6％)。ES-API:[M+H]
+＝502.2。
实施例21：Z22的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(500mg,1.48mmol)和4-氨基四氢-2H-吡喃-4-羧酸甲酯(283mg,1.78mmol)溶于N,N-二甲基乙酰胺(5mL)，加入N,N-二异丙基乙胺(573g,4.44mmol)，微波反应在120℃搅拌1.5小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到4-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(374mg,收率55％)，黄色固体。ES-API:[M+H]
+＝461.1。
步骤二：4-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(374mg,0.813mmol)溶于乙酸(10mL)，加入铁粉(455mg,8.13mmol),反应在80℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg,收率61％)，黄色固体。ES-API:[M+H]
+＝399.1
步骤三：7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(200mg，0.50mmol)溶于10mL N,N-二甲基甲酰胺，加入无水碳酸钾(414mg，3.0mmol)和碘甲烷(352mg，2.5mmol)，封管中反应在40℃搅拌3小时。向反应液中加入100mL乙酸乙酯萃取。有机相依次用水和饱和食盐水洗涤，干燥后浓缩得到4'-甲基-7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(180mg,收率87％)，灰白色固体。ES-API:[M+H]
+＝413.1。
步骤四：4'-甲基-7'-(苯磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(180mg，0.43mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(86mg，2.15mmol)，反应在65℃搅拌15小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(92mg,收率42％)，灰白色固体。ES-API:[M+H]
+＝273.1。
步骤六：4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(92mg，0.34mmol)和2-氯-4-苯氧基苯甲醛(157mg，0.68mmol)溶于甲醇(5mL)，将反应冷至0℃，加入氢氧化钾(95mg，1.70mmol)。反应在室温下搅拌3小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇＝10:1)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡咯并[3,4-b]吡嗪]-3'(1'H)-酮(110mg,收率65％)，淡黄色固体。ES-API:[M+H]
+＝505.1。
步骤七：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡咯并[3,4-b]吡嗪]-3'(1'H)-酮(110mg,0.218mmol)溶于5mL 1，4-二氧六环和1ml水中，加入DDQ(99mg，0.436mmol)，反应在室温下搅拌30分钟，反应液加入5mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。浓缩，粗品用制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(Z22，28mg,收率25％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),9.06(s,1H),8.05(s,1H),7.76(s,1H),7.60(d,J＝8.5Hz,1H),7.53–7.44(m,2H),7.30–7.15(m,4H),7.04(dd,J＝8.4,2.4Hz,1H),3.89–3.69(m,4H),3.40(s,3H),2.14–2.03(m,2H),1.60(d,J＝13.4Hz,2H).ES-API:[M+H]
+＝503.1。
实施例22：Z55的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.0g,2.96mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯(472mg,3.56mmol)溶于N,N-二甲基乙酰胺(10mL)，加入N,N-二异丙基乙胺(1.14g,8.88mmol)，微波反应在95℃搅拌15小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(770mg,收率60％)，黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：3-羟基-2-甲基-2-甲基(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(770mg,1.77mmol)溶于乙酸(10mL)，加入铁粉(1.98g,35.4mmol),反应在80℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(羟甲基)-2-甲基-7-(苯磺酰基)-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3(2H)-酮(462mg,收率70％)，黄色固体。ES-API:[M+H]
+＝373.0.
步骤三：2-(羟甲基)-2-甲基-7-(苯磺酰基)-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3(2H)-酮(462mg，1.24mmol)溶于30mL甲醇，5mL四氢呋喃和3mL水，加入氢氧化钠(248mg，6.2mmol)，反应在65℃搅拌6小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到2-(羟甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(110mg,收率59％)，灰白色固体。ES-API:[M+H]
+＝233.1。
步骤四：2-(羟甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(110mg，0.474mmol)和2-氯-4-((3-(三氟甲基)吡啶-2-基)氧基)苯甲醛(286mg，0.95mmol)溶于甲醇(5mL)，将反应冷至0℃，加入氢氧化钾(132mg，2.37mmol)。反应在室温下搅拌3小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH为8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/甲醇 ＝10:1)纯化得到9-((2-氯-4-((3-(三氟甲基)吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(110mg,收率43％)，淡黄色固体。ES-API:[M+H]
+＝534.1。
步骤五：9-((2-氯-4-((3-(三氟甲基)吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(110mg,0.206mmol)溶于5mL 1，4-二氧六环和1ml水中，加入DDQ(93mg，0.412mmol)，反应在室温下搅拌30分钟，反应液加入5mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-((3-(三氟甲基)吡啶-2-基)氧基)苯甲酰基)-2-(羟甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(55mg,收率50％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ10.43(s,1H),9.03(s,1H),8.48(dd,J＝5.0,1.8Hz,1H),8.33(dd,J＝7.8,1.8Hz,1H),8.24(s,1H),7.68(s,1H),7.61(d,J＝8.4Hz,1H),7.57–7.48(m,2H),7.42(dd,J＝7.6,4.9Hz,1H),7.29(dd,J＝8.4,2.3Hz,1H),5.25(s,1H),3.70(d,J＝10.5Hz,1H),3.49(d,J＝10.5Hz,1H),1.37(s,3H).ES-API:[M+H]
+＝532.1。
实施例23：Z56的合成
步骤一：氮气保护下，2-氯-4-羟基苯甲醛(2.04g,13.081mmol),2-溴-4-甲基吡啶(1.5g,8.721mmol)，磷酸钾(4.072g,19.186mmol)，碘化亚铜(166mg,0.872mmol)，和反式-N,N'-二甲基-1,2-环己二胺(248mg,1.744mmol)溶解于45mL无水N,N-二甲基甲酰胺中，反应液加热至110℃搅拌过夜。LCMS检测到有产物生成，反应液冷却至室温、过滤，滤液加入50mL乙酸乙酯和50mL水，乙酸乙酯萃取(50mL X 3),合并的有机相用饱和食盐水洗涤(30mL X 3)，然后无水硫酸钠干燥，经过滤、浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(200mg,收率9％)，白色固体。ES-API:[M+H]
+＝248.1。
步骤二：冰水浴下，氢氧化钾(113mg,2.025mmol)加入到2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(200mg,0.810mmol)和2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(94mg,0.405mmol)的二氯甲烷(8mL)溶液中，反应液室温搅拌3小 时。LCMS检测到有产物生成。加入1N HCl
(aq.)将反应液pH调至7左右，乙酸乙酯萃取(20mL X 3)，合并的有机相用饱和食盐水洗涤(10mL X 2)，然后无水硫酸钠干燥，经过滤、浓缩得到9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(132mg,收率68％)，类白色固体。ES-API:[M+H]
+＝480.1.
步骤三：室温下，2,3-二氯-5,6-二氰基-1,4-苯醌(125mg,0.551mmol)加入到9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(132mg,0.276mmol)的二氯甲烷(15mL)溶液中，反应液室温搅拌3小时。LCMS检测到有产物生成。反应液减压浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(羟甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z56，52.5mg,收率40％)，类白色固体。ES-API:[M+H]
+＝478.1。
1H NMR(500MHz,DMSO-d
6)δ8.25(s,1H),8.09(d,J＝6.5Hz,1H),7.67(s,1H),7.56(d,J＝10.5Hz,1H),7.52(s,1H),7.38(d,J＝3.0Hz,1H),7.19(dd,J1＝2.5Hz,J2＝10.5Hz,1H),7.06(d,J＝5.5Hz,1H),6.99(s,1H),6.06(bs,1H),3.69(d,J＝13.5Hz,1H),3.48(d,J＝13.0Hz,1H),2.37(s,3H),1.36(m 3H).
参照实施例1至23的制备方法通过更改部分原料来制备以下化合物：
实施例27 Z24-1及其异构体、Z24-2及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.28g,3.79mmol)和1-氨基-3-羟基环戊烷-1-羧酸乙酯盐酸盐(662mg,3.16mmol)溶于N,N-二甲基乙酰胺(20mL)，加入N,N-二异丙基乙胺(1.225g,9.48mmol)，反应在95℃搅拌16小时。反应液中加入120mL乙酸乙酯，依次用40mL稀盐水洗涤4次，40mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到3-羟基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氨基)氨基]环戊烷-1-甲酸乙酯(1.1g,收率71％)，黄色液体。ES-API:[M+H]
+＝475.1。
步骤二：3-羟基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氨基)氨基]环戊烷-1-甲酸乙酯(550mg,1.16mmol)溶于乙酸(7mL)，加入铁粉(649mg,11.6mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用30mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得到3-羟基-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(410mg,收率88.8％)，黄色液体。ES-API:[M+H]
+＝399.1
步骤三：3-羟基-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(410mg,1.03mmol)溶于10mL甲醇，4mL四氢呋喃和2mL水，加入氢氧化钠(206mg，5.15mmol)，反应在65℃搅拌6小时,反应液减压浓缩得到粗品。ES-API:[M+H]
+＝259.1。
步骤四：将上述粗品和2-氯-4-苯氧基苯甲醛(719mg，3.09mmol)溶于甲醇(8mL)， 将反应冷至0℃，加入氢氧化钾(404mg，7.21mmol)。反应在室温下搅拌12小时。反应液用1.0M稀盐酸调pH＝8，加入2mL水，用60mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，快速柱层析(甲醇/二氯甲烷＝0-10％)得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-羟基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(180mg,收率36.7％)，无色液体。ES-API:[M+H]
+471.1。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-羟基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(180mg,0.367mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(166mg，0.733mmol)，反应在室温下搅拌30分钟。反应液加入NaHSO
3饱和溶液20mL淬灭，用80mL乙酸乙酯萃取，有机相用30mL饱和碳酸氢钠溶液和30mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到两个对映异构体。一个对映异构体是Z24-1(81mg,峰1，保留时间7.412min，收率45％)，白色固体，ES-API:[M+H]
+＝489.1。另一个对映异构体是Z24-2(32mg,峰2，保留时间7.611min，收率18％)，白色固体。ES-API:[M+H]
+＝489.1。
步骤六：将对映异构体Z24-1(78mg)用手性制备拆分(分离柱：IC 150mm*4.6mm*5μm,流动相:正己烷:乙醇:三氟乙酸＝70:30:0.2,流速:1ml/min,柱温：30℃)得到两个单一构型的异构体。一个单一异构体，其结构任意指定为Z24-a(32mg,峰1，保留时间10.259min，收率41％)，白色固体。ES-API:[M+H]
+＝489.1。另一个单一异构体，其结构任意指定为Z24-b(32mg,峰2，保留时间17.062min，收率41％)，白色固体。ES-API:[M+H]
+＝489.1。
步骤七：将对映异构体Z24-2(30mg)用手性制备拆分(分离柱IC：150mm*4.6mm*5μm,流动相:正己烷:乙醇＝70:30,流速:1ml/min,柱温：30℃)得到两个单一构型的异构体。一个单一异构体，其结构任意指定为Z24-c(12mg,峰1，保留时间8.805min，收率40％)，淡白色固体。ES-API:[M+H]
+＝489.1。另一个单一异构体，其结构任意指定为Z24-d(12mg,峰2，保留时间11.458min，收率40％)，淡白色固体。ES-API:[M+H]
+＝489.1。
实施例28 Z25及其异构体的合成
步骤一：3-羟基-2-甲基-2-甲基((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(550mg，1.16mmol),氧化银(5.3g，23mmol)和碘甲烷(3.3g，23mmol)溶于乙腈(50mL)，反应在35℃下，避光搅拌3天。反应液用硅藻土过滤，滤饼用50ml乙酸乙酯洗涤三次，滤液浓缩后得到3-甲氧基-1-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)氨基]戊-1-羧酸乙酯(354mg，收率63％)，黄色油状。ES-API:[M+H]
+＝489.1。
步骤二：3-甲氧基-1-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)氨基]戊-1-羧酸乙酯(354mg，0.72mmol)溶于乙酸(20mL)，加入铁粉(286mg，5.11mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水洗涤2次，干燥浓缩得到3-甲氧基-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(360mg,粗品)，黄色固体。ES-API:[M+H]
+＝413.1。
步骤三：3-甲氧基-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(360mg，0.87mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(244mg，6.09mmol)，反应在65℃搅拌7小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液， 20mL饱和食盐水洗涤，干燥后浓缩得到3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(160mg,收率67％)，灰白色固体。ES-API:[M+H]
+＝273.1。
步骤四：3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(100mg，0.37mmol)和2-氯-4-苯氧基苯甲醛(172mg，0.74mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(145mg，2.59mmol)。反应在室温下搅拌16小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH＝8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-甲氧基-4',7'-二氢螺环[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(121mg,收率65％)，淡黄色固体。ES-API:[M+H]
+＝505.1。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-甲氧基-4',7'-二氢螺环[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(121mg，0.24mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(109mg，0.48mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液洗涤，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-3-甲氧基-4',7'-二氢螺环[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z25，45mg,收率53％)，白色固体。ES-API:[M+H]
+＝503.1。
步骤六：将将上述步骤制得的化合物Z25(45mg)用手性制备拆分(分离柱IA,250mm*4.6mm*5μm,流动相:正己烷:乙醇＝40:60,流速:1ml/min,柱温：30℃)得到多个异构体化合物。一个单一异构体，其结构任意指定为Z25-1(10mg,峰1，保留时间5.211min)，白色固体。ES-API:[M+H]
+＝503.1。另一个单一异构体，其结构任意指定为Z25-2(10mg,峰2，保留时间7.713min)，白色固体。ES-API:[M+H]
+＝503.1。一个对映异构体，其结构任意指定为Z25-3(28mg,峰3，保留时间12.324min)，白色固体。ES-API:[M+H]
+＝503.1。
将对映异构体Z25-3用手性制备拆分(分离柱IG,250mm*4.6mm*5μm,流动相:乙腈:异丙醇＝80:20,流速:1ml/min,柱温：30℃)得到两个单一异构体。一个单一异构体，其结构任意指定为Z25-3a(5mg,峰3，保留时间10.321min)，白色固体。ES-API:[M+H]
+＝503.1。另一个单一异构体，其结构任意指定为Z25-3b(4mg,峰4，保留时间12.944min)， 白色固体。ES-API:[M+H]
+＝503.1。
实施例29 Z26及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.06g,3.14mmol)和1-氨基-3-氰基环戊烷-1-羧酸乙酯(520mg,2.85mmol)溶于N,N-二甲基乙酰胺(20mL)，加入N,N-二异丙基乙胺(11g,8.55mmol)，反应在100℃搅拌16小时。反应液中加入120mL乙酸乙酯，依次用40mL稀盐水洗涤4次，40mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到3-氰基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)乙基戊-1-羧酸乙酯(973mg,收率71％)，黄色液体。ES-API:[M+H]
+＝484.1。
步骤二：3-氰基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)乙基戊-1-羧酸乙酯(973mg,2.01mmol)溶于乙酸(7mL)，加入铁粉(1.126g,20.1mmol),反应在80℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用30mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3-腈(780mg,收率95％)，黄色液体。ES-API:[M+H]
+＝408.1
步骤三：3'-氧代-7'-(苯磺酰基)-1',3',4',7'-四氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并 [3,4-b]吡嗪]-3-腈(390mg,0.96mmol)溶于10mL甲醇，4mL四氢呋喃和2mL水，加入氢氧化钠(192mg，4.8mmol)，反应在60℃搅拌3小时,反应液减压浓缩得到粗品。ES-API:[M+H]
+＝268.1。
步骤四：将上述粗品和2-氯-4-苯氧基苯甲醛(670mg，2.88mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(376mg，6.72mmol)。反应在室温下搅拌12小时。反应液用1.0M稀盐酸调pH＝8，加入2mL水，用60mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，快速柱层析(甲醇/二氯甲烷＝0-20％)得到9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-异氰基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(230mg,收率48％)，黄色液体。ES-API:[M+H]
+500.1。
步骤五：9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-异氰基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(230mg,0.46mmol)溶于10mL四氢呋喃，0℃下加入戴斯-马丁氧化剂(390mg，0.92mmol)，反应在室温下搅拌30分钟。反应液加入NaHSO
3饱和溶液20mL淬灭，用80mL乙酸乙酯萃取，有机相用30mL饱和碳酸氢钠溶液和30mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z26，148mg，收率64％)，白色固体。ES-API:[M+H]
+＝498.1。
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.78(s,1H),7.68(d,J＝1.8Hz,1H),7.56(dd,J＝8.5,5.7Hz,1H),7.48(dd,J＝8.4,7.2Hz,2H),7.25(td,J＝7.4,1.3Hz,1H),7.22–7.15(m,3H),7.03(ddd,J＝8.4,3.9,2.3Hz,1H),2.36–2.19(m,3H),2.18–1.98(m,2H),1.91(dd,J＝13.5,7.6Hz,1H),1.81(dd,J＝12.7,5.8Hz,1H).
步骤六：将上述步骤制得的化合物Z26(145mg,0.291mmol)用手性制备拆分(分离柱：IC 150mm*4.6mm*5μm,流动相:正己烷:异丙醇:二乙胺＝60:40:0.2,流速:1ml/min,柱温：30℃)得到多个异构体化合物。两个异构体的混合物P1(15mg,峰1，保留时间9.094min，收率10％)，白色固体。一个单一异构体，其结构任意指定为Z26-3(44.44mg,峰2，保留时间13.578min，收率31％)，淡白色固体ES-API:[M+H]
+＝498.1。另一个单一异构体，其结构任意指定为Z26-4(45.18mg,峰3，保留时间16.941min，收率31％)，淡白色固体。ES-API:[M+H]
+＝498.1。
步骤七：将两个异构体的混合物P1(15mg)用手性制备拆分(分离柱：IA150mm*4.6mm*5μm,流动相:正己烷:乙醇＝60:40,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z26-1(5.25mg,峰1，保留时间7.995min，收率35％)，白色固体ES-API:[M+H]
+＝498.1。另一个单一异构体，其结构任意指定为Z26-2(4.45mg,峰2，保留时间14.713min，收率30％)，白色固体。ES-API: [M+H]
+＝498.1。
实施例44 Z41-2及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(687mg,2.03mmol)和trans-3-氨基-6-((叔丁基二苯基硅烷基)氧基)甲基)四氢-2H-吡喃-3-羧酸甲酯(580mg,1.36mmol)溶于N,N-二甲基乙酰胺(10mL)，加入N,N-二异丙基乙胺(877mg,6.80mmol)，反应在95℃搅拌16小时。反应液中加入80mL乙酸乙酯，依次用30mL稀盐水洗涤4次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到trans-6-((叔丁基二苯基硅烷基)氧基)甲基)-3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(420mg,收率42％)，黄色固体。ES-API:[M+H]
+＝729.1。
步骤二：trans-6-((叔丁基二苯基硅烷基)氧基)甲基)-3-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(420mg,0.58mmol)溶于乙酸(10mL)，加入铁粉(325mg,5.80mmol),反应在85℃搅拌2小时。反应液加入100mL乙酸乙酯，依次用30mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩得到trans-6-((叔丁基二苯基硅烷基)氧基)甲基)-7'-(苯基磺酰基)-4',5,6,7'-四氢-2H,4H螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(350mg,收率91％)，淡棕色固体。ES-API:[M+H]
+＝667.2
步骤三：trans-6-((叔丁基二苯基硅烷基)氧基)甲基)-7'-(苯基磺酰基)-4',5,6,7'-四氢-2H,4H螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(330mg，0.49mmol)溶于10mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(119mg，2.97mmol)，反应在65℃搅拌20小时。反应液用1.0M稀盐酸调pH＝8，用100mL乙酸乙酯萃取。有机相干 燥后浓缩，用10mL石油醚打浆得到trans-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(240mg,粗品)，淡棕色固体。ES-API:[M+H]
+＝289.1。
步骤四：trans-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(220mg，粗品)和2-氯-4-苯氧基苯甲醛(531mg，2.29mmol)溶于甲醇(12mL)，将反应冷至0℃，加入氢氧化钾(300mg，5.34mmol)。反应在室温下搅拌16小时。反应液用1.0M稀盐酸调pH＝8，加入2mL水，用80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝10:1)纯化得到trans-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(165mg,两步收率64％)，淡棕色固体。ES-API:[M+H]
+＝521.2。
步骤五：trans-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(165mg,0.32mmol)溶于1,4-二氧六环(7mL)和水(0.7mL)，加入2,3-二氯-5,6-二氰对苯醌(144mg，0.64mmol)，反应在室温下搅拌1小时。反应液加入6mL饱和硫代硫酸钠溶液和6mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相依次用15mL饱和碳酸氢钠溶液，15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化后，然后手性制备拆分(分离柱：IC250mm*4.6mm*5μm,流动相:正己烷:乙醇＝70:30,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z41-2a(64mg,峰1，保留时间13.441min，收率39％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ12.54(s,1H),10.48(s,1H),8.38(s,1H),7.75(s,1H),7.66(s,1H),7.58(d,J＝8.4Hz,1H),7.48(t,J＝7.6Hz,2H),7.25(t,J＝7.6Hz,1H),7.22–7.16(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),4.71–4.66(m,1H),4.04(d,J＝11.6Hz,1H),3.61–3.50(m,2H),3.45–3.36(m,1H),3.29(d,J＝12.0Hz,1H),2.24–2.14(m,1H),1.91–1.76(m,2H),1.66–1.56(m，1H).ES-API:[M+H]
+＝519.1。另一个单一异构体，其结构任意指定为Z41-2b(61mg,峰2，保留时间15.881min，收率37％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ12.53(s,1H),10.48(s,1H),8.37(s,1H),7.75(s,1H),7.66(s,1H),7.57(d,J＝8.4Hz,1H),7.48(t,J＝7.6Hz,2H),7.25(t,J＝7.6Hz,1H),7.22–7.15(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),4.71–4.66(m,1H),4.04(d,J＝11.2Hz,1H),3.63–3.50(m,2H),3.45–3.36(m,1H),3.29(d,J＝11.6Hz,1H),2.24–2.14(m,1H),1.91–1.76(m,2H),1.66–1.56(m，1H).ES-API:[M+H]
+＝519.1。
实施例55 Z52及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.0g,2.967mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(0.6g,3.550mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(0.6g,收率46％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：-3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(600mg,1.382mmol)溶于乙腈(30mL)，依次加入氧化银(3.70g,15.96mmol)和碘甲烷(1mL,16.05mmol),氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(520mg,收率83％)，黄色固体。ES-API:[M+H]
+＝449.0。
步骤三：3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(520mg,1.272mmol)溶于乙酸(20mL)中，加入铁粉(1.42g,25.44mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,82mL饱和碳酸氢钠洗涤2次，80mL 饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg,收率52％)，黄色固体。ES-API:[M+H]
+＝387.2
步骤四：2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg,0.69734mmol)溶于丙酮/N,N-二甲基甲酰胺(10mL:2mL)的混合溶液中，依次加入碘甲烷(957mg,6.734mmol)和碳酸钾(465mg,3.367mmol)，40℃下在封管中搅拌12小时。反应完毕后，加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,82mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,收率74％)，黄色固体。ES-API:[M+H]
+＝401.2
步骤五：2-(甲氧基甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.4997mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(7140.0mg，3.498mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(253mg,粗品)，淡白色固体。ES-API:[M+H]
+＝261.1。
步骤六：2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(253mg，粗品)和2-氯-4-苯氧基苯甲醛(230mg，0.9913mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(200mg，3.5710mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，150mL乙酸乙酯萃取。有机相用70mL饱和食盐水洗涤，干燥后浓缩得到粗品9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(380mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝545.2。
步骤七：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(380mg,粗品)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(380mg，1.674mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z52,18mg,3步总收率7.3％)，淡黄色固体，ES-API:[M+H]
+＝491.1。
步骤八：将上述步骤制得的化合物Z52(18.0mg)用手性制备拆分(分离柱：IC 150mm*4.6mm*5μm,流动相:正己烷:乙醇:二乙胺＝70:30:0.2,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z52-1(2.52mg,峰1，保留时间15.908min，收率14％)，淡白色固体ES-API:[M+H]
+＝491.1。另一个单一异构体，其结构任意指定为Z52-2(1.98mg,峰2，保留时间20.198min，收率11％)，淡白色固体ES-API:[M+H]
+＝491.1。
实施例65 Z64及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(4.5g,13.35mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(4.0g,8.902mmol)溶于N,N-二甲基乙酰胺(80mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入200mL乙酸乙酯，用60mL水洗涤2次，80mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(3.3g,收率57％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(2.60g,5.990mmol)溶于乙腈(100mL)，依次加入氧化银(20.82g,89.86mmol)和碘甲烷(21.26g,149.5mmol),氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(2.20g,收率82％)，黄色固体。ES-API:[M+H]
+＝449.0。
步骤三：3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.05g,2.343mmol)溶于乙酸(30mL)中，加入铁粉(2.62g,46.87mmol)。逐渐升温 至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(650mg,收率72％)，黄色固体。ES-API:[M+H]
+＝387.2
步骤四：2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.5180mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(150mg，3.626mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和30mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(246mg,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤五：2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(246mg，粗品)和2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(230mg，0.9310mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(205mg，3.626mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(310mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝494.2。
步骤六：9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(310mg,粗品)溶于30mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(310mg，1.3656mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z64,30mg,3步总收率15.7％)，淡黄色固体，ES-API:[M+H]
+＝492.1。
1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.49(s,1H),8.28(s,1H),8.09(d,J＝5.1Hz,1H),7.70(s,1H),7.64–7.53(m,2H),7.38(d,J＝2.2Hz,1H),7.19(dd,J＝8.4,2.3Hz,1H),7.06(d,J＝5.0Hz,1H),6.99(s,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),2.37(s,3H),1.39(s,3H)。
步骤七：将上述步骤制得的化合物Z64(30mg)用手性制备拆分(分离柱：IC 150mm*4.6mm*5μm,流动相:正己烷:乙醇：二乙胺＝40:60:0.2,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z64-1(7.0mg,峰1，保留时间18.717min，收率23％)，淡白色固体ES-API:[M+H]
+＝492.1。另一个单一异构体，其结构任意指定为Z64-2(12mg,峰2，保留时间22.80min，收率40％)，淡白色固体ES-API:[M+H]
+＝492.1。
实施例67 Z66及其异构体的合成
步骤一：3-羟基-2-甲基-2-甲基((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(1.0g，2.3mmol),氧化银(5.3g，23mmol)和氘代碘甲烷(3.34g，23mmol)溶于乙腈(50mL)，反应在35℃下，避光搅拌2天。反应液用硅藻土过滤，滤饼用50ml乙酸乙酯洗涤三次，滤液浓缩后得到3-(甲氧基-d
3)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.1g,粗品)，黄色油状。ES-API:[M+H]
+＝452.1。
步骤二：3-(甲氧基-d
3)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(330mg，0.73mmol)溶于乙酸(15mL)，加入铁粉(286mg，5.11mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸氢钠，40mL饱和食盐水洗涤2次，干燥浓缩，粗品用乙酸乙酯打浆得到2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(270mg,收率95％)，黄色固体。ES-API:[M+H]
+＝390.1
步骤三：2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(270mg，0.69mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(270mg，4.83mmol)，反应在65℃搅拌7小时。向反应液中加入15mL水 和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg,收率70％)，灰白色固体。ES-API:[M+H]
+＝250.1。
步骤四：2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg，0.48mmol)和2-氯-4-苯氧基苯甲醛(222mg，0.96mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(168mg，3.01mmol)。反应在室温下搅拌48小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH＝8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg,收率52％)，淡黄色固体。ES-API:[M+H]
+＝482.1。
步骤五：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg，0.26mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(118mg，0.52mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相用20mL饱和碳酸氢钠溶液洗涤两次，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z66，80mg，收率64％)，白色固体。ES-API:[M+H]
+＝480.1。
1H NMR(400MHz,DMSO-d
6)δ12.45(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.4Hz,1H),7.51–7.44(m,2H),7.26-7.23(m,1H),7.21-7.15(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.64(d,J＝9.6Hz,1H),3.47(d,J＝9.6Hz,1H),1.38(s,3H).
步骤六：将上述步骤制得的化合物Z66(80mg)用手性制备拆分(柱：IE,250mm*4.6mm*5μm,流动相:正己烷:乙醇＝70:30,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z66-1；(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(32mg,峰1，保留时间10.837min)，白色固体。ES-API:[M+H]
+＝480.1。另一个单一异构体，其结构任意指定为Z66-2；(R)-9-(2-氯-4-苯氧基苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(31mg,峰2，保留时间12.802min)，白色固体。ES-API:[M+H]
+＝480.1。
实施例68 Z67及其异构体的合成
步骤一：3-羟基-2-甲基-2-甲基((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(1.0g，2.3mmol)，氧化银(5.3g，23mmol)和碘乙烷(3.6g，23mmol)溶于乙腈(50mL)，反应在35℃下，避光搅拌3天。反应液用硅藻土过滤，滤饼用50mL乙酸乙酯洗涤三次，滤液浓缩后得到3-乙氧基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(1.2g,粗品)，黄色油状。ES-API:[M+H]
+＝463.1。
步骤二：3-乙氧基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯(250mg，0.54mmol)溶于乙酸(15mL)，加入铁粉(212mg，3.78mmol)，反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸氢钠溶液洗涤2次，40mL饱和食盐水，干燥浓缩得到2-(乙氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(170mg,收率79％)，黄色固体。ES-API:[M+H]
+＝401.1
步骤三：2-(乙氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(170mg，0.43mmol)溶于10mL甲醇，5mL四氢呋喃和2mL水，加入氢氧化钠(119mg，2.98mmol)，反应在65℃搅拌7小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用50mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(130mg,收率100％)，灰白色固体。ES-API:[M+H]
+＝261.1。
步骤四：2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(130mg，0.5mmol)和2-氯-4-苯氧基苯甲醛(232mg，1.00mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(196mg，3.5mmol)。反应在室温下搅拌16小时。将反应液 倒入60mL水中，用1.0M稀盐酸调pH＝8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(135mg,收率55％)，淡黄色固体。ES-API:[M+H]
+＝493.1。
步骤五：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(135mg,0.27mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(123mg，0.56mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液，用50mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液和20mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C1819*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z67,70mg,收率53％)，白色固体。ES-API:[M+H]
+＝491.1。
1H NMR(400MHz,DMSO-d
6)δ12.44(s,1H),10.47(s,1H),8.30(s,1H),7.70(s,1H),7.59(s,1H),7.56-7.53(m,1H),7.51-7.44(m,2H),7.28-7.22(m,1H),7.19-7.16(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.65(d,J＝9.8Hz,1H),3.55-3.43(m,4H),1.39(s,3H),1.03(t,J＝7.0Hz,3H)。
步骤六：将上述步骤制得的化合物Z67(70mg)用手性制备拆分(分离柱IE,250mm*4.6mm*5μm,流动相:正己烷:乙醇＝70:30,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z67-1：(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(26mg,峰1，保留时间8.852min)，白色固体。ES-API:[M+H]
+＝491.1。另一个单一异构体，其结构任意指定为Z67-2：(R)-9-(2-氯-4-苯氧基苯甲酰基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg,峰2，保留时间11.215min)，白色固体。ES-API:[M+H]
+＝491.1。
实施例70 Z69及其异构体的合成
步骤一：氮气保护下，2-氟-4-羟基苯甲醛(1.652g，11.628mmol)、2-溴-4-甲基吡啶(2g，11.628mmol)、磷酸钾(5.43g，25.582mmol)、碘化亚铜(220mg，1.1.63mmol)和(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(330mg，2.326mmol)溶于N,N'-二甲基甲酰胺(20mL)，反应液微波110℃下搅拌1小时。LCMS检测反应已经完全，将反应液冷却至室温，加入30mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干得到淡黄色液体2-氟-4-((4-甲基吡啶-2-基)氧基)苯甲醛(215mg,收率8％)。ES-API:[M+H]
+＝232.1
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(68mg，0.275mmol)和2-氟-4-((4-甲基吡啶-2-基)氧基)苯甲醛(160mg，0.693mmol)溶于甲醇(10mL)，将反应液冷却至0℃，加入氢氧化钾(108mg，1.925mmol)。反应液缓慢升至室温搅拌4小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到化合物9-((2-氟-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(62mg，收率47％)。ES-API:[M+H]
+＝478.1
步骤三：将9-((2-氟-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(62mg，0.130mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(59mg，0.260mmol)，反应液室温搅拌3小时，LCMS检测反应已经完全。反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品 用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到白色固体9-(2-氟-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z69,22mg,收率35％)。ES-API:[M+H]+＝476.1
步骤四：将上述步骤得到的化合物Z69用SFC手性拆分(色谱柱:Daicel CHIRALPAK IE 250*4.6mm,5μm；流动相:己烷/乙醇＝50:50(V/V)；流速:1mL/min；柱温：室温)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z69-1(峰1，保留时间：11.371min，5.59mg)。ES-API:[M+H]
+＝476.1。另一个单一异构体，其结构任意指定为Z69-2(峰2，保留时间：14.824min，6.63mg)。ES-API:[M+H]
+＝476.1。
实施例72 Z71及其异构体的合成
步骤一：2-氟-4-羟基苯甲醛(500mg,3.57mmol)，氯化二苯碘鎓(1.24g,3.93mmol)和碳酸钾(1.48g,10.71mmol)的N,N-二甲基甲酰胺(20mL)混合液80℃下搅拌过夜。反应结束后，反应液溶于50mL乙酸乙酯，并用50mL饱和食盐水洗涤三次，有机相干燥浓缩，快速硅胶柱(0-30％乙酸乙酯/石油醚)纯化得到白色固体2-氟-4-苯氧基苯甲醛(600mg)，纯度100％，收率78％。
步骤二：往3-甲氧基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(700mg,1.56mmol)的醋酸(30mL)溶液中加入铁粉(1.74g,31.2mmol)。反应液在80℃下搅拌2小时。反应液用硅藻土过滤，50mL乙酸乙酯洗涤，滤液用30mL水洗三遍，30mL饱和碳酸氢钠洗涤三遍，有机相干燥，减压浓缩得到粗品2-(甲氧基甲基)- 2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(500mg)。ES-API:[M+H]
+＝387.1。
步骤三：将2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg，0.65mmol)和氢氧化钠(130mg，3.23mmol)加入到甲醇/水(5ml/1ml)的混合溶剂中，60℃搅拌2小时。反应液浓缩得到粗品2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg)。ES-API:[M+H]
+＝247.1。
步骤四：往上述粗品2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg，0.65mmol)的甲醇(5mL)溶液中加入2-氟-4-苯氧基苯甲醛(421mg，1.95mmol)和氢氧化钾(255mg，4.55mmol)，室温搅拌2小时。反应完毕，用1M的盐酸溶液调节pH＝7，加入20mL乙酸乙酯萃取三遍，有机相合并，干燥，浓缩，快速硅胶柱(0-20％甲醇/二氯甲烷)纯化得到黄色固体9-((2-氟-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg)，纯度100％，收率40％。ES-API:[M+H]
+＝463.1。
步骤五：往9-((2-氟-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg，0.26mmol)的1,4-二氧六环/水(5ml/0.5ml)混合溶液中加入2,3-二氯-5,6-二氰对苯醌(118mg，0.52mmol)，室温搅拌30分钟。反应完毕，加入2mL硫代硫酸钠水溶液淬灭，加入20mL乙酸乙酯，依次用20mL饱和碳酸氢钠水溶液，20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩并用制备HPLC纯化得到灰白色固体(Z71,32mg)，纯度100％，收率27％。ES-API:[M+H]
+＝461.2.
步骤六：将上述步骤制得的化合物Z71(32mg,0.07mmol)用手性制备拆分(分离柱:IA250mm*4.6mm*5μm,流动相:正己烷:异丙醇:二甲胺＝60:40:2,流速:1mL/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z71-1(10mg,峰1，保留时间9.71min，收率31％，de％＝100％)，白色固体。ES-API:[M+H]
+＝461.2。另一个单一异构体，其结构任意指定为Z71-2(10mg,峰2，保留时间14.40min，收率31％，de％＝100％)，白色固体。ES-API:[M+H]
+＝461.2。
实施例74 Z73及其异构体的合成
步骤一：将2-氯-4-羟基苯甲醛(400mg，2.6mmol)、2-氯-4-环丙基吡啶(486mg，3.12mmol)、L-脯氨酸(60mg，0.52mmol)、碘化亚铜(98mg，0.52mmol)、无水碳酸钾(896mg，6.5mmol)和N,N'-二甲基乙酰胺(8ml)加入到20ml微波管中，氮气置换，加热到130℃，反应3小时。乙酸乙酯萃取，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱硅胶纯化得到产物2-氯-4-((4-环丙基吡啶-2-基)氧基)苯甲醛(50mg，收率7％)。ES-API:[M+H]
+＝274.0。
步骤二：将2-氯-4-((4-环丙基吡啶-2-基)氧基)苯甲醛(50mg，0.183mmol)、2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2'：5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(100mg，0.40mmol)和氢氧化钾(112mg，2mmol)加入到8ml甲醇中，室温搅拌5小时。反应完毕，饱和氯化铵淬灭，加入乙酸乙酯萃取，浓缩得到9-((2-氯-4-((4-环丙基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(60mg，粗品)。ES-API:[M+H]
+＝520.1。
步骤三：将9-((2-氯-4-((4-环丙基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(60mg，0.115mmol)加入到1,4-二氧六环/水(5ml/1ml)混合溶液中，然后分批加入2,3-二氯-5,6-二氰对苯醌(52mg，0.231mmol)，室温搅拌30分钟，反应完毕。加入2ml硫代硫酸钠水溶液淬灭，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到9-(2-氯-4-((4-环丙基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(Z73,30mg，两步收率31.5％)。ES-API:[M+H]
+＝518.1。
步骤四：上述步骤制得的化合物Z73(30mg)经反相HPLC拆分纯化(柱：IG 250mm*4.6mm*5μm；流动相:正己烷:乙醇＝60:40；流速:1mL/min；柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z73-1(峰1，保留时间24.62min,12mg，收率40％，纯度100％)；ES-API:[M+H]
+＝518.1。
1H NMR(400MHz,DMSO-d
6)δ12.47(s,1H),10.50(s,1H),8.28(s,1H),8.03(d,J＝5.3Hz,1H),7.70(s,1H),7.64–7.52(m,2H),7.37(d,J＝2.3Hz,1H),7.18(dd,J＝8.4,2.3Hz,1H),6.97–6.86(m,2H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),2.05–1.97(m,1H),1.39(s,3H),1.12–1.07(m,2H),0.89–0.85(m,2H)。另一个单一异构体，其结构任意指定为Z73-2(峰2，保留时间30.46min,12mg,收率40％，纯度100％)。ES-API:[M+H]
+＝518.1。
1H NMR(400MHz,DMSO-d
6)δ12.47(s,1H),10.50(s,1H),8.28(s,1H),8.03(d,J＝5.3Hz,1H),7.70(s,1H),7.63–7.49(m,2H),7.37(d,J＝2.3Hz,1H),7.18(dd,J＝8.4,2.3Hz,1H),6.94–6.87(m,2H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.5Hz,1H),3.30(s,3H),2.01(td,J＝8.6,4.3Hz,1H),1.39(s,3H),1.13–1.07(m,2H),0.89–0.85(m,2H).
实施例75 Z74的合成
步骤一：将2-氯-4-羟基苯甲醛(1.23g，7.9mmol)、2-氯-4-三氟甲基吡啶(870mg，5.27mmol)、L-无水碳酸钾(2.18g，15.8mmol)和N,N'-二甲基甲酰胺(10ml)加入到50ml微波管中，氮气置换，加热到80℃，反应18小时。乙酸乙酯萃取，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱硅胶纯化得到产物2-氯-4-((4-三氟甲基吡啶-2-基)氧基)苯甲醛(300mg，收率20％)。ES-API:[M+H]
+＝302.0。
步骤二：将2-氯-4-((4-三氟甲基吡啶-2-基)氧基)苯甲醛(300mg，0.99mmol)、2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2'：5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(150mg，0.61mmol)和氢氧化钾(170mg，3.04mmol)加入到8ml甲醇中，室温搅拌3小时。反应完毕，饱和氯化铵淬灭，加入乙酸乙酯萃取，浓缩得到9-((2-氯-4-((4-三氟甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(160mg，粗品)。ES-API:[M+H]
+＝548.1。
步骤三：将9-((2-氯-4-((4-三氟甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)- 2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(160mg，0.29mmol)加入到1,4-二氧六环/水(5ml/1ml)混合溶液中，然后分批加入2,3-二氯-5,6-二氰对苯醌(132mg，0.58mmol)，室温搅拌30分钟，反应完毕。加入2ml硫代硫酸钠水溶液淬灭，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到9-(2-氯-4-((4-环丙基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(Z74,65mg，两步收率19.5％)。ES-API:[M+H]
+＝546.1。
1H NMR(400MHz,DMSO-d
6)δ12.49(s,1H),10.51(s,1H),8.49(dd,J＝5.3,0.9Hz,1H),8.28(s,1H),7.70(s,1H),7.64(d,J＝8.4Hz,1H),7.62–7.56(m,3H),7.54(d,J＝2.3Hz,1H),7.31(dd,J＝8.4,2.3Hz,1H),3.65(d,J＝9.5Hz,1H),3.49(d,J＝9.5Hz,1H),3.30(s,3H),1.39(s,3H).
实施例Z78-1和Z78-2的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(3.0g,8.90mmol)和2-氨基-4-甲氧基-2-甲基丁酸乙酯盐酸盐(2.4g,11.57mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(9.3mL,53.40mmol)，反应在95℃搅拌16小时。反应液中加入200mL乙酸乙酯，依次用70mL稀盐水洗涤3次，70mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-30％)得到4-甲氧基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丁酸乙酯(2.6g,收率61％)，黄色固体。ES-API:[M+H]
+＝477.1。
步骤二：4-甲氧基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丁酸乙酯(2.5g,5.25mmol)溶于乙酸(40mL)，加入铁粉(2.06g,36.75mmol),反应在85℃搅拌2小时。反应液加入300mL乙酸乙酯，依次用80mL水洗涤2次，80mL饱和碳酸钾洗涤,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩得到2-(2-甲氧基乙基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(2.0g, 收率95％)，白色固体。ES-API:[M+H]
+＝401.2
步骤三：2-(2-甲氧基乙基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.0g，2.50mmol)溶于25mL甲醇，10mL四氢呋喃和5mL水，加入氢氧化钠(400mg，10.0mmol)，反应在55℃搅拌16小时。反应液用1.0M稀盐酸调pH＝8，浓缩后粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得到2-(2-甲氧基乙基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(580mg,产率89％)，淡棕色固体。ES-API:[M+H]
+＝261.3。
步骤四：2-(2-甲氧基乙基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(550mg，2.11mmol)和2-氯-4-苯氧基苯甲醛(1.47g，6.33mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(827mg，14.77mmol)。反应在室温下搅拌2小时。反应液用4.0M稀盐酸调pH＝8，浓缩后粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(2-甲氧基乙基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(825mg,收率79％)，淡棕色固体。ES-API:[M+H]
+＝493.2。
步骤五：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(2-甲氧基乙基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(800mg,1.63mmol)溶于1,4-二氧六环(20mL)和水(2mL)，加入2,3-二氯-5,6-二氰对苯醌(474mg，2.09mmol)，反应在室温下搅拌1小时。反应液加入25mL饱和硫代硫酸钠溶液和25mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取2次。有机相依次用30mL饱和碳酸氢钠溶液，30mL饱和食盐水洗涤，干燥后浓缩，粗品用手性制备拆分(分离柱IG 250mm*4.6mm*5μm,流动相:正己烷:乙醇＝50:50,流速:1ml/min,柱温：30℃)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z78-1(205mg,峰1，保留时间10.078min，收率26％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ12.50(s,1H),10.44(s,1H),8.19(s,1H),7.72(s,1H),7.63(s,1H),7.56(d,J＝8.4Hz,1H),7.53–7.42(m,2H),7.25(t,J＝7.6Hz,1H),7.21-7.15(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.54–3.42(m,2H),3.15(s,3H),2.10–2.03(m,1H),1.89–1.78(m,1H),1.43(s,3H).ES-API:[M+H]
+＝491.1。另一个单一异构体，其结构任意指定为Z78-2(185mg,峰2，保留时间22.662min，收率23％)，淡黄色固体。
1H NMR(400MHz,DMSO-d
6)δ12.50(s,1H),10.44(s,1H),8.18(s,1H),7.72(s,1H),7.63(s,1H),7.57(d,J＝8.4Hz,1H),7.52–7.42(m,2H),7.25(t,J＝7.6Hz,1H),7.21-7.15(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.54–3.42(m,2H),3.15(s,3H),2.10–2.03(m,1H),1.89–1.77(m,1H),1.43(s,3H).ES-API:[M+H]
+＝491.1。
实施例80:Z79的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.5g,4.451mmol)和(S)-2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(1.5g,8.902mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(S)-3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.3g,收率67％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：(S)-3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.30g,2.9947mmol)溶于乙腈(40mL)，依次加入氧化银(10.41g,44.92mmol)和碘甲烷(6.38g,44.92mmol),氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(S)-3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.41g,粗品)，黄色固体。ES-API:[M+H]
+＝449.0。
步骤三：(S)-3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.41g,粗品)溶于乙酸(40mL)中，加入铁粉(2.52g,44.99mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(1.05g,收率90.8％)，黄色固体。ES-API:[M+H]
+＝387.2
步骤四：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(1.05g，2.7187mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(761.0mg，19.03mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水 和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(2.20g,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤五：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(209mg，粗品)和2-氯苯甲醛(80mg，0.5181mmol)溶于甲醇(10.0mL)，将反应冷至0℃，加入氢氧化钾(100mg，1.785mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH为8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(80mg,2步收率80％)，淡黄色固体。ES-API:[M+H]
+＝387.3。
步骤六：(2S)-9-(((2-氯苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(80mg,0.2071mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(94mg，0.4142mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(Z79，22mg，收率28％)，淡黄色固体，ES-API:[M+H]
+＝385.1。
1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),10.49(s,1H),8.29(s,1H),7.70(s,1H),7.56(dt,J＝26.0,6.7Hz,3H),7.49–7.42(m,2H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),1.39(s,3H)。
实施例81:Z122的合成
步骤一：2-氯-4-羟基苯甲醛(500mg，3.193mmol)、溴代环戊烷(476mg，3.193mmol)和碳酸钾(883mg，6.383mmol)溶于N，N-二甲基甲酰胺(15mL)，反应于90℃下搅拌3小时，LCMS检测反应已经完全，将反应液冷却至室温，加入30mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干得到淡黄色液体2-氯-4-(环戊氧基)苯甲醛(560mg,收率78％)。ES-API: [M+H]
+＝225.1
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(36.5mg，0.148mmol)和2-氯-4-(环戊氧基)苯甲醛(83mg，0.371mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(58mg，1.036mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-(((2-氯-4-(环戊氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(70mg,收率100％)。ES-API:[M+H]
+＝471.3
步骤三：(2S)-9-(((2-氯-4-(环戊氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(70mg,0.149mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(78mg，0.346mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到淡黄色固体(S)-9-(2-氯-4-(环戊氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z122，17.88mg,收率26％)。ES-API:[M+H]
+＝469.1。
1H NMR(500MHz,DMSO-d6)δ10.48(bs,1H),8.30(s,1H),7.68(s,1H),7.50(s,1H),7.45(d,J＝8.5Hz,1H),7.08(d,J＝2.5Hz,1H),6.96(dd,J1＝3.0Hz,J2＝8.5Hz,1H),4.96-4.92(m,1H),3.64(d,J＝9.5Hz,1H),3.46(d,J＝9.0Hz,1H),3.29(s,3H),1.99-1.92(m,2H),1.78-1.68(m,4H),1.65-1.58(m,2H),1.38(s,3H)。
参照实施例80或81的制备方法通过更改部分原料来制备以下化合物：
实施例124 Z124-1的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.40g，3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g，24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,粗收率66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(480mg，1.950mmol)和2-氯-4-((6-甲基吡啶-2-基)氧基)苯甲醛(750mg，3.036mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(152mg，2.720mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-((2-氯-4-((6-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.10g,粗品)，淡黄色固体。ES-API:[M+H]
+＝494.2。
步骤三：(2S)-9-((2-氯-4-((6-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg,粗品)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(400mg，1.762mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((6-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z124-1,12mg,两步总收率6％)，淡黄色固体，ES-API:[M+H]
+＝492.1。
1H NMR(400MHz,DMSO-d6)
1δ8.29(s,1H),7.80(t,J＝7.7Hz,1H),7.70(s,1H),7.59(d,J＝7.1Hz,2H),7.38(d,J＝2.1Hz,1H),7.22–7.17(m,1H),7.09(d,J＝7.3Hz,1H),6.92(d,J＝8.1Hz,1H),3.65(d,J＝9.4Hz,1H),3.48(d,J＝9.5Hz,1H),3.30(s,3H),2.38(s,3H),1.39(s,3H)。
实施例125 Z125-1的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.40g，2.7187mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(290.0mg，7.252mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.70g,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(209mg，粗品)和4-苯氧基苯甲醛(410mg，2.072mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(406mg，7.252mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(羟基(4-苯氧基苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,2步收率67％)，淡黄色固体。ES-API:[M+H]
+＝445.1.1。
步骤三：(2S)-9-(羟基(4-苯氧基苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,0.6548mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(300mg，1.321mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-2-(甲氧基甲基)-2-甲基-9-(4-苯氧基苯甲酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z125-1,20mg,收率7％)，淡黄色固体，ES-API:[M+H]
+＝443.2。
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),10.46(s,1H),8.30(s,1H),7.82(d,J＝8.8Hz,3H),7.69(s,1H),7.56–7.43(m,2H),7.25(d,J＝7.4Hz,1H),7.19–7.14(m,2H),7.08(d,J＝8.7Hz,2H),3.64(d,J＝9.4Hz,1H),3.46(d,J＝9.5Hz,1H),3.28(s,3H),1.37(s,3H)。
实施例126 Z126的合成
步骤一：3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(50mg，0.18mmol)和2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(89mg，0.36mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(71mg，1.26mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到9'-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(72mg,收率77％)，淡黄色固 体。ES-API:[M+H]
+＝520.1。
步骤二：9'-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(72mg，0.14mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(79mg，0.35mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到9'-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-3-甲氧基-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z126,19mg，收率26％)，白色固体。ES-API:[M+H]
+＝518.1。
1H NMR(400MHz,DMSO-d
6)δ12.56-12.47(m,1H),10.54-10.50(m,1H),8.33-8.31(m,1H),8.09(d,J＝5.2Hz,1H),7.76(d,J＝10.0Hz,1H),7.66–7.49(m,2H),7.44–7.33(m,1H),7.19(dd,J＝8.4,2.0Hz,1H),7.06(d,J＝5.0Hz,1H),6.99(s,1H),4.07-3.94(m,1H),3.21(s,3H),2.37(s,3H),2.35-2.32(m,1H),2.32–2.06(m,2H),1.98–1.78(m,3H).
实施例127 Z127-1的合成
步骤一：氮气保护下，2-氯-4-羟基苯甲醛(2.520g，16.124mmol)、2-溴-4,6-二甲基吡啶(2g，10.750mmol)、磷酸钾(5.0g，23.650mmol)、碘化亚铜(204mg，1.075mmol)和L-脯氨酸(247mg，2.150mmol)溶于N,N'-二甲基甲酰胺(20mL)，反应液微波115℃下搅拌2小时。LCMS检测反应已经完全，将反应液冷却至室温，加入30mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干得到淡黄色液体2-氯-4-((4,6-二甲基吡啶-2-基)氧基)苯甲醛(185mg,收率7％)。ES-API:[M+H]
+＝262.1
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(87mg，0.354mmol)和2-氯-4-((4,6-二甲基吡啶-2-基)氧基)苯甲醛(185mg，0.709mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(139mg，2.478mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反 应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-4-((4,6-二甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(179mg,收率100％)。ES-API:[M+H]
+＝508.1
步骤三：(2S)-9-((2-氯-4-((4,6-二甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(179mg,0.354mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(179mg，0.789mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到白色固体(S)-9-(2-氯-4-((4,6-二甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z127-1,53.68mg,收率30％)。ES-API:[M+H]+＝506.1。
1H NMR(500MHz,DMSO-d
6)δ10.32(s,1H),8.10(s,1H),7.52(s,1H),7.40-7.38(m,2H),7.15(d,J＝2.0Hz,1H),6.97(dd,J1＝2.5Hz,J2＝8.0Hz,1H),6.75(s,1H),6.57(s,1H),3.47(d,J＝9.5Hz,2H),3.11(s,3H),2.14(s,3H),2.13(s,3H),1.20(s,3H)。
实施例128 Z189-1的合成
步骤一：氮气保护下，2-氟-4-羟基苯甲醛(2.256g，16.124mmol)、2-溴-4,6-二甲基吡啶(2g，10.750mmol)、磷酸钾(5.0g，23.650mmol)、碘化亚铜(204mg，1.075mmol)和L-脯氨酸(247mg，2.150mmol)溶于N,N'-二甲基甲酰胺(20mL)，反应液微波115℃下搅拌2小时。LCMS检测反应已经完全，将反应液冷却至室温，加入30mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干得到淡黄色液体4-((4,6-二甲基吡啶-2-基)氧基)-2-氟苯甲醛(274mg,收率10％)。ES-API:[M+H]
+＝246.2
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡 嗪-3-酮(85mg，0.346mmol)和4-((4,6-二甲基吡啶-2-基)氧基)-2-氟苯甲醛(220mg，0.898mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(136mg，2.422mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-(((4-((4,6-二甲基吡啶-2-基)氧基)-2-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(170mg,收率100％)。ES-API:[M+H]
+＝492.3
步骤三：(2S)-9-(((4-((4,6-二甲基吡啶-2-基)氧基)-2-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(170mg,0.346mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(170mg，0.747mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到白色固体(S)-9-(4-((4,6-二甲基吡啶-2-基)氧基)-2-氟苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z189-1,39mg,收率23％)。ES-API:[M+H]+＝490.1。
1H NMR(500MHz,DMSO-d
6)δ12.46(s,1H),10.48(s,1H),8.26(s,1H),7.75(s,1H),7.69(s,1H),7.63(t,J＝8.0Hz,1H),7.15(dd,J1＝2.5Hz,J2＝11.0Hz,1H),7.02(dd,J1＝2.5Hz,J2＝8.5Hz,1H),6.95(s,1H),6.77(s,1H),3.65(d,J＝9.0Hz,1H),3.47(d,J＝9.5Hz,1H),3.30(s,3H),2.34(s,3H),2.32(s,3H),1.38(s,3H)。
实施例129 Z131的合成
步骤一：将2-氯-4-氟苯甲醛(1g，6.31mmol)、3-氰基苯酚(1.12g，9.46mmol)、无水碳酸钾(3.06g，22.2mmol)和N,N'-二甲基甲酰胺(10ml)加入到50ml反应瓶中，氮气置换，加热到90℃，反应3小时。乙酸乙酯萃取，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱硅胶纯化得到产物3-(2-氯-4-甲酰基苯氧基)苄腈(1g，收率62％)。ES-API:[M+H]
+＝258.0。
步骤二：将3-(2-氯-4-甲酰基苯氧基)苄腈(470mg，1.83mmol)、(S)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2'：5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(150mg，0.61mmol)和氢氧化钾(170mg，3.05mmol)加入到10ml甲醇中，室温搅拌3小时。反应完毕，饱和氯化铵淬灭，加入乙酸乙酯萃取，浓缩得到3-(3-氯-4-(羟基((S)-2-(甲氧基甲基)-2-甲基-3-氧代-2,3,4,7-四氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲基)苯氧基)苄腈(20mg，收率6.5％)。ES-API:[M+H]
+＝504.1。
步骤三：将3-(3-氯-4-(羟基((S)-2-(甲氧基甲基)-2-甲基-3-氧代-2,3,4,7-四氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲基)苯氧基)苄腈(20mg，0.039mmol)加入到1,4-二氧六环/水(5ml/1ml)混合溶液中，然后分批加入2,3-二氯-5,6-二氰对苯醌(18mg，0.079mmol)，室温搅拌30分钟，反应完毕。加入2ml硫代硫酸钠水溶液淬灭，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到(S)-3-(3-氯-4-(2-(甲氧基甲基)-2-甲基-3-氧代-2,3,4,7-四氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-羰基)苯氧基)苄腈(Z131,5mg，收率25.6％)。ES-API:[M+H]
+＝502.1。
1H NMR(400MHz,DMSO-d
6)δ10.46(s,1H),8.29(s,1H),7.75–7.62(m,4H),7.62–7.49(m,2H),7.34(d,J＝2.4Hz,1H),7.12(dd,J＝8.4,2.4Hz,1H),3.64(d,J＝9.6Hz,1H),3.47(d,J＝9.6Hz,1H),3.30(s,3H),1.38(s,3H).
实施例130 Z132的合成
步骤一：将2-氯-4-羟基苯甲醛(1.16g，7.4mmol)、2-溴-3-氟-4-甲基吡啶(1.67g，8.9mmol)、L-脯氨酸(85mg，0.74mmol)、碘化亚铜(280mg，1.48mmol)、无水碳酸钾(3.06g，22.2mmol)和N,N'-二甲基乙酰胺(8ml)加入到20ml微波管中，氮气置换，加热到140℃，反应3小时。乙酸乙酯萃取，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱硅胶纯化得到产物2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲醛(157mg，收率8％)。ES-API:[M+H]
+＝266.0。
步骤二：将2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲醛(157mg，0.592mmol)、(S)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2'：5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(145mg，0.59mmol)和氢氧化钾(165mg，2.95mmol)加入到10ml甲醇中，室温搅拌8小时。反应 完毕，饱和氯化铵淬灭，加入乙酸乙酯萃取，浓缩得到9-((2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(100mg，收率33％)。ES-API:[M+H]
+＝512.1。
步骤三：将9-((2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(100mg，0.195mmol)加入到1,4-二氧六环/水(5ml/1ml)混合溶液中，然后分批加入2,3-二氯-5,6-二氰对苯醌(85.5mg，0.39mmol)，室温搅拌30分钟，反应完毕。加入2ml硫代硫酸钠水溶液淬灭，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到9-(2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-4,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3(2H)-酮(Z132,50mg，两步收率50.4％)。ES-API:[M+H]
+＝510.1。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.28(s,1H),7.90(d,J＝5.0Hz,1H),7.69(s,1H),7.60(d,J＝8.4Hz,1H),7.54(s,1H),7.47(d,J＝2.3Hz,1H),7.25(dd,J＝8.4,2.3Hz,1H),7.20(t,J＝5.0Hz,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),2.37(d,J＝1.9Hz,3H),1.39(s,3H).
实施例131 Z133的合成
步骤一：氮气保护下，将苯酚(100mg，1.06mmol)，5-溴-3-氯吡啶甲醛(234mg,1.06mmol)，2,2,6,6-四甲基-3,5-庚二酮(20mg,0.11mmol)，碘化亚铜(10mg,0.05mmol)和碳酸铯(346mg，1.06mmol)的N,N-二甲基乙酰胺(3mL)混合物在80℃微波反应30分钟。反应液溶于30mL乙酸乙酯，并依次用30mL饱和食盐水和30mL水洗涤，有机相干燥浓缩后用快速硅胶柱(0-10％乙酸乙酯/石油醚)纯化得到无色液体3-氯-5-苯基吡啶甲醛(100mg)，纯度95％，收率40％。ES-API:[M+H]
+＝234.1。
步骤二：往(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg，0.41mmol)的甲醇(5mL)溶液中加入3-氯-5-苯基吡啶甲醛(100mg，0.43mmol)和氢氧化钾(160mg，2.84mmol)，室温搅拌2小时。反应完毕，用1M的盐酸溶液调节pH＝7，加入20mL乙酸乙酯萃取三遍，有机相合并，干燥，浓缩并用快速硅胶柱(0-10％甲醇/二氯甲烷)纯化得到黄色固体(2S)-9-(((3-氯-5-苯氧基吡啶-2-基)(羟基)甲 基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3-酮(80mg)，纯度100％，收率41％。ES-API:[M+H]
+＝480.2。
步骤三：往(2S)-9-(((3-氯-5-苯氧基吡啶-2-基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3-酮(80mg，0.16mmol)的1,4-二氧六环/水(2ml/0.2ml)混合溶液中加入2,3-二氯-5,6-二氰对苯醌(76mg，0.33mmol)，室温搅拌30分钟。反应完毕，加入2mL硫代硫酸钠水溶液淬灭，加入20mL乙酸乙酯，依次用20mL饱和碳酸氢钠水溶液，20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩并用制备HPLC纯化得到灰白色固体(Z133,17mg，纯度100％，收率21％)。
1H NMR(400MHz,DMSO-d
6)δ12.54(s,1H),10.51(s,1H),8.39(d,J＝2.4Hz,1H),8.23(s,1H),7.77(s,1H),7.75(d,J＝2.4Hz,1H),7.70(s,1H),7.53–7.47(m,2H),7.31–7.23(m,3H),3.65(d,J＝9.6Hz,1H),3.46(d,J＝9.6Hz,1H),3.29(s,3H),1.39(s,3H).ES-API:[M+H]
+＝478.1.
实施例132 Z134和Z135的合成
步骤一：2-氯-4-羟基苯甲醛(1g，6.387mmol)、2,4-二氯-6-甲基吡啶(1.034g，6.387mmol)和碳酸钾(1.765g，12.744mmol)溶于二甲基亚砜(10mL)，反应混合物微波130℃下搅拌8小时，LCMS检测反应已经完全，将反应液冷却至室温，加入50mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干，残留物经combifalsh纯化分别得到2-氯-4-((4-氯-6-甲基吡啶-2-基)氧基)苯甲醛(133mg,收率7.4％)和2-氯-4-((2-氯-6-甲基吡啶-4-基)氧基)苯甲醛(167mg,收率9.3％)。ES-API:[M+H]
+＝282.1
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(65mg，0.264mmol)和2-氯-4-((4-氯-6-甲基吡啶-2-基)氧基)苯甲醛(133mg，0.473 mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(103mg，1.848mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-4-((4-氯-6-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(139mg,收率100％)。ES-API:[M+H]
+＝528.1
步骤三：(2S)-9-((2-氯-4-((4-氯-6-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(139mg,0.264mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(139mg，0.612mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到淡红色固体(S)-9-(2-氯-4-((4-氯-6-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z134,29.63mg,收率21％)。ES-API:[M+H]
+＝526.2。
1H NMR(500MHz,DMSO-d
6)δ12.47(s,1H),10.49(s,1H),8.28(s,1H),7.70(s,1H),7.61-7.60(m,2H),7.45(d,J＝1.5Hz,1H),7.25-7.23(m,2H),7.12(s,1H),3.65(d,J＝9.0Hz,1H),3.48(d,J＝9.5Hz,1H),3.30(s,3H),2.37(s,3H),1.39(s,3H)。
步骤四：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(65mg，0.264mmol)和2-氯-4-((2-氯-6-甲基吡啶-4-基)氧基)苯甲醛(167mg，0.594mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(103mg，1.848mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-4-((2-氯-6-甲基吡啶-4-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(139mg,收率100％)。ES-API:[M+H]
+＝528.1
步骤五：(2S)-9-((2-氯-4-((2-氯-6-甲基吡啶-4-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(139mg,0.264mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(139mg，0.612mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC (柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到淡黄色固体(S)-9-(2-氯-4-((2-氯-6-甲基吡啶-4-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z135,24.97mg,收率18％)。ES-API:[M+H]
+＝528.0。
1H NMR(500MHz,DMSO-d
6)δ12.51(s,1H),10.50(s,1H),8.27(s,1H),7.77(s,1H),7.70(s,1H),7.65(d,J＝8.0Hz,1H),7.53(d,J＝2.5Hz,1H),7.28(dd,J1＝2.5Hz,J2＝9.0Hz,1H),7.07(d,J＝2.0Hz,1H),7.01(d,J＝2.0Hz,1H),3.65(d,J＝10.0Hz,1H),3.49(d,J＝10.0Hz,1H),3.31(s,3H),2.44(s,3H),1.39(s,3H)。
实施例133 Z136的合成
步骤一：2-氯-4-羟基苯甲醛(1g，6.4mmol)、2-溴吡啶(1.1g，7.04mmol)和碳酸钾(1.3g，9.6mmol)溶于N,N'-二甲基甲酰胺(30mL)，反应于130℃下搅拌过夜，将反应冷至0℃，加入50mL乙酸乙酯，分别加入50mL水洗三次，有机相用50mL饱和食盐水洗涤，干燥后浓缩，用柱层析方法(石油醚：乙酸乙酯＝20:1)纯化得到产物2-氯-4-(吡啶-2-基氧基)苯甲醛(442mg,收率30％)，淡黄色固体。ES-API:[M+H]
+＝234.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-一(150mg，0.61mmol)和2-氯-4-(吡啶-2-基氧基)苯甲醛(308mg，1.32mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(137mg，2.44mmol)。反应在室温下搅拌16小时。将反应液倒入15mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到(2S)-9-(((2-氯-4-(吡啶-2-基氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(101mg,收率35％)，淡黄色固体。ES-API:[M+H]
+＝480.1。
步骤三：(2S)-9-(((2-氯-4-(吡啶-2-基氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(101mg,0.21mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(95mg，0.42mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL 乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到(S)-9-(2-氯-4-(吡啶-2-基氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z136,30mg,收率30％)，白色固体。ES-API:[M+H]
+＝478.1。
1H NMR(400MHz,DMSO-d
6)δ12.48(s,1H),10.51(s,1H),8.38–8.16(m,2H),8.03–7.78(m,1H),7.70(s,1H),7.63–7.54(m,2H),7.42(d,J＝2.2Hz,1H),7.29–7.20(m,2H),7.16(d,J＝8.4Hz,1H),3.65(d,J＝9.6Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),1.39(s,3H).
实施例134 Z137的合成
步骤一：将3-(二甲基氨基)-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(200mg，0.47mmol)和氢氧化钠(94mg，2.35mmol)加入到甲醇/水(4ml/0.8ml)的混合溶剂中，60℃搅拌8小时。反应液浓缩得到粗品3-(二甲氨基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(134mg)。ES-API:[M+H]
+＝286.2。
步骤二：往上述粗品3-(二甲氨基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(134mg，0.47mmol)的甲醇(5mL)溶液中加入2-氯-4-苯氧基苯甲醛(328mg，1.41mmol)和氢氧化钾(184mg，3.29mmol)，室温搅拌2小时。反应完毕，用1M的盐酸溶液调节pH＝7，加入20mL乙酸乙酯萃取三遍，有机相合并，干燥，浓缩得到黄色固体9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-(二甲基氨基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(400mg)。ES-API:[M+H]
+＝518.2。
步骤三：往9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-(二甲基氨基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(400mg，0.77mmol)的1,4-二氧六环/水(5ml/0.5ml)混合溶液中加入2,3-二氯-5,6-二氰对苯醌(175mg，0.77mmol)，室温搅拌30分钟。反应完毕，加入2mL硫代硫酸钠水溶液淬灭，加入20mL乙酸乙酯，依次用20mL饱和碳酸氢钠水溶液，20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩并用制备HPLC纯化得到灰白色固体(Z137,54mg，纯度100％，三步总收率22％)。
1H NMR(400 MHz,DMSO-d
6)δ12.55(s,1H),10.52(s,1H),8.34(s,1H),7.76(s,1H),7.66(s,1H),7.58(d,J＝8.4Hz,1H),7.53–7.45(m,2H),7.29–7.22(m,1H),7.21–7.15(m,3H),7.08–7.00(m,1H),2.88–2.75(m,1H),2.38–2.29(m,1H),2.12(s,6H),2.06–1.99(m,1H),1.99–1.95(m,2H),1.76–1.57(m,2H).ES-API:[M+H]
+＝516.1.
实施例135 Z139的合成
步骤一：(S)-3-羟基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.0g，2.3mmol)和碘化亚铜(437mg，2.3mmol)溶于乙腈(50mL)，充氮气保护，反应在85℃下滴加2,2-二氟-2-(氟磺酰基)乙酸(2.05g，11.5mmol)。反应50mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用柱层析分离(石油醚：乙酸乙酯＝20:1)得到(S)-3-(二氟甲氧基)-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(200mg,收率18％)，黄色固体。ES-API:[M+H]
+＝485.0。
步骤二：(S)-3-(二氟甲氧基)-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(156mg，0.32mmol)溶于乙酸(15mL)，加入铁粉(125mg，2.24mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩得到(S)-2-(((二氟甲氧基)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(126mg,收率93％)，黄色固体。ES-API:[M+H]
+＝423.0
步骤三：(S)-2-(((二氟甲氧基)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(126mg，0.29mmol)溶于10mL甲醇，5mL四氢呋喃和 2mL水，加入氢氧化钠(81mg，2.03mmol)，反应在65℃搅拌7小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用50mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到(S)-2-(((二氟甲氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(72mg,收率88％)，灰白色固体。ES-API:[M+H]
+＝283.0。
步骤四：(S)-2-(((二氟甲氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(72mg，0.26mmol)和2-氯-4-苯氧基苯甲醛(121mg，0.52mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(114mg，2.03mmol)。反应在室温下搅拌18小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH＝8，加80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((二氟甲氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(110mg,收率82％)，淡黄色固体。ES-API:[M+H]
+＝515.0。
步骤五：(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((二氟甲氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(110mg，0.21mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(118mg，0.52mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-((二氟甲氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z139,38mg,收率64％)，白色固体。ES-API:[M+H]
+＝513.0。
1H NMR(400MHz,DMSO-d
6)δ12.50(s,1H),10.65(s,1H),8.35(s,1H),7.73(s,1H),7.63(s,1H),7.55(d,J＝8.4Hz,1H),7.48(t,J＝8.0Hz,2H),7.26-7.23(m,1H),7.19-7.13(m,3H),7.02(dd,J＝8.4,2.2Hz,1H),6.90-6.53(m,1H),4.17(d,J＝10.0Hz,1H),3.97(d,J＝10.0Hz,1H),1.43(s,3H).
实施例136 Z140的合成
步骤一：3-氯-4-羟基苯甲醛(1.16g,7.4mmol)2-溴-3-甲基吡啶(1.53g,8.9mmol)，CuI(280mg,1.48mmol)，L-Proline(85mg,0.74mmol)，碳酸钾(3.06g,22.2mmol)溶于1，4二氧六环(30mL)中，N2保护下，油浴110℃并搅拌12小时。反应完毕后，反应液硅藻土过滤，滤液减压旋干后，柱层析(乙酸乙酯/石油醚＝0-30％)得到3-氯-4-((3-甲基吡啶-2-基)氧基)苯甲醛(1.3g,收率71％)，无色液体。ES-API:[M+H]
+＝248.1；
步骤二：2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(193mg，0.5mmol)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(290mg，7.264mmol)，反应在65℃搅拌7小时。反应液减压浓缩得到粗品，棕色固体。ES-API:[M+H]
+＝247.1；
步骤三：将上一步粗品和2-氯-4-苯氧基苯甲醛(247mg，1mmol)溶于甲醇(10.0mL)，将反应冷至0℃，加入氢氧化钾(140mg，2.5mmol)。反应转移至30℃搅拌1小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩，柱层析(甲醇/二氯甲烷＝0-10％)得到(2S)-9-((2-氯-4-((3-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(137mg,收率55％)，棕色固体。ES-API:[M+H]
+＝494.2；
步骤四：(2S)-9-((2-氯-4-((3-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(137mg,0.277mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(125mg，0.554mmol)，反应在室温下搅拌30分钟。反应液加入NaHSO
3饱和溶液20mL淬灭，用80mL乙酸乙酯萃取，有机相用30mL饱和碳酸氢钠溶液和30mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z140,9.65mg,收率7％)，白色固体，ES-API:[M+H]
+＝492.1。
实施例137 Z141的合成
步骤一：向100mL圆底烧瓶中加入1-氨基-3-羟基环戊烷-1-羧酸乙酯盐酸盐(1.1g，5.24mmol)，4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.7g，5.24mmol)，N,N-二异丙基乙胺(2g，15.72mmol)和DMF(20mL)。反应在100℃下搅拌16小时。将反应液中倒入冰水中，用乙酸乙酯萃取。有机相干燥后浓缩，粗品用柱层析(0-50％乙酸乙酯/石油醚)得到3-羟基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氨基)氨基]环戊烷-1-甲酸乙酯(600mg，24％)，黄色固体。ES-API:[M+H]
+＝475.1
步骤二：零度下，向100mL反应瓶中加入3-羟基-1-(((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氨基)氨基]环戊烷-1-甲酸乙酯(600mg，1.26mmol)、戴斯-马丁氧化剂(1.07g，2.52mmol)和10mL二氯甲烷。反应在室温下搅拌16小时，停止反应。向反应液中加入50mL饱和碳酸氢钠，用乙酸乙酯萃取3次，有机相干燥浓缩后用快速硅胶柱纯化(0-80％乙酸乙酯/石油醚)得到1-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)-3-氧代环戊烷-1-甲酸乙酯(450mg，75％)，黄色固体。ES-API:[M+H]
+＝473.2
步骤三：向100mL圆底烧瓶中加入1-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)-3-氧代环戊烷-1-甲酸乙酯(450mg，0.95mmol)，铁粉(1.06g，19.0mmol)和乙酸(15mL)。反应在80℃下搅拌2小时。反应用水淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥。有机相浓缩后得到粗品7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3,3'(1'H)-二酮(240mg，64％)。ES-API:[M+H]
+＝397.1
步骤四：向100mL圆底烧瓶中加入7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3,3'(1'H)-二酮(240mg，0.61mmol)，吗啉(422mg，4.85mmol)，乙酸(73mg，1.22mmol)和1,2-二氯乙烷(10mL)。向反应液中加入NaBH(OAc)
3(647mg，3.05mmol)。反应在室温下搅拌2小时。反应用水淬灭，用二氯甲烷萃取。有机相用无水硫酸钠干燥。有机相浓缩后得到粗品，用快速硅胶柱纯化(0-20％甲醇/乙酸乙酯)得到3-吗 啉代-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3(1'H)-酮(210mg，73％)。ES-API:[M+H]
+＝468.2
步骤五：向100mL圆底烧瓶中加入3-吗啉代-7'-(苯磺酰基)-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3(1'H)-酮(210mg，0.45mmol)，氢氧化钠(89mg，2.24mmol)，水(5mL)和甲醇(1mL)。反应在65℃下搅拌4小时。反应用饱和氯化铵水溶液淬灭，浓缩干得到粗品3-吗啉代-4',7'-二氢螺环[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(147mg)。ES-API:[M+H]
+＝328.1
步骤六：向100mL圆底烧瓶中加入3-吗啉代-4',7'-二氢螺环[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(147mg，粗品)，2-氯-4-苯氧基苯甲醛(260mg，1.12mmol)，氢氧化钾(252mg，4.5mmol)和甲醇(6mL)。反应在30℃下搅拌5小时。反应用2N盐酸淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥。有机相浓缩后得到粗品9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-吗啉代-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(250mg，粗品)。ES-API:[M+H]
+＝560.2。
步骤七：零度下，向100mL圆底烧瓶中加入9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-3-吗啉代-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(250mg，粗品)，二氯甲烷(10mL)和水(0.5mL)。向其中加入2,3-二氯-5,6-二氰对苯醌(227mg,0.54mmol)。反应在室温下搅拌1小时。反应用饱和碳酸氢钠水溶液淬灭，用二氯甲烷萃取。有机相用无水硫酸钠干燥。有机相浓缩后，粗品用制备HPLC纯化得到9'-(2-氯-4-苯氧基苯甲酰基)-3-吗啉代-4',7'-二氢螺[环戊烷-1,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z141,50mg，三步收率20％)。ES-API:[M+H]
+＝558.1
实施例138 Z142的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪-3-酮(250mg，0.65mmol)溶于6mL N,N-二甲基甲酰胺，依次加入无水碳酸钾(359mg,2.60mmol)，1-溴-2-甲氧基乙烷(271mg，1.95mmol)，反应在70℃下搅拌3天。反应液倒入20mL水中，用60mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-3％)得到(S)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg,收率90％)，黄色固体。ES-API:[M+H]
+＝445.1。
步骤二：(S)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg，0.58mmol)溶于10mL甲醇，4mL四氢呋喃和2mL水，加入氢氧化钠(116mg，2.90mmol)，反应在60℃搅拌5小时。反应液用1.0M稀盐酸调pH＝8，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-5％)得到(S)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(150mg,收率84％)，淡黄色固体。ES-API:[M+H]
+＝305.2。
步骤三：(S)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(75mg，0.25mmol)和2-氯-4-苯氧基苯甲醛(172mg，0.75mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(98mg，1.75mmol)。反应在室温下搅拌6小时。反应液用1.0M稀盐酸调pH＝8，加入3mL水，用60mL乙酸乙酯萃取。干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-5％)得到(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6] 吡啶并[3,4-b]吡嗪-3-酮(110mg,产率83％)，淡黄色固体。ES-API:[M+H]
+＝537.3。
步骤四：(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-甲氧基乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(110mg,0.20mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)，室温下加入2,3-二氯-5,6-二氰对苯醌(91mg，0.40mmol)，反应在室温下搅拌2小时。反应液加入6mL饱和硫代硫酸钠溶液和10mL饱和碳酸氢钠溶液，用50mL乙酸乙酯萃取3次。合并有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到(Z142,95mg,产率87％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ12.25(s,1H),8.54(s,1H),8.06(s,1H),7.66(s,1H),7.56(d,J＝8.4Hz,1H),7.48(t,J＝7.6Hz,2H),7.25(t,J＝7.6Hz,1H),7.22–7.15(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),4.29–4.11(m,2H),3.62–3.50(m,4H),3.29(s,3H),3.26(s,3H),1.36(s,3H).ES-API:[M+H]
+＝535.1。
实施例139 Z143的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶基[3,4-b]吡嗪-3-酮(250mg，0.65mmol)溶于6mL N,N-二甲基甲酰胺，依次加入无水碳酸钾(359mg,2.60mmol)，叔丁基(2-碘乙氧基)二甲基硅烷(555mg，1.95mmol)，反应在60℃下搅拌3天。反应液倒入20mL水中，用60mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-3％)得到(S)-4-(2-((叔丁基二甲基硅基)氧基)乙基)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(330mg,收率93％)，淡黄色固体。ES-API: [M+H]
+＝545.1。
步骤二：(S)-4-(2-((叔丁基二甲基硅基)氧基)乙基)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，0.55mmol)溶于10mL甲醇，4mL四氢呋喃和2mL水，加入氢氧化钠(110mg，2.75mmol)，反应在65℃搅拌16小时。反应液用1.0M稀盐酸调pH＝8，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得到(S)-4-(2-羟乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(140mg,收率87％)，淡黄色固体。ES-API:[M+H]
+＝291.3。
步骤三：(S)-4-(2-羟乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(75mg，0.26mmol)和2-氯-4-苯氧基苯甲醛(180mg，0.78mmol)溶于甲醇(6mL)，将反应冷至0℃，加入氢氧化钾(102mg，1.85mmol)。反应在室温下搅拌6小时。反应液用1.0M稀盐酸调pH＝8，加入3mL水，用60mL乙酸乙酯萃取。干燥后浓缩，粗品用薄层制备板(甲醇/二氯甲烷＝10：1)得到(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-羟乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,产率74％)，淡黄色固体。ES-API:[M+H]
+＝523.2。
步骤四：(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-4-(2-羟乙基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,0.19mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)，室温下加入2,3-二氯-5,6-二氰对苯醌(86mg，0.38mmol)，反应在室温下搅拌30分钟。反应液加入6mL饱和硫代硫酸钠溶液和6mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相依次用15mL饱和碳酸氢钠溶液，15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到目标产物(Z143,90mg,产率90％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ12.56(s,1H),8.53(s,1H),8.09(s,1H),7.65(s,1H),7.55(d,J＝8.4Hz,1H),7.51–7.42(m,2H),7.25(t,J＝7.2Hz,1H),7.21–7.14(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),4.90(s,1H),4.10–3.98(m,2H),3.63-3.55(m,3H),3.51(d,J＝9.6Hz,1H),3.29(s,3H),1.36(s,3H).ES-API:[M+H]
+＝521.2。
实施例140 Z144的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg，0.203mmol)和2-氯-4-((3-氟吡啶-2-基)氧基)苯甲醛(102mg，0.406mmol)溶于甲醇(3mL)，将反应冷至0℃，加入氢氧化钾(80mg，1.42mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(40mL)萃取。有机相用饱和食盐水(20mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-((2-氯-4-((3-氟吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg，0.05mmol,产率25％)，淡黄色固体。ES-API:[M+H]
+＝498.1。
步骤二：(2S)-9-((2-氯-4-((3-氟吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg，0.05mmol)溶于四氢呋喃(1mL)和水(0.1mL)室温下加入2,3-二氯-5,6-二氰对苯醌(34mg，0.151mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(5mL)和饱和碳酸氢钠溶液(5mL)淬灭反应，而后用乙酸乙酯萃取(20mL)。有机相依次用饱和碳酸氢钠溶液(10mL)，饱和食盐水洗涤(10mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-氟吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z144,8mg，0.016mmol,产率33％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.48(s,1H),10.50(s,1H),8.28(s,1H),8.05(s,1H),7.98–7.90(m,1H),7.70(s,1H),7.62(d,J＝8.5Hz,1H),7.58–7.50(m,2H),7.32–7.27(m,2H),3.65(d,J＝10.0Hz,1H),3.48(d,J＝10.0Hz,1H),3.30(s,3H),1.39(s,3H).ES-API:[M+H]
+＝496.1。
实施例141 Z145的合成
步骤一：(S)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg，0.203mmol)和2-氯-4-((3-氟吡啶-2-基)氧基)苯甲醛(102mg，0.406mmol)溶于甲醇(3mL)，将反应冷至0℃，加入氢氧化钾(80mg，1.42mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(40mL)萃取。有机相用饱和食盐水(20mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得 到(2S)-9-((2-氯-4-((3-氟吡啶-2-基)氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg，0.05mmol,产率25％)，淡黄色固体。ES-API:[M+H]
+＝501.1。
步骤二：(2S)-9-((2-氯-4-((3-氟吡啶-2-基)氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg，0.05mmol)溶于四氢呋喃(1mL)和水(0.1mL)室温下加入2,3-二氯-5,6-二氰对苯醌(34mg，0.151mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(5mL)和饱和碳酸氢钠溶液(5mL)淬灭反应，而后用乙酸乙酯萃取(20mL)。有机相依次用饱和碳酸氢钠溶液(10mL)，饱和食盐水洗涤(10mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-氟吡啶-2-基)氧基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z145,8mg，0.016mmol,产率33％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.48(s,1H),10.50(s,1H),8.28(s,1H),8.05(s,1H),7.98–7.90(m,1H),7.70(s,1H),7.62(d,J＝8.5Hz,1H),7.58–7.50(m,2H),7.32–7.27(m,2H),3.65(d,J＝10.0Hz,1H),3.48(d,J＝10.0Hz,1H),1.39(s,3H).ES-API:[M+H]
+＝499.1。
实施例142 Z146的合成
步骤一：2-溴-3-氟-4-甲基吡啶(7.0g，36.84mmol)和2-氯-4-羟基苯甲醛(8.65g，55.26mmol)溶于1,4-二氧六环(300mL)，加入碘化亚铜(702mg，3.68mmol),L-脯氨酸(848mg，7.37mmol)和碳酸钾(15.27g,110.52mmol),反应在110℃、氮气氛围下搅拌24小时。反应液冷却至室温后，用硅藻土过滤，滤饼用乙酸乙酯(300mL)洗涤。滤液浓缩后，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-20％)得到2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲醛(1.8g,6.78mmol，收率18.4％)，白色固体。ES-API:[M+H]
+＝266.1。
步骤二：(S)-2-(((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg，0.201mmol)和2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲醛(160mg， 0.602mmol)溶于甲醇(3mL)，将反应冷至0℃，加入氢氧化钾(79mg，1.40mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(40mL)萃取。有机相用饱和食盐水(20mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-((2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(20mg，0.038mmol,产率19.3％)，淡黄色固体。ES-API:[M+H]
+＝515.1。
步骤三：(2S)-9-((2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(20mg，0.038mmol)溶于四氢呋喃(1mL)和水(0.1mL)室温下加入2,3-二氯-5,6-二氰对苯醌(26mg，0.117mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(5mL)和饱和碳酸氢钠溶液(5mL)淬灭反应，而后用乙酸乙酯萃取(20mL)。有机相依次用饱和碳酸氢钠溶液(10mL)，饱和食盐水洗涤(10mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-氟-4-甲基吡啶-2-基)氧基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z146,8mg，0.016mmol,产率40％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.47(s,1H),10.50(s,1H),8.28(s,1H),7.90(d,J＝5.0Hz,1H),7.70(s,1H),7.61(d,J＝8.5Hz,1H),7.55(s,1H),7.48(d,J＝2.5Hz,1H),7.26(dd,J＝8.5,2.5Hz,1H),7.20(t,J＝5.0Hz,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.5Hz,1H),2.37(s,3H),1.40(s,3H).ES-API:[M+H]
+＝513.1。
实施例143 Z149的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(5.4g，15.96mmol),(S)-2-氨基-2-(羟甲基)丙酸甲酯-3,3,3-d
3盐酸盐(2.3g,13.3mmol)和DIEA(6.6ml)溶于无水DMA(40ml)中，反应在95℃下，搅拌过夜，恢复室温，反应液加入100mL乙酸乙酯，依次用60mL水洗涤3次，50ml饱和食盐水洗一次，干燥浓缩，粗品用柱层析(石油醚：乙酸乙酯＝30:1)纯化得到化合物(S)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯-3,3,3-d
3(3.1g,收率44％)ES-API:[M+H]
+＝438.1。
步骤二：(S)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯-3,3,3-d
3(1.0g,2.3mmol),氧化银(11g,45.8mmol)和碘甲烷(6.5g,45.8mmol)溶于乙腈(50mL)，反应在35℃下，避光搅拌2天。反应液用硅藻土过滤，滤饼用50ml乙酸乙酯洗涤三次，滤液浓缩后得到(S)-2-(甲氧甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯-3,3,3-d
3(1.1g,粗品)，黄色油状。ES-API:[M+H]
+＝452.2。
步骤三：(S)-2-(甲氧甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯-3,3,3-d
3(1.1g,2.4mmol)溶于乙酸(30mL)，加入铁粉(941mg,16.8mmol),反应在85℃搅拌3小时。反应液加入100mL乙酸乙酯，依次用60mL水洗涤2次，40mL饱和碳酸钠洗涤2次,40mL饱和碳酸氢钠洗涤2次，40mL饱和食盐水，干燥浓缩得到(S)-2-(甲氧基甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(950mg,粗品100％)，黄色固体。ES-API:[M+H]
+＝390.1
步骤四：(S)-2-(甲氧基甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(950mg，2.44mmol)溶于20mL甲醇，4mL四氢呋喃和2mL水，加入氢氧化钠(683mg，17.08mmol)，反应在65℃搅拌6小时。向反应液中加入15mL水和4mL饱和氯化铵溶液，用100mL乙酸乙酯萃取。有机相依次用20mL饱和碳酸氢钠溶液，20mL饱和食盐水洗涤，干燥后浓缩得到(S)-2-(甲氧基甲基)-2-(甲基-d
3)-1,2,4,7-四 氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(650mg,粗品100％)，淡黄色固体，ES-API:[M+H]
+＝250.1。
步骤五：(S)-2-(甲氧基甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(650mg，2.61mmol)和2-氯-4-苯氧基苯甲醛(1.21g，5.22mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(1.02g，18.27mmol)。反应在室温下搅拌16小时。将反应液倒入60mL水中，用1.0M稀盐酸调pH＝8，80mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:7.5)纯化得到(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(850mg,收率68％)，淡黄色固体。ES-API:[M+H]
+＝482.2。
步骤六：(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(850mg,1.77mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(804mg，3.54mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用60mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z149,350mg,收率41％)，白色固体。ES-API:[M+H]
+＝480.1。
1H NMR(400MHz,DMSO-d
6)δ12.48(s,1H),10.50(s,1H),8.27(s,1H),7.69(s,1H),7.61(s,1H),7.56(d,J＝8.4Hz,1H),7.51-7.36(m,2H),7.25(t,J＝7.4Hz,1H),7.19-7.17(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),3.64(d,J＝9.6Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,3H).
实施例144 Z150的合成
步骤一：4-氟-2-(三氟甲基)苯甲醛(500mg，2.6mmol)、苯酚(221mg，2.34mmol)和碳酸铯(929mg，2.86mmol)溶于N,N'-二甲基甲酰胺(30mL)，反应于65℃下搅拌两小时，将反应冷至0℃，加入50mL乙酸乙酯，分别加入50mL水洗三次，有机相用50mL饱和食盐水洗涤，干燥后浓缩，用柱层析方法(石油醚：乙酸乙酯＝30:1)纯化得到产物4-苯氧 基-2-(三氟甲基)苯甲醛(330mg,收率48％)，淡黄色固体。ES-API:[M+H]
+＝267.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg，0.41mmol)和4-苯氧基-2-(三氟甲基)苯甲醛(218mg，0.82mmol)溶于甲醇(20mL)，将反应冷至0℃，加入氢氧化钾(161mg，2.87mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到(2S)-9-(羟基(4-苯氧基-2-(三氟甲基)苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(121mg,收率58％)，淡黄色固体。ES-API:[M+H]
+＝513.2。
步骤三：(2S)-9-(羟基(4-苯氧基-2-(三氟甲基)苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(121mg，0.24mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(109mg，0.48mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到(S)-2-(甲氧基甲基)-2-甲基-9-(4-苯氧基-2-(三氟甲基)苯甲酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z150,50mg,收率30％)，白色固体。ES-API:[M+H]
+＝511.1。
1H NMR(400MHz,DMSO-d
6)δ12.48(s,1H),10.51(s,1H),8.22(s,1H),7.78-7.61(m,2H),7.60(s,1H),7.52-7.48(m,2H),7.43(s,1H),7.29-7.25(m,2H),7.22-7.20(m,2H),3.63(d,J＝12.5Hz,1H),3.44(d,J＝12.5Hz,1H),3.28(s,3H),1.38(s,3H).
实施例145 Z153及其异构体的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1g，2.967mmol),2-氨基-3-(2-甲氧基乙氧基)-2-甲基丙酸乙酯(791mg,3.858mmol)和N,N-二异丙基乙胺(1.914g，14.835mmol)溶于无水N,N-二甲基乙酰胺(20mL)中，反应混合物在封管内被加热至95℃反应6小时。LCMS检测反应已经完全，反应液冷却至室温，加入50mL乙酸乙酯稀释，然后加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩，粗品用combiflash(石油醚/乙酸乙酯＝0～80％)纯化得到化合物3-(2-甲氧基乙氧基)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(900mg,收率60％)。ES-API:[M+H]+＝507.1
步骤二：氮气保护下，3-(2-甲氧基乙氧基)-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(800mg,1.581mmol)溶于乙酸(30mL)，加入铁粉(2.656g,47.431mmol),反应混合物加热至80℃搅拌1小时。LCMS检测反应已经完全，反应液冷却至室温，加入100mL乙酸乙酯稀释，依次用水(30mL X 3)洗涤，饱和碳酸钠水溶液(30mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩，粗品用combiflash(石油醚/乙酸乙酯＝0～80％)纯化得到黄色固体2-((2-甲氧基乙氧基)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(545mg,收率80％)。ES-API:[M+H]+＝431.2
步骤三：2-((2-甲氧基乙氧基)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，0.698mmol)溶于5mL甲醇，2.5mL四氢呋喃和0.5mL水，加入氢氧化钠(140mg，3.488mmol)，反应混合物在封管内被加热至60℃ 搅拌6小时。LCMS检测反应已经完全，反应液冷却至室温。加入2mol/L的稀盐酸将反应液的PH调至7.0，然后反应液减压浓缩，残留物经combiflash(二氯甲烷/甲醇＝0～9.5％)纯化得到化合物2-((2-甲氧基乙氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(167mg,收率83％)。ES-API:[M+H]+＝291.3
步骤四：2-((2-甲氧基乙氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(167mg，0.576mmol)和2-氯-4-苯氧基苯甲醛(267mg，1.152mmol)溶于甲醇(15mL)，将反应液冷却至0℃，加入氢氧化钾(226mg，4.032mmol)。反应液缓慢升至室温搅拌18小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((2-甲氧基乙氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(310mg)。ES-API:[M+H]
+＝523.2
步骤五：将粗品9-(2-氯-4-苯氧基苯甲酰基)-2-((2-甲氧基乙氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(310mg)溶于30mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(310mg，1.366mmol)，反应液室温搅拌2小时，LCMS检测反应已经完全。反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到淡黄色固体9-(2-氯-4-苯氧基苯甲酰基)-2-((2-甲氧基乙氧基)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z153,182mg,收率59％)。ES-API:[M+H]+＝521.2
步骤六：将上述得到的化合物Z153用SFC手性拆分(色谱柱:Daicel CHIRALPAK IE250*4.6mm,5μm；流动相:HEX(0.1％DEA)/ETOH(0.1％DEA)＝60:40(V/V)；流速:1mL/min；柱温：室温)得到两个单一异构体化合物。一个单一异构体，其结构任意指定为Z153-1(保留时间：8.790min；74.07mg)。ES-API:[M+H]
+＝521.2。另一个单一异构体，其结构任意指定为Z153-2(保留时间：10.732min；75.05mg)。ES-API:[M+H]
+＝521.2。
实施例146 Z155的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.40g，3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g，24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,粗收率66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(213mg，0.8667mmol)和2-氯-4-(2-氟苯氧基)苯甲醛(433mg，1.733mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(340mg，6.067mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.250g,收率58％)，淡黄色固体。ES-API:[M+H]
+＝497.2。
步骤三：(2S)-9-(((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,0.5038mmol)溶于25mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(228mg，1.007mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2-氟苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z155,115mg,收率46％)，淡黄色固体，ES-API:[M+H]
+＝495.1。
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),10.49(s,1H),8.27(s,1H),7.69(s,1H),7.63–7.54(m,2H),7.53–7.43(m,1H),7.43–7.28(m,3H),7.21(d,J＝2.3Hz,1H),7.00(dd,J＝8.4,2.3Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例147 Z156的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡 啶并[3,4-b]吡嗪-3-酮(1.40g，3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g，24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,粗收率66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(213mg，0.8667mmol)和2-氟-4-(2-氟苯氧基)苯甲醛(405mg，1.733mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(340mg，6.067mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氟-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(237mg,收率57％)，淡黄色固体。ES-API:[M+H]
+＝481.3。
步骤三：(2S)-9-(((2-氟-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯烷[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(237mg,0.4934mmol)溶于25mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(224mg，0.9869mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氟-4-(2-氟苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z156,73mg,收率31％)，淡黄色固体，ES-API:[M+H]
+＝479.2。
1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.74(s,1H),7.68(s,1H),7.62(t,J＝8.3Hz,1H),7.47(dd,J＝11.1,8.0Hz,1H),7.34(tdd,J＝13.7,10.8,7.0Hz,3H),7.02(dd,J＝11.1,2.2Hz,1H),6.91–6.84(m,1H),6.07(s,0H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,2H),3.29(s,3H),1.37(s,3H)。
实施例148 Z157的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡 啶并[3,4-b]吡嗪-3-酮(1.40g，3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g，24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,粗收率66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(213mg，0.8667mmol)和2-氯-4-(3-氟苯氧基)苯甲醛(433mg，1.733mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(340mg，6.067mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(305mg,收率70％)，淡黄色固体。ES-API:[M+H]
+＝497.2。
步骤三：(2S)-9-(((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(305mg,0.6146mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(280mg，1.230mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(3-氟苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z157100mg,收率33％)，淡黄色固体，ES-API:[M+H]
+＝495.1。
1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),10.50(s,1H),8.27(s,1H),7.70(s,1H),7.65(s,1H),7.58(d,J＝8.4Hz,1H),7.49(dd,J＝15.2,8.2Hz,1H),7.29(d,J＝2.3Hz,1H),7.15–7.05(m,3H),7.02(dd,J＝8.2,2.0Hz,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),1.39(s,3H)。
实施例149 Z160的合成
步骤一：(S)-2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6] 吡啶并[3,4-b]吡嗪-3-酮(500mg，1.28mmol)溶于甲醇(6mL)，四氢呋喃(3mL)和水(1mL)，加入氢氧化钠(359mg，8.99mmol)，反应在60℃搅拌16小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入30mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(30mL)洗涤一次，饱和食盐水(30mL)洗涤两次，干燥后浓缩得到(S)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(320mg，1.28mmol,收率100％)，白色固体。ES-API:[M+H]
+＝250.1。
步骤二：(S)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮320mg，1.28mmol)和2-氯-4-(2-氟苯氧基)苯甲醛(644mg，2.57mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(504mg，8.99mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(460mg，0.92mmol,产率72％)，淡黄色固体。ES-API:[M+H]
+＝500.1。
步骤三：(2S)-9-(((2-氯-4-(2-氟苯氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(460mg，0.92mmol)溶于四氢呋喃(10mL)和水(1mL)室温下加入2,3-二氯-5,6-二氰对苯醌(538mg，2.36mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2-氟苯氧基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z160,170mg，0.341mmol,产率37％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.45(s,1H),10.48(s,1H),8.26(s,1H),7.69(s,1H),7.59–7.54(m,2H),7.50–7.43(m,1H),7.39–7.28(m,3H),7.20(d,J＝2.4Hz,1H),7.00(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),1.38(s,3H).ES-API:[M+H]
+＝498.1。
实施例150 Z161的合成
步骤一：(S)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(500mg，1.14mmol)溶于乙腈(15mL),加入氧化银(II)(3.97g,17.15mmol)和氘代碘甲烷(2.49g,17.15mmol),反应在35℃搅拌48小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(20mL)洗涤。所得滤液经真空浓缩得到(S)-2-(((甲氧基-d
3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(520mg,1.14mmol,收率100％),黄色固体。ES-API:[M+H]
+＝455.1。
步骤二：(S)-2-(((甲氧基-d
3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸氘代甲酯(520mg,1.14mmol)溶于乙酸(10mL)，加入铁粉(447mg,8.01mmol),反应在90℃搅拌2小时。反应液冷却至室温后用硅藻土过滤，滤饼用乙酸乙酯(20mL)洗涤。滤液真空浓缩,所得粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-100％)得到(S)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,0.87mmol，收率78％)，浅黄色固体。ES-API:[M+H]
+＝393.2。
步骤三：(S)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,0.87mmol)溶于甲醇(3mL)，四氢呋喃(2mL)和水(0.8mL)，加入氢氧化钠(250mg，6.24mmol)，反应在65℃搅拌6小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(20mL)洗涤一次，饱和食盐水(20mL)洗涤两次，干燥后浓缩得到(S)-2-(((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(225mg，0.89mmol,收率100％)，白色固体。ES-API:[M+H]
+＝253.1。
步骤四：(S)-2-(((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(225mg，0.89mmol)和2-氯-4-苯氧基苯甲醛(622mg，2.68mmol溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(350mg，6.24mmol)。反应在室温下搅拌16 小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.412mmol,产率46％)，淡黄色固体。ES-API:[M+H]
+＝485.1。
步骤五：(2S)-9-(((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.412mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(281mg，1.24mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z161,76mg，0.157mmol,产率38％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.46(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.5Hz,1H),7.48(t,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.20–7.16(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H).ES-API:[M+H]
+＝483.1。
实施例151 Z162的合成
步骤一：(S)-2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，0.776mmol)溶于甲醇(3mL)，四氢呋喃(2mL)和水(0.8mL)，加入氢氧化钠(217mg，5.43mmol)，反应在60℃搅拌16小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(20mL)洗涤一次，饱和食盐水(20mL)洗涤两次，干燥后浓缩得到(S)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(192mg，0.770mmol,收率100％)，白色固体。ES-API:[M+H]
+＝250.1。
步骤二：(S)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(191mg，0.776mmol)和2-氯-4-(3-氟苯氧基)苯甲醛(579mg，2.31mmol溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(302mg，5.39mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.402mmol,产率52％)，淡黄色固体。ES-API:[M+H]
+＝500.1。
步骤三：(2S)-9-(((2-氯-4-(3-氟苯氧基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.402mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(269mg，1.18mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(3-氟苯氧基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z162,70mg，0.181mmol,产率45％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ10.48(s,1H),8.27(s,1H),7.70(s,1H),7.64(s,1H),7.58(d,J＝8.5Hz,1H),7.49(dd,J＝15.0,8.5Hz,1H),7.29(d,J＝2.5Hz,1H),7.12–7.05(m,3H),7.02(dd,J＝8.5,2.5Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),1.39(s,3H).ES-API:[M+H]
+＝498.1。
实施例152 Z163的合成
步骤一：2-氯-4-氟苯甲醛(2g，12.61mmol)和2-甲氧基苯酚(1.57g，12.61mmol)溶于无水N,N-二甲基甲酰胺(50mL),加入无水碳酸钾(3.49g,25.32mmol)，反应在90℃下搅拌 3小时。反应液冷却至室温后倒入500mL水中，用乙酸乙酯(250mL)萃取。有机相用饱和食盐水(80mL)洗涤3次，用无水硫酸钠干燥后浓缩得到2-氯-4-(2-甲氧基苯氧基)苯甲醛(3g,11.42mmol，收率90％)，白色固体。ES-API:[M+H]
+＝263.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，0.776mmol)溶于甲醇(3mL)，四氢呋喃(2mL)和水(0.8mL)，加入氢氧化钠(217mg，5.43mmol)，反应在60℃搅拌16小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(20mL)洗涤一次，饱和食盐水(20mL)洗涤两次，干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(191mg，0.776mmol,收率100％)，白色固体。ES-API:[M+H]
+＝247.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(191mg，0.776mmol)和2-氯-4-(2-甲氧基苯氧基)苯甲醛(611mg，2.33mmol溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(305mg，5.43mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-(2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg，0.497mmol,产率60％)，淡黄色固体。ES-API:[M+H]
+＝509.1。
步骤四：(2S)-9-(((2-氯-4-(2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg，0.497mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(269mg，1.18mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z163,162mg，0.320mmol,产率65％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.42(s,1H),10.47(s,1H),8.28(s,1H),7.69(s,1H),7.53(s,1H),7.50(d,J＝8.5Hz,1H),7.32–7.27(m,1H),7.26–7.22(m,1H),7.20(dd,J＝8.5,1.5Hz,1H),7.07–7.02(m,1H),7.00(d,J＝2.5Hz,1H),6.85(dd,J＝8.5,2.5Hz,1H),3.78(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(3,2H),1.38(s,3H).ES-API:[M+H]
+＝507.1。
实施例153 Z164的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.40g，3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g，24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,粗收率66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(223mg，0.9065mmol)和2-氯-4-(2-氯苯氧基)苯甲醛(484mg，1.8127mmol)溶于甲醇(25.0mL)，将反应冷至0℃，加入氢氧化钾(350mg，6.250mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯-4-(2-氯苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(190mg,收率41％)，淡黄色固体。ES-API:[M+H]
+＝513.1/515.0。
步骤三：(2S)-9-(((2-氯-4-(2-氯苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(190mg,0.3711mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(170mg，0.7422mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2-氯苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z164,80.5mg,收率42％)，淡黄色固体，ES-API:[M+H]
+＝511.1/513.2。
1H NMR(500MHz,DMSO-d6)δ12.46(s,1H),10.49(s,1H),8.27(s,1H),7.76–7.64(m,2H),7.62–7.54(m,2H),7.46(t,J＝7.7Hz,1H),7.32(dd,J＝16.2,7.4Hz,2H),7.18(d,J＝2.2Hz,1H),6.96(dd,J＝8.4,2.2Hz,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例154 Z166的合成
步骤一：2-氯-4-氟苯甲醛(2g，12.61mmol)和3-甲氧基苯酚(1.57g，12.61mmol)溶于无水N,N-二甲基甲酰胺(50mL),加入无水碳酸钾(3.49g,25.32mmol)，反应在90℃下搅拌3小时。反应液冷却至室温后倒入500mL水中，用乙酸乙酯(250mL)萃取。有机相用饱和食盐水(80mL)洗涤3次，用无水硫酸钠干燥后浓缩得到2-氯-4-(3-甲氧基苯氧基)苯甲醛(2.5g,9.52mmol，收率75％)，白色固体。ES-API:[M+H]
+＝263.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg，0.776mmol)溶于甲醇(3mL)，四氢呋喃(2mL)和水(0.8mL)，加入氢氧化钠(217mg，5.43mmol)，反应在60℃搅拌16小时。反应液冷却至室温后用稀盐酸(1.0M)调至pH＝8，而后加入20mL饱和碳酸氢钠溶液，用乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸氢钠溶液(20mL)洗涤一次，饱和食盐水(20mL)洗涤两次，干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]]吡啶并[3,4-b]吡嗪-3-酮(191mg，0.776mmol,收率100％)，白色固体。ES-API:[M+H]
+＝247.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(191mg，0.776mmol)和2-氯-4-(3-甲氧基苯氧基)苯甲醛(611mg，2.33mmol溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(305mg，5.43mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-(3-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.395mmol,产率51％)，淡黄色固体。ES-API:[M+H]
+＝509.1。
步骤四：(2S)-9-(((2-氯-4-(3-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.395mmol)溶于四氢呋 喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(269mg，1.18mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(3-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z166,70mg，0.138mmol,产率35％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.44(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.60(s,1H),7.55(d,J＝8.5Hz,1H),7.37(t,J＝8.5Hz,1H),7.19(d,J＝2.5Hz,1H),7.03(dd,J＝8.5,2.5Hz,1H),6.83(dd,J＝8.5,2.5Hz,1H),6.76(t,J＝2.5Hz,1H),6.75-6.70(m,1H),3.78(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.38(s,3H).ES-API:[M+H]
+＝507.1。
实施例155 Z167的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.5g,4.451mmol)和(S)-2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(1.5g,8.902mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在95℃搅拌16小时。反应液中加入100mL乙酸乙酯，用60mL水洗涤2次，30mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(S)-3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.3g,收率72％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：(S)-3-羟基-2-甲基-2-(((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(300mg,0.6911mmol)溶于乙腈(40mL)，依次加入氧化银(1.60g,6.911mmol)和碘乙烷(1.078g,6.911mmol),氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到(S)-3-乙氧基-2-甲 基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(223mg,收率70％)，黄色固体。ES-API:[M+H]
+＝463.1。
步骤三：(S)-3-乙氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(223mg,0.4827mmol)溶于乙酸(20mL)中，加入铁粉(405mg,7.240mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用80mL水洗涤2次，60mL饱和碳酸钠洗涤2次,80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水，干燥浓缩，粗品用乙酸乙酯打浆得到(S)-2-(乙氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(220mg,粗品)，黄色固体。ES-API:[M+H]
+＝401.2
步骤四：(S)-2-(乙氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(220mg，粗品)溶于12mL甲醇，3mL四氢呋喃和2mL水，加入氢氧化钠(135mg，3.378mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg,粗品)，淡白色固体。ES-API:[M+H]
+＝261.1。
步骤五：(S)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg，粗品)和2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(240mg，0.9654mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(190mg，3.379mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg,3步收率65％)，淡黄色固体。ES-API:[M+H]
+＝508.1。
步骤六：(2S)-9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg,0.3155mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(145mg，0.6310mmol)，反应在室温下搅拌2小时。反应液加入65mL饱和碳酸氢钠溶液，用83mL乙酸乙酯萃取。有机相用70mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(乙氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z167,65mg,收率40％)，淡黄色固体，ES-API:[M+H]
+＝506.1。
1H NMR(500MHz,DMSO-d6)δ10.39(s,1H),8.32(s,1H),8.09(d,J＝ 5.1Hz,1H),7.70(s,1H),7.58–7.47(m,2H),7.37(d,J＝2.2Hz,1H),7.19(dd,J＝8.3,2.3Hz,1H),7.06(d,J＝5.1Hz,1H),6.99(s,1H),3.65(d,J＝9.7Hz,1H),3.53–3.43(m,3H),2.37(s,3H),1.40(s,3H),1.04(t,J＝7.0Hz,3H)。
实施例156 Z168的合成
步骤一：将2-氯-4-氟苯甲醛(1.58g,10.0mmol)和2-氟-6-甲氧基苯酚(1.42g,10.0mmol)溶于干燥的N,N-二甲基乙酰胺(30mL)，最后加入碳酸铯(9.60g,30.0mmol)，氮气保护下加热至90℃反应2小时。反应完毕后，向冷却液中加入乙酸乙酯(200mL)并用饱和食盐水(3*80mL)洗3次，将乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干得到2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲醛(2.40g,收率85％)。，ES-API:[M+H]
+＝281.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.05g，2.7187mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(761.0mg，19.03mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(2.20g,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg，0.8130mmol)和2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲醛(300mg，1.070mmol)溶于甲醇(15.0mL)，将反应冷至0℃，加入氢氧化钾(318mg，5.690mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯-4-(2-氟-6-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg,2步收率56％)，淡黄色固体。ES-API:[M+H]
+＝527.2。
步骤四：(2S)-9-(((2-氯-4-(2-氟-6-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg,0.4561mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(240mg，1.057mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z168,67.8mg,收率28％)，淡黄色固体，ES-API:[M+H]
+＝525.1。
1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),10.50(s,1H),8.27(s,1H),7.68(s,1H),7.61–7.49(m,2H),7.40–7.24(m,1H),7.19–7.04(m,3H),6.86(d,J＝8.0Hz,1H),3.82(s,3H),3.64(d,J＝9.4Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例157 Z170的合成
步骤一：2-氯-4-甲基苯甲酸(2g,11.72mmol)和过氧化苯甲酰(284mg,1.17mmol)溶于四氯化碳(60mL)。反应在90℃下搅拌一个小时后，而后加入溴代丁二酰亚胺(2.13g，11.96mmol)，反应在90℃继续搅拌五个小时。反应冷却至室温后倒入水(200mL)中，用二氯甲烷(300mL)萃取。有机相用饱和食盐水(80mL)洗涤3次，用无水硫酸钠干燥后浓缩得到4-(溴甲基)-2-氯苯甲酸(2.8g,11.22mmol，收率96％)，白色固体。ES-API:[M+H]
+＝249.1。
步骤二：4-(溴甲基)-2-氯苯甲酸(2g,8.02mmol)溶于无水四氢呋喃(30mL),将反应冷至0℃，缓慢滴加硼烷四氢呋喃络合物(1M,24.05mL，24.05mmol)。滴加完毕后，反应在0℃下继续搅拌一个小时。反应液用无水甲醇(20mL)淬灭后，浓缩得到(4-(溴甲基)-2-氯苯基)甲醇(1.89g,8.02mmol，收率100％)，白色固体。ES-API:[M+H]
+＝235.1。
步骤三：吡唑(52mg,0.763mmol)溶于N,N-二甲基甲酰胺(2mL),将反应冷至0℃，加入叔丁醇钾固体(107mg，0.955mmol)。反应在0℃搅拌半小时后，加入4-(溴甲基)-2-氯 苯甲酸(150mg，0.637mmol)。反应在0℃下继续搅拌一个小时。反应液倒入水(20mL)中，用乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL)洗涤3次，用无水硫酸钠干燥后浓缩得到(4-(((1H-吡唑-1-基)甲基)-2-氯苯基)甲醇(140mg,0.629mmol，收率98％)，白色固体。ES-API:[M+H]
+＝223.1。
步骤四：4-(((1H-吡唑-1-基)甲基)-2-氯苯基)甲醇(140mg,0.629mmol)溶于乙酸乙酯(5mL)和乙醇(5mL)，加入活性二氧化锰(328mg，3.77mmol)，反应在室温条件下搅拌十七个小时。反应液用硅藻土过滤后，滤液经浓缩得到4-((1H-吡唑-1-基)甲基)-2-氯苯甲醛(120mg,0.543mmol，收率86％)，黄色油状液体。ES-API:[M+H]
+＝221.1。
步骤五：(S)-2-(((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg，0.201mmol)和4-((1H-吡唑-1-基)甲基)-2-氯苯甲醛(120mg,0.543mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(79mg，1.40mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((4-((1H-吡唑-1-基)甲基)-2-氯苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(80mg，0.17mmol,产率85％)，淡黄色固体。ES-API:[M+H]
+＝470.1。
步骤六：(2S)-9-(((4-((1H-吡唑-1-基)甲基)-2-氯苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(80mg，0.17mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(116mg，0.511mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(4-(((1H-吡唑-1-基)甲基)-2-氯苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z170,70mg，0.138mmol,产率35％)，白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.76(br s,1H),10.48(s,1H),8.47(s,1H),8.25(s,1H),7.91(d,J＝2.5Hz,1H),7.69(s,1H),7.55–7.55(m,2H),7.44(s,1H),7.37(s,1H),7.23(d,J＝8.0Hz,1H),6.33(t,J＝2.5Hz,1H),5.45(s,2H),3.63(d,J＝9.5Hz,1H),3.46(d,J＝9.5Hz,1H),1.38(s,3H).ES-API:[M+H]
+＝468.1。
实施例158 Z171、Z174和Z175的合成
步骤一：3-甲基-1H-吡唑(126mg,1.53mmol)溶于N,N-二甲基甲酰胺(5mL),将反应冷至0℃，加入叔丁醇钾固体(214mg，1.91mmol)。反应在0℃搅拌半小时后，加入4-(溴甲基)-2-氯苯甲酸(300mg，1.27mmol)。反应在0℃下继续搅拌一个小时。反应液倒入水(20mL)中，用乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL)洗涤3次，用无水硫酸钠干燥后浓缩得到((2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯基)甲醇和(2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯基)甲醇的混合物(300mg,共1.27mmol，收率98％)，白色固体。ES-API:[M+H]
+＝237.1。
步骤二：(2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯基)甲醇和(2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯基)甲醇的混合物(300mg,共1.27mmol)溶于乙酸乙酯(8mL)和乙醇(8mL)，加入活性二氧化锰(771mg，8.89mmol)，反应在室温条件下搅拌十七个小时。反应液用硅藻土过滤后，滤液经浓缩得到2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯甲醛和2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯甲醛的混合物(290mg,1.24mmol，收率98％)，黄色油状液体。ES-API:[M+H]
+＝235.1。
步骤三：2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯甲醛和2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯甲醛的混合物(290mg,1.24mmol)以及(S)-2-(((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(108mg,0.430mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(153mg，2.72mmol)。反应在室温下搅拌16小时。反应液用稀盐酸(1.0M)调至pH＝8，用乙酸乙酯(100mL)萃取。有机相用饱和食盐水(30mL)洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(2S)-9-(((2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮和(2S)-9-(((2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮的混合物(120mg，0.248mmol,产率20％)，淡黄色固体。ES-API:[M+H]
+＝484.1。
步骤四：((2S)-9-(((2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮和(2S)-9-(((2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮的混合物(120mg，0.248mmol)溶于四氢呋喃(5mL)和水(0.5mL)室温下加入2,3-二氯-5,6-二氰对苯醌(169mg，0.744mmol)，反应在室温下搅拌2小时。向反应液中加入饱和亚硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL)淬灭反应，而后用乙酸乙酯萃取(50mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(20mL)，干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮和(S)-9-(2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮的混合物(Z171,16mg，0.248mmol,产率14％)，白色固体。
将所得混合物Z171经手性拆分得到两个化合物：
一个是化合物Z174：(S)-9-(2-氯-4-((3-甲基-1H-吡唑-1-基)甲基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(6mg)(柱型：IE250mm，10mm，5μm；流动相体系：(A：正己烷；B：乙醇)；流速：1ml/min；B％＝0-40％；柱温：室温；峰1，保留时间：10.996)；白色固体；
1H NMR(500MHz,DMSO-d
6)δ12.43(s,1H),10.48(s,1H),8.25(s,1H),7.76(d,J＝2.0Hz,1H),7.69(s,1H),7.52(d,J＝8.0Hz,1H),7.46(s,1H),7.38(s,1H),7.23(d,J＝8.0Hz,1H),6.09(d,J＝2.0Hz,1H),5.33(s,2H),3.63(d,J＝9.5Hz,1H),3.46(d,J＝9.5Hz,1H),2.17(s,3H),1.38(s,3H).ES-API:[M+H]
+＝482.1。
另一个是化合物Z175：(S)-9-(2-氯-4-((5-甲基-1H-吡唑-1-基)甲基)苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(3mg)(柱型：IE 250mm，10mm，5μm；流动相体系：(A：正己烷；B：乙醇)；流速：1ml/min；B％＝0-30％；柱温：室温；峰2，保留时间：13.181)；白色固体。
1H NMR(500MHz,DMSO-d
6)δ12.43(s,1H),10.48(s,1H),8.25(s,1H),7.69(s,1H),7.51(d,J＝7.5Hz,1H),7.47(s,1H),7.42(s,1H),7.25(s,1H),7.09(d,J＝7.5Hz,1H),6.13(s,1H),5.40(s,2H),3.63(d,J＝9.5Hz,1H),3.46(d,J＝9.5Hz,1H),2.25(s,3H),1.38(s,3H).ES-API:[M+H]
+＝482.1。
实施例159 Z173的合成
步骤一：2-氯-4-氟苯甲醛(972mg，6.127mmol)、3-氟-2-甲氧基苯酚(870mg，6.127mmol)和碳酸钾(2.540g，18.381mmol)溶于N,N'-二甲基甲酰胺(30mL)，反应于90℃下搅拌3小时，LCMS检测反应已经完全，将反应液冷却至室温，加入30mL乙酸乙酯，分别加入30mL水洗1次，饱和食盐水(25mL X 3)洗涤，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩至干得到淡黄色液体2-氯-4-(3-氟-2-甲氧基苯氧基)苯甲醛(1314mg,收率77％)。ES-API:[M+H]
+＝281.0
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(36.5mg，0.148mmol)和2-氯-4-(3-氟-2-甲氧基苯氧基)苯甲醛(104mg，0.371mmol)溶于甲醇(6mL)，将反应液冷却至0℃，加入氢氧化钾(58mg，1.036mmol)。反应在室温下搅拌24小时。LCMS检测反应已经完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mL X 3)，有机相用20mL饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到粗品(2S)-9-(((2-氯-4-(3-氟-2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(78mg,收率100％)。ES-API:[M+H]
+＝527.2
步骤三：(2S)-9-(((2-氯-4-(3-氟-2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(78mg,0.148mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(78mg，0.344mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙 酸乙酯萃取。有机相用15mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC(柱:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到淡黄色固体(S)-9-(2-氯-4-(3-氟-2-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z173,12mg,收率15％)。ES-API:[M+H]
+＝525.3。
1H NMR(500MHz,DMSO-d
6)δ12.43(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.56-7.54(m,2H),7.24-7.16(m,3H),7.05(d,J＝7.5Hz,1H),6.99(dd,J1＝2.0Hz,J2＝8.0Hz,1H),3.83(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.0Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例160 Z177的合成
步骤一：将2-氯-4-氟苯甲醛(1.0g,6.329mmol)和2,3-二氟-6-甲氧基苯酚(1.06g,6.250mmol)溶于干燥的N,N-二甲基乙酰胺(30mL)，最后加入碳酸铯(5.0g,15.34mmol)，氮气保护下加热至90℃并反应2小时。反应完毕后，向冷却液中加入乙酸乙酯(200mL)并用饱和食盐水(3*80mL)洗3次，将乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干得到2-氯-4-(2,3-二氟-6-甲氧基苯氧基)苯甲醛(1.20g,收率63％)。ES-API:[M+H]
+＝299.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(1.05g，2.7187mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(761.0mg，19.03mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(2.20g,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(209mg，粗品)和2-氯-4-(2,3-二氟-6-甲氧基苯氧基)苯甲醛(237mg，0.7953mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(152mg，2.720mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得到粗品目标产物(2S)-9-(((2-氯-4-(2,3-二氟-6-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(60mg,2步收率28％)，淡黄色固体。ES-API:[M+H]
+＝545.2。
步骤四：(2S)-9-(((2-氯-4-(2,3-二氟-6-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(60mg,0.1102mmol)溶于10mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(50mg，0.2205mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(2,3-二氟-6-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z177,13mg,收率22％)，淡黄色固体，ES-API:[M+H]
+＝543.2。
1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),10.48(s,1H),8.27(s,1H),7.69(s,1H),7.59–7.50(m,2H),7.43(dd,J＝19.1,9.5Hz,1H),7.17(d,J＝2.4Hz,1H),7.15–7.05(m,1H),6.94(dd,J＝8.5,2.3Hz,1H),3.80(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例161 Z187的合成
步骤一：向100mL圆底烧瓶中加入2-氟-6-甲氧基苯酚(880mg，6.19mmol)，2-氯-4-氟苯甲醛(982mg，6.19mmol)，碳酸钾(2.56g，18.57mmol)和DMF(15mL)。反应在95℃下搅拌3小时。将反应液中倒入冰水中，用乙酸乙酯萃取。有机相干燥后浓缩得到粗品 2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲醛(1.5g，86％)，黄色固体。ES-API:[M+H]
+＝281.0
步骤二：向100mL反应瓶中加入2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲醛(800mg，2.86mmol)和10mL二氯甲烷。体系冷至0℃，向其中滴加三溴化硼的二氯甲烷溶液(8.6mL,8.6mmol,1M)。反应在室温下搅拌2小时，停止反应。将反应液中倒入冰的50mL饱和碳酸氢钠，用二氯甲烷萃取3次，有机相干燥浓缩后用快速硅胶柱纯化(0-20％乙酸乙酯/石油醚)得到2-氯-4-(2-氟-6-羟基苯氧基)苯甲醛(500mg，65％)，黄色固体。ES-API:[M+H]
+＝267.1
步骤三：向100mL圆底烧瓶中加入2-氯-4-(2-氟-6-羟基苯氧基)苯甲醛(400mg，1.5mmol)，氘代碘甲烷(654mg，14.5mmol)，碳酸钾(414mg，3.05mmol)和DMF(16mL)。反应在40℃下搅拌3小时。反应用水淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥。有机相浓缩后得到粗品，用快速硅胶柱纯化(0-20％乙酸乙酯/石油醚)得到2-氯-4-(2-氟-6-(甲氧基-d
3)苯氧基)苯甲醛(130mg，30％)。
1HNMR(500MHz,DMSO-d
6):10.21(s,1H),7.86(d,J＝9.0Hz,1H),7.37-7.34(m,1H),7.11-7.03(m,3H),6.97(dd,J＝9.0,2.0Hz,1H),7.65(d,J＝1.2,1H),6.35(s,1H),3.89(s,3H),2.44(s,3H).ES-API:[M+H]
+＝284.1
步骤四：向100mL圆底烧瓶中加入2-氯-4-(2-氟-6-(甲氧基-d
3)苯氧基)苯甲醛(130mg，0.46mmol)，(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(113mg，0.46mmol)，氢氧化钾(180mg，3.22mmol)和甲醇(6mL)。反应在室温下搅拌24小时。反应用2N盐酸淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥。有机相浓缩后得到粗品(2S)-9-(((2-氯-4-(2-氟-6-(甲氧基-d
3)苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(130mg，粗品)。ES-API:[M+H]
+＝530.2
步骤五：零度下，向100mL圆底烧瓶中加入(2S)-9-(((2-氯-4-(2-氟-6-(甲氧基-d
3)苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(130mg，粗品)和四氢呋喃(5mL)。向其中加入2,3-二氯-5,6-二氰对苯醌(111mg,0.48mmol)。反应在室温下搅拌30分钟。反应用饱和碳酸氢钠水溶液淬灭，用二氯甲烷萃取。有机相用无水硫酸钠干燥。浓缩后，粗品用制备HPLC纯化得到目标产物(Z187,43mg，两步收率34％)。ES-API:[M+H]
+＝528.2。
参照实施例1至23的制备方法通过更改部分原料来制备以下化合物：
实施例165 Z85的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(1.40g,3.570mmol)溶于36mL甲醇，9mL四氢呋喃和6mL水，加入氢氧化钠(1.01g,24.99mmol)，反应在65℃搅拌7小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(377mg,收率43％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg,0.6501mmol)和2-氯-5-氟苯甲醛(210mg,1.324mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(253mg,4.517mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到(2S)-9-((2-氯-5-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(270mg,粗品)，淡黄 色固体。ES-API:[M+H]
+＝405.1。
步骤三：(2S)-9-((2-氯-5-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(270mg,粗品)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(303mg,1.335mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-5-氟苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z85,115mg,2步总收率44％)，淡黄色固体。ES-API:[M+H]
+＝403.1。
1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),10.49(s,1H),8.22(s,1H),7.70(s,1H),7.66–7.58(m,2H),7.51(dd,J＝8.3,3.0Hz,1H),7.41(td,J＝8.6,3.1Hz,1H),3.65(d,J＝9.6Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),1.39(s,3H)。
实施例166 Z86的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.8mmol)和2-溴苯甲醛(293mg,1.6mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(314mg,5.6mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到(2S)-9-((2-溴苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(227mg,收率66％)，淡黄色固体。ES-API:[M+H]
+＝433.1。
步骤二：(2S)-9-((2-溴苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(227mg,0.53mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(301mg,1.33mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，无水硫酸钠干燥后浓缩，粗品用制备HPLC(柱型号:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到目标产物(S)-9-(2-溴苯甲酰 基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(Z86,130mg,收率57％)，白色固体。ES-API:[M+H]
+＝431.0。
1H NMR(500MHz,DMSO)δ12.43(s,1H),10.49(s,1H),8.29(s,1H),7.74(d,J＝7.5Hz,1H),7.70(s,1H),7.54-.48(m,2H),7.48-.43(m,1H),7.41(s,1H),3.65(d,J＝9.5Hz,1H),3.45(d,J＝9.5,1H),3.30(s,3H),1.39(s,3H)。
实施例167 Z89的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.8mmol)和苯甲醛(170mg,1.6mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(314mg,5.6mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:5)纯化得到(2S)-9-(羟基(苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(197mg,收率70％)，淡黄色固体。ES-API:[M+H]
+＝353.1。
步骤二：(2S)-9-(羟基(苯基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(197mg,0.53mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(301mg,1.33mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，无水硫酸钠干燥后浓缩，粗品用制备HPLC(柱型号:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到目标产物(S)-9-苯甲酰基-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z89,109mg,收率59％)，白色固体。ES-API:[M+H]
+＝351.1。
1H NMR(500MHz,DMSO)δ10.61-10.41(m,1H),8.35(s,1H),7.76(d,J＝7.5Hz,2H),7.73(s,1H),7.69(s,1H),7.62(t,J＝7.5Hz,1H),7.54(t,J＝7.5Hz,2H),7.04-6.71(m,1H),3.65(d,J＝9.5Hz,1H),3.45(t,J＝9.4Hz,1H),3.32(s,3H),1.38(s,3H)。
实施例168 Z113的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.8mmol)和2-氯-4-甲氧基苯甲醛(272mg,1.6mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(314mg,5.6mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到目标产物(2S)-9-((2-氯-4-甲氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(171mg,收率51％)，淡黄色固体。ES-API:[M+H]
+＝417.2。
步骤二：(2S)-9-((2-氯-4-甲氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(171mg,0.41mmol)溶于20mL四氢呋喃和2mL水，加入2,3-二氯-5,6-二氰对苯醌(227mg,1.0mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，无水硫酸钠干燥后浓缩，粗品用制备HPLC(柱型号:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到目标产物(S)-9-(2-氯-4-甲氧基苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z113,77mg,收率45.4％)，白色固体。ES-API:[M+H]
+＝415.1。
1H NMR(500MHz,DMSO)δ12.36(s,1H),10.47(s,1H),8.29(s,1H),7.69(s,1H),7.49(d,J＝10.0Hz,2H),7.15(d,J＝2.0Hz,1H),7.01(dd,J＝8.5,2.5Hz,1H),3.85(s,3H),3.64(d,J＝9.6Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例169 Z120的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.0g,2.967mmol)和2-氨基-2-甲基丙酸甲酯盐酸盐(1.0g,6.509mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(7.64g,59.15mmol)，反应在85℃搅拌12小时。反应液中加入100mL乙酸乙酯，用水洗涤(2X60mL)，饱和食盐水洗涤(3X30mL)，无水硫酸钠干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.1g,收率88％)，淡黄色固体。ES-API:[M+H]
+＝419.1。
步骤二：2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.10g,2.63mmol)溶于乙酸(30mL)中，加入铁粉(1.50g,26.31mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用水洗涤(2X80mL)，饱和碳酸钠洗涤(2X60mL)，饱和食盐水次(2X80mL)，有机相无水硫酸钠干燥，浓缩，粗品用乙酸乙酯(20mL)打浆得到2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg,收率25％)，黄色固体。ES-API:[M+H]
+＝357.1。
步骤三：2,2-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(240mg,0.6739mmol)溶于20mL甲醇，6mL四氢呋喃和4mL水，加入氢氧化钠(188.0mg,4.717mmol)，反应在65℃搅拌12小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2,2-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,粗品)，淡白色固体。ES-API:[M+H]
+＝217.1。
步骤四：2,2-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,粗品)和2-氯-苯甲醛(188mg,1.342mmol)溶于甲醇(25.0mL)，将反应冷至0℃，加入氢氧化钾(264mg,4.714mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水 溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品9-((2-氯苯基)(羟基)甲基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(210mg,2步收率87％)，淡黄色固体。ES-API:[M+H]
+＝357.2。
步骤五：(9-((2-氯苯基)(羟基)甲基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(210mg,0.5898mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(267mg,1.176mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物9-(2-氯苯甲酰基)-2,2-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z120,95mg,收率45％)，淡黄色固体。ES-API:[M+H]
+＝355.1。
1H NMR(500MHz,DMSO-d6)δ10.67(d,J＝236.9Hz,2H),8.10(s,1H),7.76(s,1H),7.63–7.51(m,3H),7.51–7.37(m,2H),1.41(s,6H)。
实施例170 Z190的合成
步骤一：向封管中加入(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(400mg,1.036mmol)、氘代碘甲烷(1.50g,10.36mmol)、碳酸钾(430mg,3.108mmol)和混合液丙酮/N,N-二甲基甲酰胺(20mL/4.0mL)，40℃下反应12小时。反应完毕，冷却到室温，加入乙酸乙酯萃取(1X200mL)，用饱和食盐水洗涤(3X100mL)，有机相用无水硫酸钠干燥、过滤、减压旋干溶剂得到粗品(S)-2-(甲氧基甲 基)-2-甲基-4-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(530mg,粗品)。ES-API:[M+H]
+＝404.2。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(530mg,粗品)溶于30mL甲醇，7.5mL四氢呋喃和5mL水，加入氢氧化钠(290mg,7.252mmol)，反应在65℃下搅拌16小时。反应完毕后，冷却到室温，向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.60g,粗品)，淡白色固体。ES-API:[M+H]
+＝264.3。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.60g,粗品)和2-氯-4-苯氧基苯甲醛(480mg,2.069mmol)溶于甲醇(25.0mL)，将反应冷至0℃，加入氢氧化钾(406mg,7.25mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,3步总收率58％)，淡黄色固体。ES-API:[M+H]
+＝496.3。
步骤四：(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,0.6057mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(275mg,1.211mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z190,136mg,收率45％)，淡黄色固体。ES-API:[M+H]
+＝494.2。
1H NMR(500MHz,DMSO-d6)δ12.55(s,1H),8.53(s,1H),7.95(s,1H),7.66(s,1H),7.56(d,J＝8.4Hz,1H),7.48(t,J＝8.0Hz,2H),7.25(t,J＝7.4Hz,1H),7.19(dd,J＝5.1,2.6Hz,3H),7.03(dd,J＝8.4,2.3Hz,1H),3.64(d,J＝9.6Hz,1H),3.50(d,J＝9.6Hz,1H),3.28(s,3H),1.38(s,3H)。
实施例171 Z193的合成
步骤一：向封管中加入(S)-2-((甲氧基-d
3)甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,0.8995mmol)、氘代碘甲烷(1.30g,8.995mmol)、碳酸钾(372mg,2.698mmol)和混合液丙酮/N,N-二甲基甲酰胺(20mL/4.0mL)，40℃下反应12小时。反应完毕，冷却到室温，加入乙酸乙酯萃取(1X200mL)，饱和食盐水洗涤(3X100mL)，有机相用无水硫酸钠干燥、过滤、减压旋干溶剂得到(S)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(340mg,收率93％)。ES-API:[M+H]
+＝407.2。
步骤二：(S)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(340mg,0.8370mmol)溶于24mL甲醇，6mL四氢呋喃和4mL水，加入氢氧化钠(234mg,5.859mmol)，反应在65℃搅拌16小时。反应完毕后，冷却到室温，向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg,粗品)，淡白色固体。ES-API:[M+H]
+＝267.3。
步骤三：(S)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg,粗品)和2-氯-4-苯氧基苯甲醛(420mg,1.810mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(355mg,6.34mmol)。反应在室温下搅拌6小 时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(265mg,2步总收率63％)，淡黄色固体。ES-API:[M+H]
+＝499.3。
步骤四：(2S)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(300mg,0.6057mmol)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(265mg,0.5318mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-((甲氧基-d
3)甲基)-2-甲基-4-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z193,102mg,收率38％)，淡黄色固体。ES-API:[M+H]
+＝497.2。
1H NMR(500MHz,DMSO-d6)δ8.53(s,1H),7.94(s,1H),7.65(s,1H),7.56(d,J＝8.4Hz,1H),7.48(t,J＝8.0Hz,2H),7.25(t,J＝7.4Hz,1H),7.18(dd,J＝5.0,2.6Hz,3H),7.02(dd,J＝8.4,2.3Hz,1H),3.63(d,J＝9.6Hz,1H),3.50(d,J＝9.6Hz,1H),1.38(s,3H)。
实施例172 Z194的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg,0.6501mmol)和2-氯-3氟-4-甲氧基苯甲醛(232mg,1.298mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(253mg,4.517mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-3-氟-4-甲氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：(2S)-9-((2-氯-3-氟-4-甲氧基苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基- 1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,粗品)溶于20mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(295mg,1.300mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-9-(2-氯-3-氟-4-甲氧基苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z194,70.9mg,2步总收率25％)，淡黄色固体。ES-API:[M+H]
+＝433.1。
1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),7.69(s,1H),7.60(s,1H),7.38(dd,J＝8.5,1.4Hz,1H),7.26(t,J＝8.2Hz,1H),3.95(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.6Hz,1H),3.29(s,4H),1.39(s,3H)。
实施例173 Z195的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(160mg,0.6501mmol)和2-氯-3,4-二氟苯甲醛(232mg,1.298mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(253mg,4.517mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(2S)-9-((2-氯-3,4-二氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝423.1。
步骤二：(2S)-9-((2-氯-3,4-二氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(120mg,粗品)溶于15.0mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(230mg,1.013mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-9-(2-氯-3,4-二氟苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z195,42mg,2步总收率35％)，淡黄色固体，ES-API:[M+H]
+＝421.1.1。
1H NMR(500MHz,DMSO-d6)δ12.53(s,1H),10.49(s,1H),8.18(s,1H),7.70(d,J＝3.4Hz,2H),7.58(dd,J＝17.2,8.7Hz,1H),7.50–7.36(m,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H), 1.38(s,3H)。
实施例174 Z103的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg,0.2mmol)和3-氯噻吩-2-甲醛(88mg,0.6mmol)溶于甲醇(10mL)，将反应冷至0℃，加入氢氧化钾(56mg,1mmol)。反应在室温下搅拌16小时。将反应液倒入30mL水中，用1.0M稀盐酸调pH＝8，50mL乙酸乙酯萃取。有机相用25mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用薄层制备板(二氯甲烷/7M氨甲醇＝100:8)纯化得到(2S)-9-((3-氯噻吩-2-基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(49mg,收率61％)，淡黄色固体。ES-API:[M+H]
+＝393.1。
步骤二：(2S)-9-((3-氯噻吩-2-基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(49mg,0.125mmol)溶于10mL四氢呋喃和1mL水，加入2,3-二氯-5,6-二氰对苯醌(57mg,0.25mmol)，反应在室温下搅拌1小时，反应液加入20mL饱和硫代硫酸钠溶液，用60mL乙酸乙酯萃取，有机相依次用20mL饱和碳酸氢钠溶液和15mL饱和食盐水洗涤两次，无水硫酸钠干燥后浓缩，粗品用制备HPLC(柱型号:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到目标产物(S)-9-(3-氯噻吩-2-羰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z103,28mg,收率57％)，淡黄色固体。ES-API:[M+H]
+＝391.1。
实施例175 Z196的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(20mg,0.081mmol)和2-氯-6-氟苯甲醛(26mg,0.162mmol)溶于甲醇(5mL)，将反应液冷却至0℃，加入氢氧化钾(32mg,0.567mmol)。反应在室温下搅拌24小时。LCMS 检测反应完全，加入20mL饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(15mLX 3)，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯-6-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(32mg,收率100％)。ES-API:[M+H]
+＝405.1。
步骤二：将上述粗品(2S)-9-((2-氯-6-氟苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(32mg,0.081mmol)溶于5mL四氢呋喃，加入2,3-二氯-5,6-二氰对苯醌(32mg,0.141mmol)，反应在室温下搅拌2小时，反应液加入20mL饱和硫代硫酸钠溶液和20mL饱和碳酸氢钠溶液，用30mL乙酸乙酯萃取。有机相用15mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC(柱型号:xbridge C18 19*150mm,5μm；体系：10mmol/L,NH
4HCO
3水溶液；流速：15mL/min；梯度:20～45％CH
3CN-NH
4HCO
3；柱温：室温)纯化得到类白色固体(S)-9-(2-氯-6-氟苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(Z196,3.02mg,收率9％)。ES-API:[M+H]+＝403.1。
1H NMR(500MHz,DMSO)δ12.58(bs,1H),10.50(s,1H),8.11(s,1H),7.70(d,J＝9.5Hz,2H),7.60-7.56(m,1H),7.46(d,J＝8.0Hz,1H),7.41-7.37(m,1H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.0Hz,1H),3.32(s,3H),1.39(d,J＝3.0Hz,3H)。
实施例176 Z197的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.60g,4.7477mmol)和4-氨基四氢-2H-吡喃-4-羧酸甲酯(0.5g,3.141mmol)溶于N,N-二甲基乙酰胺(30mL)，加入N,N-二异丙基乙胺(2.35g,18.18mmol)，反应在115℃搅拌12小时。反应液中加入100mL乙 酸乙酯，水洗涤(2X60mL)，饱和食盐水洗涤(3X30mL)，无水硫酸钠干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(560mg,收率38％)，淡黄色固体。ES-API:[M+H]
+＝461.2。
步骤二：4-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(560mg,1.217mmol)溶于乙酸(20mL)中，加入铁粉(1.36g,24.34mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干后加入200mL乙酸乙酯，依次用水洗涤(2X80mL)，饱和碳酸钠洗涤(2X60mL)，饱和食盐水洗涤(2X80mL)，有机相无水硫酸钠干燥浓缩，粗品用乙酸乙酯(20mL)打浆得到7'-(苯基磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(336mg,收率69％)，黄色固体。ES-API:[M+H]
+＝399.1。
步骤三：7'-(苯基磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(336.0mg,0.844mmol)溶于15mL甲醇，4mL四氢呋喃和3mL水，加入氢氧化钠(236.0mg,5.908mmol)，反应在65℃搅拌12小时。向反应液中加入20mL水和15mL饱和氯化铵溶液，用150mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(358mg,粗品)，淡白色固体。ES-API:[M+H]
+＝259.1。
步骤四：2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(358.0mg,粗品)和2-氯-苯甲醛(240.0mg,1.707mmol)溶于甲醇(15.0mL)，将反应冷至0℃，加入氢氧化钾(331.0mg,5.909mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，干燥后浓缩得9'-((2-氯苯基)(羟基)甲基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(150mg,2步收率44％)，淡黄色固体。ES-API:[M+H]
+＝399.1。
步骤五：9'-((2-氯苯基)(羟基)甲基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(150mg,0.3768mmol)溶于15.0mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(171.0mg,0.7533mmol)，反应在室温下搅拌2小时。反应液加入60mL饱和碳酸氢钠溶液，用80mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9'-(2-氯苯甲酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z197,44mg,收率29％)，淡黄色固体，ES-API:[M+H]
+＝397.1。
1H NMR(500MHz,DMSO-d6)δ12.58(s,1H),10.54(s,1H),8.86 (s,1H),7.79(s,1H),7.65–7.53(m,4H),7.48(td,J＝7.4,1.1Hz,1H),3.96–3.81(m,2H),3.75(dd,J＝11.9,10.3Hz,2H),2.16–2.02(m,2H),1.62(d,J＝12.4Hz,2H)。
实施例177 Z198的合成
步骤一：向20mL微波管中依次加入5-溴-4-氟-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(500mg,1.41mmol)，2-氨基-2-甲基丙烷-1-醇(376mg,4.23mmol)，N,N-二甲基乙酰胺(8mL)，和N,N-二异丙基乙胺(364mg,2.82mmol)，在微波反应器中150℃反应2小时。反应液中加入乙酸乙酯(80mL)，用稀食盐水(30mL×3)洗涤，饱和食盐水(30mL)洗涤，无水硫酸钠干燥浓缩，粗品用薄层色谱制备板纯化(二氯甲烷/甲醇＝30:1)得到目标产物2-((5-溴-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)-2-甲基丙烷-1-醇(280mg,收率46％)，类白色固体。ES-API:[M+H]
+＝424.1,426.1。
步骤二：向5mL微波管中依次加入2-((5-溴-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)-2-甲基丙烷-1-醇(140mg,0.33mmol)，醋酸钯(8mg,0.033mmol)，[1,1'-双萘]-2-基二叔丁基膦(20mg,0.05mmol)，碳酸铯(162mg,0.50mmol)和甲苯(4mL)，氮气吹2分钟，在微波反应器中115℃反应1小时。反应液过滤，用二氯甲烷洗涤，滤液浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-40％)得到2,2-二甲基-7-(苯磺酰基)-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪(95mg,收率83％)，类白色固体。ES-API:[M+H]
+＝344.2
步骤三：2,2-二甲基-7-(苯磺酰基)-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪(190mg,0.55mmol)溶于甲醇(8mL)，四氢呋喃(2mL)和水(2mL)，加入氢氧化钠(88mg,2.2mmol)，反应在65℃搅拌18小时.反应液用1.0M稀盐酸调pH＝8，加入乙酸乙酯(80mL)，依次用饱和碳酸氢钠溶液洗涤(25mL×2)，饱和食盐水(25mL)洗涤，无水硫酸钠干 燥浓缩得到2,2-二甲基-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪(113mg,收率100％)，淡黄色固体。ES-API:[M+H]
+＝204.1。
步骤四：2,2-二甲基-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪(107mg,0.53mmol)和2-氯苯甲醛(223mg,1.59mmol)溶于甲醇(8mL)，将反应冷至0℃，加入氢氧化钾(208mg,3.71mmol)。反应在室温下搅拌16小时。反应液用1.0M稀盐酸调pH＝8，乙酸乙酯萃取(80mL)。有机相用饱和食盐水洗涤(30mL)，无水硫酸钠干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-5％)得到(2-氯苯基)(2,2-二甲基-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪-9-基)甲醇(160mg,产率88％)，类白色固体。ES-API:[M+H]
+＝344.2。
步骤五：(2-氯苯基)(2,2-二甲基-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪-9-基)甲醇(160mg,0.47mmol)溶于1,4-二氧六环(7mL)和水(0.7mL)，室温下加入2,3-二氯-5,6-二氰对苯醌(160mg,0.70mmol)，反应在室温下搅拌1小时。反应液加入5mL饱和硫代硫酸钠溶液(6mL)和饱和碳酸氢钠溶液(6mL)，用乙酸乙酯萃取(70mL)。有机相依次用饱和碳酸氢钠溶液洗涤(20mL×2)，饱和食盐水洗涤(20mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(2-氯苯基)(2,2-二甲基-1,2,3,7-四氢吡咯并[3',2':5,6]吡啶并[3,4-b][1,4]噁嗪-9-基)甲酮(Z198,75mg,产率47％)，淡黄色固体。
1H NMR(500MHz,DMSO-d
6)δ12.33(s,1H),8.07(s,1H),7.73(s,1H),7.60–7.55(m,1H),7.55–7.49(m,2H),7.48–7.42(m,1H),7.35(s,1H),3.83(s,2H),1.29(s,6H).ES-API:[M+H]
+＝341.1。
实施例178 Z199的合成
步骤一：向(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(500mg,1.298mmol)的甲苯(20mL)溶液中加入劳森试剂(577.5mg, 1.427mmol)，在氮气保护下于90℃下反应3小时。反应完毕后减压旋干溶剂，粗品用硅胶柱纯化[石油醚:乙酸乙酯＝100:0～20:80(v/v)]得到目标化合物(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(283mg,收率54％)。[M+H]
+＝403.1。
步骤二：向(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(50mg,0.1243mmol)的N,N-二甲基甲酰胺(0.5mL)溶液中加入碘甲烷(20mg,0.1408mmol)和碳酸钠(20mg,0.1886mmol)室温下反应1小时。反应完毕，冷却到室温，加入乙酸乙酯萃取(1×80mL)，用饱和食盐水洗(3×30mL)，有机相用无水硫酸钠干燥、过滤、减压旋干溶剂，粗品用硅胶柱纯化[石油醚:乙酸乙酯＝100:0～20:80(v/v)]得到目标化合物(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-7-(苯磺酰基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(48mg,收率93％)。ES-API:[M+H]
+＝417.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-7-(苯磺酰基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(210mg,0.5047mmol)溶于18mL甲醇，5.0mL四氢呋喃和3.0mL水，加入氢氧化钠(141.0mg,3.533mmol)，反应在65℃搅拌16小时。反应完毕后，冷却到室温，向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(264.0g,粗品)，淡白色固体。ES-API:[M+H]
+＝277.1。
步骤四：(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(264.0mg,粗品)和2-苯甲醛(141.3mg,1.010mmol)溶于甲醇(20.0mL)，将反应冷至0℃，加入氢氧化钾(198mg,3.530mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到粗品(2S)-9-((2-氯苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(180mg,2步总收率85％)，淡黄色固体。ES-API:[M+H]
+＝417.1。
步骤五：(2S)-9-((2-氯苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(180mg,0.4326mmol)溶于12mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(196mg,0.8652mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-(2-氯苯基)(2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲酮(Z199, 47mg,收率26％)，淡黄色固体。ES-API:[M+H]
+＝415.1。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),8.30(s,1H),7.95(s,1H),7.56(dt,J＝26.2,7.2Hz,3H),7.51–7.33(m,2H),3.59(d,J＝9.8Hz,1H),3.48(d,J＝9.8Hz,1H),3.30(s,3H),2.44(s,3H),1.48(s,3H)。
实施例179 Z200的合成
步骤一：(S)-9-(2-氯苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,0.26mmol)溶于二氯甲烷(25mL)加入三甲基氧鎓四氟硼酸盐(115mg,0.78mmol)，反应在室温下搅拌18小时。反应液中加入饱和碳酸氢钠(15mL)，用二氯甲烷(30mL)萃取。有机层用饱和食盐水(15mL)洗涤，无水硫酸钠干燥浓缩，粗品用制备HPLC纯化得到目标产物(S)-(2-氯苯基)(3-甲氧基-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲酮(Z200,40mg,产率38％)，黄色固体。
1H NMR(500MHz,DMSO-d
6)δ12.40(s,1H),8.35(s,1H),7.80(s,1H),7.60–7.56(m,1H),7.55–7.51(m,2H),7.49–7.43(m,1H),7.41(s,1H),3.82(s,3H),3.64(d,J＝10.0Hz,1H),3.42(d,J＝10.0Hz,1H),3.30(s,3H),1.42(s,3H).ES-API:[M+H]
+＝399.1。
实施例180 Z201的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(280mg,0.6965mmol)溶于15mL甲醇，5mL四氢呋喃和3.0mL水，加入氢氧化钠(195.0mg,4.875mmol)，反应在65℃搅拌16小时。反应完毕后，冷却到室温，向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。 有机相依次用30mL饱和碳酸氢钠溶液洗涤，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(308g,粗品)，淡白色固体。ES-API:[M+H]
+＝277.1。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(308g,粗品)和2-氯-4-苯氧基苯甲醛(352.0mg,1.517mmol)溶于甲醇(15.0mL)，将反应冷至0℃，加入氢氧化钾(272mg,4.857mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用硅胶柱纯化[二氯甲烷:甲醇＝100:0～10:1(v/v)]得到(2-氯-4-苯氧基苯基)((S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲醇(175mg,2步总收率50％)，淡黄色固体。ES-API:[M+H]
+＝509.0。
步骤三：(2-氯-4-苯氧基苯基)((S)-2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲醇(175mg,0.3493mmol)溶于12mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(160mg,0.6986mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-(2-氯-4-苯氧基苯基)(2-(甲氧基甲基)-2-甲基-3-(甲硫基)-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲酮(Z201,22mg,收率12.4％)，淡黄色固体。ES-API:[M+H]
+＝507.1。
1H NMR(500MHz,DMSO-d6)δ12.51(s,1H),8.29(s,1H),7.95(s,1H),7.48(t,J＝7.9Hz,2H),7.25(t,J＝7.3Hz,1H),7.22–7.14(m,3H),7.02(dd,J＝8.4,2.2Hz,1H),3.59(d,J＝9.9Hz,1H),3.47(d,J＝9.8Hz,1H),3.30(s,3H),2.44(s,3H),1.47(s,3H)。
实施例181 Z202的合成
步骤一：向(S)-9-(2-氯-4-苯氧基苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(50mg,0.1050mmol)的甲苯(3.0mL)溶液中加入劳森 试剂(84.0mg,0.2100mmol)，在氮气保护下于115℃下反应2小时。反应完毕后减压旋干溶剂，粗品用制备HPLC纯化得到目标化合物(S)-(2-氯-4-苯氧基苯甲酰基)(2-(甲氧基甲基)-2-甲基-3-硫代-2,3,4,7-四氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲酮(Z202,22mg,收率42％)。[M+H]
+＝493.1。
1H NMR(500MHz,DMSO-d6)δ12.38(s,2H),8.33(s,1H),7.94(s,1H),7.65(s,1H),7.57(d,J＝8.4Hz,1H),7.48(t,J＝7.8Hz,2H),7.25(t,J＝7.3Hz,1H),7.18(d,J＝6.7Hz,3H),7.02(dd,J＝8.4,2.0Hz,1H),3.74(dd,J＝25.0,9.4Hz,2H),3.35(s,3H),1.51(s,3H)。
实施例182 Z203的合成
步骤一：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-硫酮(430mg,1.069mmol)溶于15mL甲醇，5mL四氢呋喃和3.0mL水，加入氢氧化钠(300mg,7.487mmol)，反应在65℃搅拌16小时。反应完毕后，冷却到室温，向反应液中加入20mL水和15mL饱和氯化铵溶液，用200mL乙酸乙酯萃取。有机相依次用30mL饱和碳酸氢钠溶液，80mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩得到(S)-3-(乙硫基)-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(412g,粗品)，淡白色固体。ES-API:[M+H]
+＝291.1。
步骤二：(S)-3-(乙硫基)-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪(412g,粗品)和2-氯-4-苯氧基苯甲醛(496mg,2.138mmol)溶于甲醇(12.0mL)，将反应冷至0℃，加入氢氧化钾(420mg,7.483mmol)。反应在室温下搅拌6小时。将反应液倒入30mL饱和氯化铵水溶液中，调pH＝8，100mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品用硅胶柱纯化[二氯甲烷:甲醇＝100:0～10:1(v/v)]得到(2-氯-4-苯氧基苯基)((S)-3-(乙硫基)-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲醇(320mg,2步总收率60％)，淡黄色固体。ES-API:[M+H]
+＝523.2。
步骤三：(2-氯-4-苯氧基苯基)((S)-3-(乙硫基)-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲醇(320mg,0.6299mmol)溶于15mL四氢呋喃，加入2,3-二氯-5,6-二氰基-1,4-苯醌(286mg,1.2598mmol)，反应在室温下搅拌2小时。反应液加入63mL饱和碳酸氢钠溶液，用88mL乙酸乙酯萃取。有机相用60mL饱和食盐水洗涤，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到目标产物(S)-(2-氯-4-苯氧基苯基)(3-(乙硫基)-2-(甲氧基甲基)-2-甲基-2,7-二氢-1H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-9-基)甲酮(Z203,82mg,收率25％)，淡黄色固体。ES-API:[M+H]
+＝521.2。
1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.04(s,1H),7.73(s,1H),7.60(d,J＝8.5Hz,1H),7.49(t,J＝7.9Hz,2H),7.27(t,J＝7.4Hz,1H),7.20(dd,J＝8.7,5.1Hz,3H),7.04(dd,J＝8.4,2.3Hz,1H),3.68(d,J＝10.0Hz,1H),3.52(d,J＝10.1Hz,1H),3.11(q,J＝7.3Hz,2H),1.54(s,3H),1.31(t,J＝7.3Hz,3H)。
实施例183 Z204的合成
步骤一：(R)-2-氨基-3-羟基丙酸甲酯盐酸盐(23g,193mmol)溶于四氢呋喃(300mL)中，加入特戊醛(19.96g,231mmol)、三乙胺(23.45g,231mmol)，70℃条件下反应4小时，冷至室温，反应液不经处理直接用于下一步反应。
步骤二：前一步反应液，加入碳酸钾溶液(28.74g,208.3mmol)，二碳酸二叔丁酯(30.27g,138.86mmol)，室温反应16小时，加入水(500mL)、乙酸乙酯分液(500mL)，有机相用饱和食盐水洗涤(500mLX1)，N-甲基哌嗪洗涤(50mL)，无水硫酸钠干燥，浓缩，得到3-(叔丁基)4-甲基(2S,4R)-2-(叔丁基)噁唑烷-3,4-二羧酸酯(26g,收率:65.16％)。ES-API:[M-Boc+1]
+＝188.1。
步骤三：3-(叔丁基)4-甲基(2S,4R)-2-(叔丁基)噁唑烷-3,4-二羧酸酯(26g,90.48mmol)溶于四氢呋喃(300mL)中，降温至-78℃，加入双三甲基硅基胺基锂的四氢呋喃溶液(104 mL,1M)，反应0.5小时，加入氘代碘甲烷(65.60g,452mmol)，-78℃条件下反应1小时，氯化铵淬灭反应(500mL)，乙酸乙酯萃取(300mLX2)，有机相用稀盐酸(500mLX1)、碳酸氢钠(500mLX1)、饱和食盐水洗涤(500mLX1)，无水硫酸钠干燥，浓缩，粗品经柱层析(石油醚/乙酸乙酯＝5/1)纯化得到产物3-(叔丁基)4-甲基(2S,4R)-2-(叔丁基)-4-(甲基-d
3)噁唑烷-3,4-二羧酸酯(8.6g,收率:31.2％)。ES-API:[M-55]
+＝249.2。
步骤四：3-(叔丁基)4-甲基(2S,4R)-2-(叔丁基)-4-(甲基-d
3)噁唑烷-3,4-二羧酸酯酸(8.6g,28.25mmol)溶于二氧六环(25mL)，加入浓盐酸(25mL)，50℃条件下反应2小时，浓缩，粗品溶于1M盐酸(100mL)，乙酸乙酯反萃取(50mLX2)，水相浓缩，得到产物甲基(R)-2-氨基-2-(羟甲基)丙酸酯-3,3,3-d
3盐酸盐(3g,收率:77.9％)。ES-API:[M+H]
+＝137.1。
步骤五：甲基(R)-2-氨基-2-(羟甲基)丙酸酯-3,3,3-d
3盐酸盐(3g,22.03mmol)溶于N,N-二甲基乙酰胺(30mL)中，加入N,N-二异丙基乙胺(8.54g,66.10mmol)，4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(7.44g,22.03mmol)，100℃条件下反应16小时，冷却，加水(100mL)、乙酸乙酯分液(50mL)，有机相食盐水洗涤(50mLX1)，干燥，浓缩，粗品经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到产物甲基(R)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯-3,3,3-d
3(3g,收率:31.13％)。ES-API:[M+H]
+＝438.1。
步骤六：甲基(R)-2-(羟甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯-3,3,3-d
3(2.5g,5.72mmol)，溶于乙腈(40mL)中，加入氧化亚银(10.6g,45.72mmol)，氘代-碘甲烷(12.43g,85.73mmol)，35℃条件下反应16小时，过滤，浓缩，粗品经柱层析(乙酸乙酯/石油醚＝0～35％)纯化得到甲基(R)-2-((甲氧基-d
3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯-3,3,3-d
3(620mg,收率:23.87％)。ES-API:[M+H]
+＝455.2。
步骤七：甲基(R)-2-((甲氧基-d
3)甲基)-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸酯-3,3,3-d
3(600mg,1.32mmol)溶于醋酸(25mL)，加入铁粉(737mg,13.2mmol)，80℃条件下反应2小时，过滤，浓缩，粗品经柱层析(石油醚/乙酸乙酯＝1/2)纯化得到产物(R)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(400mg,收率:77.2％)。ES-API:[M+H]
+＝393.1。
步骤八：冰水浴下，将氢氧化钠(71.34mg,1.78mmol)的水溶液(1mL)缓慢滴加到(R)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,0.25mmol)的甲醇溶液中(5mL)，冰水浴下搅拌10分钟，60℃条件下反应2小时，冷却到0℃，缓慢滴加6M的盐酸溶液至体系pH＝7，过滤，滤液浓缩得到 (R)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,粗品)。ES-API:[M+H]
+＝253.1。
步骤九：(R)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,粗品)和2-氯-4-苯氧基苯甲醛(368mg,1.59mmol)溶于无水甲醇(10mL)，在冰浴条件下，慢慢滴加氢氧化钾(133mg,2.38mmol)的甲醇溶液(1mL)。室温反应3小时，加入饱和氯化铵溶液(5mL)，乙酸乙酯萃取(10mLX3)，浓缩，粗品经柱层析(二氯甲烷/甲醇＝100:1～20:1)纯化得到产物(2R)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,收率:65.03％)。ES-API:[M+H]
+＝485.2。
步骤十：(2R)-9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(150mg,3.09mmol)溶于四氢呋喃(10mL)和水(2mL)的混合溶液中，加入2,3-二氯-5,6-二氰基苯醌(140mg，6.18mmol)，室温反应2小时，LCMS检测反应完全，反应液加乙酸乙酯(10mL)，然后用饱和亚硫酸钠溶液洗涤(10mLX2)，有机相再用饱和碳酸氢钠溶液洗涤(10mLX2)，无水硫酸钠干燥，浓缩，粗品经柱层析(二氯甲烷:甲醇＝100:1～20:1)纯化得到化合物(R)-9-(2-氯-4-苯氧基苯基)-2-((甲氧基-d
3)甲基)-2-(甲基-d
3)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,收率：6.7％)，ES-API:[M+H]
+＝483.2。
1H NMR(400MHz,CDCl
3)δ8.65(s,1H),8.05(s,1H),7.41-7.45(m,4H),7.23(t,J＝7.6Hz,1H),7.09-7.11(m,3H),6.96(dd,J＝8.4Hz,2.3Hz,1H),3.89(d,J＝9.6Hz,1H),3.59(d,J＝9.6Hz,1H)。
实施例184 Z41-a和Z41-b的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(2.7g,8.01mmol)和cis-3-氨基-6-(羟甲基)四氢-2H-吡喃-3-羧酸甲酯盐酸盐(600mg,2.67mmol)溶于N,N-二甲基乙酰胺(20mL)，加入N,N-二异丙基乙胺(3.44g,26.70mmol)，在95℃搅拌反应16小时。反应液中加入乙酸乙酯(120mL)，依次用稀盐水(40mL×4)，饱和食盐水洗涤(40mL)，无水硫酸钠干燥，浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到cis-6-(羟甲基)-3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(220mg,收率:17％)，淡棕色固体。ES-API:[M+H]
+＝491.0。
步骤二：cis-6-(羟甲基)-3-((5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-3-羧酸甲酯(200mg,0.41mmol)溶于乙酸(7mL)，加入铁粉(230mg,4.10mmol)，在85℃下搅拌反应3小时。反应液加入乙酸乙酯(100mL)，依次用水(30mL×2)、饱和碳酸钠(40mL×2)、饱和碳酸氢钠(40mL×2)、饱和食盐水洗涤(40mL)，无水硫酸钠干燥，浓缩，得到cis-6-(羟甲基)-7'-(苯磺酰基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(175mg,收率:100％)，淡棕色固体。ES-API:[M+H]
+＝429.1。
步骤三：cis-6-(羟甲基)-7'-(苯磺酰基)-4',5,6,7'-四氢-2H,4H螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(155mg,0.36mmol)溶于甲醇(10mL)、四氢呋喃(4mL)和水(2mL)，加入氢氧化钠(72mg,1.80mmol)，在65℃下搅拌反应16小时。反应液用1.0M稀盐酸调pH＝8，用乙酸乙酯萃取(100mL)。有机相无水硫酸钠干燥后浓缩得到cis-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮 (150mg,粗品)，淡棕色固体。ES-API:[M+H]
+＝289.1。
步骤四：cis-6-(羟甲基)-4',5,6,7'-四氢-2H,4H螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(150mg,粗品)和2-氯-4-苯氧基苯甲醛(314mg,1.35mmol)溶于甲醇(8mL)，反应冷至0℃，加入氢氧化钾(177mg,3.16mmol)。在室温下搅拌反应16小时。反应液用1.0M稀盐酸调pH＝8，加入水(2mL)，用乙酸乙酯萃取(60mL)。有机相用饱和食盐水洗涤(25mL)，无水硫酸钠干燥后浓缩，粗品用薄层色谱制备板(二氯甲烷/甲醇＝10:1)纯化得到cis-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪]-3'(1'H)-酮(115mg,2步收率:61％)，淡棕色固体。ES-API:[M+H]
+＝521.2。
步骤五：cis-9'-((2-氯-4-苯氧基苯基)(羟基)甲基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺环[吡喃-3,2'-吡咯[3',2':5,6]吡啶[3,4-b]吡嗪](105mg,0.20mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)，加入2,3-二氯-5,6-二氰对苯醌(91mg,0.40mmol)，反应在室温下搅拌1小时。反应液加入饱和硫代硫酸钠溶液(6mL)和饱和碳酸氢钠溶液(6mL)，用乙酸乙酯萃取(60mL)。有机相依次用饱和碳酸氢钠溶液(15mL)，饱和食盐水洗涤(15mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化后，然后手性制备HPLC拆分(分离柱:IE250mm*4.6mm*5um,流动相:正己烷:乙醇:二乙胺＝60:40:2,流速:1ml/min,柱温：30℃)得到(3R,6S)-9'-(2-氯-4-苯氧基苯甲酰基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺[吡喃3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z41-a,35mg,峰1，保留时间11.479min，收率:33％)，淡黄色固体。ES-API:[M+H]
+＝519.1。
1H NMR(400MHz,DMSO-d
6)δ12.51(s,1H),10.54(s,1H),8.78(s,1H),7.74(s,1H),7.65(s,1H),7.57(d,J＝8.4Hz,1H),7.51–7.43(m,2H),7.25(t,J＝7.6Hz,1H),7.22–7.16(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),4.68(t,J＝5.6Hz,1H),3.87(dd,J＝11.2Hz,2.0Hz,1H),3.80(d,J＝11.2Hz,1H),3.57–3.50(m,1H),3.48–3.40(m,1H),3.37–3.30(m,1H),1.98–1.82(m,2H),1.61–1.49(m,2H)；(3S,6R)-9'-(2-氯-4-苯氧基苯甲酰基)-6-(羟甲基)-4',5,6,7'-四氢-2H,4H-螺[吡喃3,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(Z41-b,35mg,峰2，保留时间13.649min，收率33％)，淡黄色固体。ES-API:[M+H]
+＝519.1。
1H NMR(400MHz,DMSO-d
6)δ12.51(s,1H),10.54(s,1H),8.78(s,1H),7.75(s,1H),7.65(s,1H),7.57(d,J＝8.4Hz,1H),7.52–7.44(m,2H),7.25(t,J＝7.6Hz,1H),7.22–7.16(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),4.68(t,J＝5.6Hz,1H),3.87(dd,J＝11.2Hz,2.0Hz,1H),3.80(d,J＝11.2Hz,1H),3.57–3.50(m,1H),3.48–3.40(m,1H),3.37–3.30(m,1H),1.98–1.82(m,2H),1.61–1.49(m,2H)。
实施例185 Z51和Z51-1和Z51-2的合成
步骤一：2-(羟甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.5375mmol)溶于丙酮/N,N-二甲基甲酰胺(10mL:2mL)的混合溶液中，依次加入碘甲烷(764mg,5.375mmol)和碳酸钾(371mg,2.687mmol)，40℃下在封管中搅拌12小时。反应完毕后，加入乙酸乙酯(200mL)，依次用水(80mLX2)、饱和碳酸钠(60mLX2)、饱和碳酸氢钠(82mLX2)、饱和食盐水(80mL)洗涤，无水硫酸钠干燥，浓缩，粗品用乙酸乙酯打浆得到2-(羟甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(200mg,收率:96％)，黄色固体。ES-API:[M+H]
+＝387.1。
步骤二：2-(羟甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(200mg,0.5180mmol)溶于甲醇(12mL)、四氢呋喃(3mL)和水(2mL)，加入氢氧化钠(150mg,3.750mmol)，在65℃搅拌反应7小时。向反应液中加入水(20mL)和饱和氯化铵溶液(15mL)，用乙酸乙酯萃取(150mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(60mL)，无水硫酸钠干燥浓缩得到2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(237mg,粗品)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤三：2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(237mg,粗品)和2-氯-4-苯氧基苯甲醛(240mg,1.034mmol)溶于甲醇(20.0mL)，反应冷至0℃，加入氢氧化钾(203mg,3.625mmol)。在室温下搅拌反应6小时。将反应液倒入饱和氯化铵水溶液中(30mL)，溶液调pH＝8，乙酸乙酯萃取(200mL)。有机相用饱和食盐水 洗涤(80mL)，无水硫酸钠干燥后浓缩得到9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(360mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝479.2。
步骤四：9-((2-氯-4-苯氧基苯基)(羟基)甲基)-2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(360mg,粗品)溶于四氢呋喃(20mL)，加入2,3-二氯-5,6-二氰基-1,4-苯醌(360mg,1.586mmol)，在室温下搅拌反应2小时。反应液加入饱和碳酸氢钠溶液(60mL)，用乙酸乙酯萃取(80mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥，浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-苯氧基苯甲酰基)-2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(Z51,68mg,3步总收率:27.5％)，淡黄色固体，ES-API:[M+H]
+＝477.1。
步骤五：9-(2-氯-4-苯氧基苯甲酰基)-2-(羟甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3'，2'：5,6]吡啶[3,4-b]吡嗪-3-酮(Z51,68mg,0.1424mmol)用手性制备拆分(分离柱:IC150mm*4.6mm*5um,流动相:正己烷:乙醇：二乙胺＝70:30:0.2,流速:1ml/min,柱温：30℃)得到(Z51-1,19.34mg,峰1,保留时间10.161min,收率:28％)，淡白色固体。ES-API:[M+H]
+＝477.1。
1H NMR(400MHz,DMSO-d6)δ12.69–12.18(m,1H),8.49(s,1H),7.92(s,1H),7.63(s,1H),7.58–7.44(m,3H),7.25(t,J＝7.4Hz,1H),7.22–7.17(m,2H),7.02(dd,J＝8.4,2.4Hz,1H),5.22(t,J＝5.5Hz,1H),3.68(dd,J＝10.6,6.0Hz,1H),3.55–3.48(m,1H),3.36(s,3H),1.36(s,3H)。(Z51-2,21.07mg,峰2,保留时间12.24min,收率:31％)，淡白色固体。ES-API:[M+H]
+＝477.1。
1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.49(s,1H),7.92(s,1H),7.63(s,1H),7.55(d,J＝8.4Hz,1H),7.48(dd,J＝8.4,7.5Hz,2H),7.25(t,J＝7.4Hz,1H),7.22–7.16(m,3H),7.02(dd,J＝8.4,2.4Hz,1H),5.23(t,J＝5.4Hz,1H),3.68(dd,J＝10.6,6.0Hz,1H),3.49(dd,J＝10.7,5.0Hz,1H),3.36(s,3H),1.36(s,3H)。
实施例186 Z65的合成
步骤一：4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯[2,3-b]吡啶(1.0g,2.967mmol)和2-氨基-3-羟基-2-甲基丙酸甲酯盐酸盐(4.5g,13.35mmol)溶于N,N-二甲基乙酰胺(80mL)，加入N,N-二异丙基乙胺(11.75g,91mmol)，在95℃搅拌反应16小时。反应液中加入乙酸乙酯(300mL)，用水洗涤(100mLX2)，饱和食盐水洗涤(150mLX3)，无水硫酸钠干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-羟基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(0.735g,收率:57％)，淡黄色固体。ES-API:[M+H]
+＝435.1。
步骤二：3-羟基-2-甲基-2-((5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(2.60g,5.990mmol)溶于乙腈(100mL)，依次加入氧化银(20.82g,89.86mmol)和碘甲烷(21.26g,149.75mmol)，氮气保护下室温避光搅拌48小时。反应完毕，加硅藻土过滤，滤液减压旋干，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-50％)得到3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(2.20g,收率:82％)，黄色固体。ES-API:[M+H]
+＝449.0。
步骤三：3-甲氧基-2-甲基-2-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)丙酸甲酯(1.05g,2.343mmol)溶于乙酸(30mL)中，加入铁粉(2.62g,46.87mmol)。逐渐升温至80℃并搅拌1小时。反应完毕后，溶剂减压旋干，加入乙酸乙酯(200mL)，依次用水洗涤(80mLX2)，饱和碳酸钠洗涤(60mLX2)，饱和碳酸氢钠洗涤(82mLX2)，饱和食盐水(80mL)，无水硫酸钠干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(650mg,收率:72％)，黄色固 体。ES-API:[M+H]
+＝387.2。
步骤四：2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(500mg,1.292mmol)溶于丙酮/N,N-二甲基甲酰胺(20mL:4mL)的混合溶液中，依次加入碘甲烷(1.83g,12.92mmol)和碳酸钾(892mg,6.458mmol)，40℃下在封管中搅拌12小时。反应完毕后，加入乙酸乙酯(200mL)，依次用水(80mLX2)，饱和碳酸钠(60mLX2)，饱和碳酸氢钠(82mLX2)，饱和食盐水(80mL)洗涤，无水硫酸钠干燥浓缩，粗品用乙酸乙酯打浆得到2-(甲氧基甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(450mg,收率:86.8％)，黄色固体。ES-API:[M+H]
+＝401.2。
步骤五：2-(甲氧基甲基)-2,4-二甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(450mg,1.125mmol)溶于甲醇(20mL)，四氢呋喃(5mL)和水(4mL)，加入氢氧化钠(315mg,7.875mmol)，在65℃搅拌反应7小时。向反应液中加入水(20mL)和饱和氯化铵溶液(15mL)，用乙酸乙酯萃取(200mL)。有机相依次用饱和碳酸氢钠溶液(20mL)，饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩得到2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(500mg,粗品)，淡白色固体。ES-API:[M+H]
+＝261.2。
步骤六：2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(250mg,粗品)和2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲醛(250mg,1.012mmol)溶于甲醇(20.0mL)，反应冷至0℃，加入氢氧化钾(220mg,3.937mmol)。在室温下搅拌反应6小时。将反应液倒入饱和氯化铵水溶液中(30mL)，调pH＝8，乙酸乙酯萃取(150mL)。有机相用饱和食盐水洗涤(70mL)，干燥后浓缩得到9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(350mg,粗品)，淡黄色固体。ES-API:[M+H]
+＝508.1。
步骤七：9-((2-氯-4-((4-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(330mg,粗品)溶于四氢呋喃(20mL)，加入2,3-二氯-5,6-二氰基-1,4-苯醌(350mg,1.542mmol)，在室温下搅拌反应2小时。反应液加入饱和碳酸氢钠溶液(60mL)，用乙酸乙酯萃取(80mL)。有机相用饱和饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到9-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-2-(甲氧基甲基)-2,4-二甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮甲酸盐(50mg,3步总收率:17.6％)，淡黄色固体，ES-API:[M+H]
+＝506.2。
1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.61(s,1H),8.09(d,J＝5.1Hz,1H),7.96(s,1H),7.75–7.57(m,2H),7.39(d,J＝2.2Hz,1H),7.20(dd,J＝8.4,2.2 Hz,1H),7.07(d,J＝5.1Hz,1H),6.99(s,1H),3.65(d,J＝9.6Hz,1H),3.51(d,J＝9.6Hz,1H),3.38(s,4H),3.29(s,3H),2.37(s,3H),1.39(s,3H)。
实施例187 Z72的合成
步骤一：向含有4-氯-5-硝基-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(500mg,1.48mmol)、4-氨基四氢-2H-吡喃-4-羧酸甲酯(353mg,2.22mmol)和干燥的N,N-二异丙基乙胺(954mg,7.4mmol)混合物的微波管中加入干燥的N,N-二甲基乙酰胺(8ml)，微波加热115℃反应2小时。加入乙酸乙酯(100ml)，依次用水(30mlX2)、饱和食盐水(30mX1)洗涤，无水硫酸钠干燥，浓缩，粗品经快速硅胶柱纯化(石油醚/乙酸乙酯＝40/60)得到4-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(560mg,收率:82％)。ES-API:[M+H]
+＝461.1。
步骤二：向含有4-((5-硝基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)四氢-2H-吡喃-4-羧酸甲酯(500mg,1.08mmol)的烧瓶中加入铁粉(1.21g,21.7mmol)和醋酸(10ml)，油浴加热80℃反应3小时。加入乙酸乙酯(100ml)，依次用水(30mlX2)、饱和食盐水(30mX1)洗涤，无水硫酸钠干燥，浓缩，粗品经快速硅胶柱纯化(石油醚/乙酸乙酯＝10/90)得到7'-(苯基磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(300mg,收率:69.7％)。ES-API:[M+H]
+＝399.1。
步骤三：向含有7'-(苯基磺酰基)-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(300mg,0.75mmol)的N,N-二甲基甲酰胺(8ml)溶液中加入碘甲烷(852mg,6.0mmol)和碳酸钾(621mg,4.5mmol)，油浴加热40℃反应4小时。加入乙酸乙酯(100ml)，依次用水(30mlX2)、饱和食盐水(30mX1)洗涤，无水硫酸钠干燥，浓缩，粗品经 快速硅胶柱纯化(石油醚/乙酸乙酯＝10/90)得到4'-甲基-7'-(苯基磺酰基)-2,3,4',5,6,7'六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(200mg,收率:64.7％)。ES-API:[M+H]
+＝413.1。
步骤四：向含有4'-甲基-7'-(苯基磺酰基)-2,3,4',5,6,7'六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(200mg,0.485mmol)的烧瓶中加入氢氧化钠(136mg,3.39mmol)、甲醇(12mL)和水(3mL)，油浴加热65℃反应15小时。加入乙酸乙酯(30ml)，依次用水(1mlX2)、饱和食盐水(10mX1)洗涤，无水硫酸钠干燥，浓缩，粗品经制备薄层色谱(二氯甲烷/甲醇＝10/1)纯化得到产物4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(65mg,收率:49.2％)。ES-API:[M+H]
+＝273.3。
步骤五：向含有4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(65mg,0.239mmol)的甲醇(3ml)溶液中加入2-氯-4-((6-甲基吡啶-3-基)氧基)苯甲醛(117mg,0.478mmol)和氢氧化钾(67mg,1.19mmol)，室温反应5小时。滴加1M稀盐酸调pH＝7～8，加入乙酸乙酯(100ml)，依次用水(30mlX2)、饱和食盐水(30mLX1)洗涤，无水硫酸钠干燥，过滤，浓缩得到9'-((2-氯-4-((5-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(130mg,粗品)。ES-API:[M+H]
+＝520.1。
步骤六：将9'-((2-氯-4-((5-甲基吡啶-2-基)氧基)苯基)(羟基)甲基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(130mg,粗品)溶解在1,4-二氧六环(5ml)和水(1ml)溶液中，缓慢加入2,3-二氯-5,6-二氰基苯醌(108mg,0.478mmol)，室温反应0.5小时。滴加亚硫酸氢钠水溶液(5mL)猝灭，加入乙酸乙酯(20ml)，依次用水(10mlX2)、饱和食盐水(10mLX1)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经过HPLC纯化得到9'-(2-氯-4-((4-甲基吡啶-2-基)氧基)苯甲酰基)-4'-甲基-2,3,4',5,6,7'-六氢螺[吡喃-4,2'-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪]-3'(1'H)-酮(80mg,2步收率:65％)。ES-API:[M+H]
+＝518.1。
1H NMR(400MHz,DMSO-d
6)δ12.70(s,1H),9.07(s,1H),8.09(d,J＝5.1Hz,1H),8.06(s,1H),7.72(s,1H),7.64(d,J＝8.3Hz,1H),7.41(d,J＝2.3Hz,1H),7.22(dd,J＝8.3,2.2Hz,1H),7.07(d,J＝5.2Hz,1H),7.00(s,1H),3.84(dt,J＝11.4,3.7Hz,2H),3.81–3.70(m,2H),3.41(s,3H),2.37(s,3H),2.09(td,J＝12.8,5.1Hz,2H),1.61(d,J＝13.4Hz,2H)。
实施例188 Z147的合成
步骤一：将2-氯-4-羟基苯甲醛(3.0g,19.23mmol)，2-溴-3-氯吡啶(2.40g,12.56mmol)，碘化亚铜(350mg,1.742mmol)，磷酸钾(9.0g,42.45mmol)和L-脯氨酸(0.50g,4.343mmol)溶于干燥的N,N-二甲基乙酰胺(70mL)，氮气保护下加热至115℃反应24小时。反应完毕后，向冷却液中加入乙酸乙酯(200mL)，饱和食盐水(80mLX3)洗涤，乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干，粗品用快速硅胶柱纯化[PE:EA＝100:0～70:30,(v/v)]得到2-氯-4-((3-氯吡啶-2-基)氧基)苯甲醛(675mg,收率:20％)。ES-API:[M+H]
+＝268.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(550mg,0.6796mmol)和2-氯-4-((3-氯吡啶-2-基)氧基)苯甲醛(400mg,1.498mmol)溶于甲醇(25.0mL)，反应冷至0℃，加入氢氧化钾(266mg,4.757mmol)，在室温下搅拌反应6小时。将反应液倒入饱和氯化铵水溶液(30mL)中，调pH＝8，乙酸乙酯萃取(100mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩得到(2S)-9-((2-氯-4-((3-氯吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(190mg,收率:54％)，淡黄色固体。ES-API:[M+H]
+＝514.2。
步骤三：(2S)-9-((2-氯-4-((3-氯吡啶-2-基)氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(190mg,0.3702mmol)溶于四氢呋喃(20mL)，加入2,3-二氯-5,6-二氰基-1,4-苯醌(170mg,0.7404mmol)，在室温下搅拌反应2小时。反应液加入饱和碳酸氢钠溶液(63mL)，用乙酸乙酯萃取(88mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-((3-氯吡啶-2-基)氧基)甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(110mg,收率:57％)，淡黄色固体。ES-API:[M+H]
+＝512.0。
1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),10.51(s,1H),8.28(s,1H),8.20–8.16(m,1H),8.13(dd,J＝7.8,1.6Hz,1H),7.70(s,1H),7.62(d,J＝8.4Hz,1H),7.56(s,1H),7.50(d,J＝2.2Hz,1H),7.31–7.24(m,2H),3.65(d,J＝9.5Hz,1H),3.49(d,J＝9.6Hz,1H),3.30(s,3H),1.40(s,3H)。
实施例189 Z165的合成
步骤一：将2-氯-4-氟苯甲醛(1.58g,10.0mmol)和3-氯苯酚(1.20g,9.375mmol)溶于干燥的N,N-二甲基乙酰胺(20mL)，加入碳酸铯(10.0g,30.69mmol)，氮气保护下加热至90℃反应2小时。反应完毕后，向冷却液中加入乙酸乙酯(200mL)并用饱和食盐水(80mLX3)洗涤，乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干得到2-氯-4-(3-氯苯氧基)苯甲醛(2.60g,粗品)。ES-API:[M+H]
+＝267.1/269.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-7-(苯磺酰基)-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶[3,4-b]吡嗪-3-酮(1.40g,3.570mmol)溶于甲醇(36mL)，四氢呋喃(9mL)和水(6mL)，加入氢氧化钠(1.01g,24.99mmol)，在65℃搅拌反应7小时。向反应液中加入水(20mL)和饱和氯化铵溶液(15mL)，用乙酸乙酯萃取(200mL)。有机相依次用饱和碳酸氢钠溶液(30mL)，饱和食盐水洗涤(80mL)，无水硫酸钠干燥，浓缩得到(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(0.58g,收率:66％)，淡白色固体。ES-API:[M+H]
+＝247.1。
步骤三：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(223mg,0.9065mmol)和2-氯-4-(3-氯苯氧基)苯甲醛(484mg,1.8127mmol)溶于甲醇(25.0mL)，反应冷至0℃，加入氢氧化钾(355mg,6.345mmol)。在室温下搅拌反应6小时。将反应液倒入饱和氯化铵水溶液中(30mL)，调pH＝8，乙酸乙酯萃取(100mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥，浓缩得到(2S)-9-((2-氯-4-(3-氯苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(215mg,2步总收率:46％)，淡黄色固体。ES-API:[M+H]
+＝513.1/515.0。
步骤四：(2S)-9-((2-氯-4-(3-氯苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(213mg,0.4152mmol)溶于四氢呋喃(20mL)，加入2,3-二氯-5,6-二氰基-1,4-苯醌(190mg,0.8304mmol)，在室温下搅拌反应2小时。反应液加入饱和碳酸氢钠溶液(63mL)，用乙酸乙酯萃取(88mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(3-氯苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(80.8mg,收率:40％)，淡黄色固体。ES-API:[M+H]
+＝511.1/513.2。
1H NMR(500MHz,DMSO-d6)δ12.48(s,1H),10.49(s,1H),8.27(s,1H),7.70(s,1H),7.65(s,1H),7.58(d,J＝8.3Hz,1H),7.48(t,J＝8.2Hz,1H),7.29(s,3H),7.15(d,J＝7.8Hz,1H),7.09(d,J＝7.9Hz,1H),3.65(d,J＝9.5Hz,1H),3.48(d,J＝9.6Hz,1H),3.30(s,3H),1.39(s,3H)。
实施例190 Z169的合成
步骤一：将2-氯-4-氟苯甲醛(1.58g,10.0mmol),5-氟-2-甲氧基苯酚(1.40g,9.856mmol)和碳酸铯(9.60g,29.46mmol)溶于干燥的N,N-二甲基乙酰胺(30.0mL)，氮气保护下加热至95℃反应2小时。反应完毕后，向冷却液中加入乙酸乙酯(200mL)并用饱和食盐水(80mLX3)洗涤，乙酸乙酯相用无水硫酸钠干燥，过滤，减压旋干，粗品用快速硅胶柱纯化[PE:EA＝100:0～70:30,(v/v)]得到2-氯-4-(5-氟-2-甲氧基苯氧基)苯甲醛(2.60g,收率:94％)。ES-API:[M+H]
+＝281.0。
步骤二：(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(200mg,0.8130mmol)和2-氯-4-(5-氟-2-甲氧基苯氧基)苯甲醛(300mg,1.070mmol)溶于甲醇(25.0mL)，反应冷至0℃，加入氢氧化钾(318mg,5.691mmol)，在室温下搅拌反应6小时。将反应液倒入饱和氯化铵水溶液中(30mL)，调pH＝8，乙酸乙酯萃取(100mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩得到(2S)-9-((2-氯-4-(5-氟-2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg,收率:60％)，淡黄色固体。ES-API:[M+H]
+＝527.2。
步骤三：(2S)-9-((2-氯-4-(5-氟-2-甲氧基苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(260mg,0.4941mmol)溶于四氢呋喃(20mL)，加入2,3-二氯-5,6-二氰基-1,4-苯醌(224mg,0.9882mmol)，在室温下搅拌反应2小时。反应液加入饱和碳酸氢钠溶液(80mL)，用乙酸乙酯萃取(100mL)。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥后浓缩，粗品用制备HPLC纯化得到(S)-9-(2-氯-4-(5-氟-2-甲氧基苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(54.03mg,收率:21％)。淡黄色固体。ES-API:[M+H]
+＝525.1。
1H NMR(500MHz,DMSO-d6)δ12.46(s,1H),10.51(s,1H),8.28(s,1H),7.69(s,1H),7.60–7.47(m,2H),7.30–7.05(m,4H),6.91(dd,J＝8.4,2.3Hz,1H),3.77(s,3H),3.64(d,J＝9.5Hz,1H),3.47(d,J＝9.5Hz,1H),3.29(s,3H),1.38(s,3H)。
实施例191 Z178的合成
步骤一：向100mL反应瓶中加入2-氯-4-(2-氟-6-甲氧基苯氧基)苯甲醛(800mg,2.86mmol)和二氯甲烷(10mL)。体系冷至0℃，向其中滴加三溴化硼的二氯甲烷溶液(8.6mL,8.6mmol,1M)。在室温下搅拌反应2小时。将反应液中倒入冰的饱和碳酸氢钠溶液(50mL)，用二氯甲烷(50mLX3)萃取，有机相无水硫酸钠干燥，浓缩，粗品用快速硅胶柱纯化(0-20％乙酸乙酯/石油醚)得到2-氯-4-(3-氟-2-羟基苯氧基)苯甲醛(500mg,粗品)，黄色固体。ES-API:[M+H]
+＝267.1。
步骤二：向100mL圆底烧瓶中加入2-氯-4-(3-氟-2-羟基苯氧基)苯甲醛(400mg,1.5mmol)，氘代碘甲烷(654mg,14.5mmol)，碳酸钾(414mg,3.05mmol)和N,N-二甲基甲酰胺(16mL)。在40℃下搅拌反应3小时。用水淬灭(50mL)反应，乙酸乙酯萃取(50mLX3)。有机相用无水硫酸钠干燥，浓缩，粗品用快速硅胶柱纯化(0-20％乙酸乙酯/石油醚)得到2- 氯-4-(3-氟-2-(甲氧基-d
3)苯氧基)苯甲醛(64mg,收率:15％)，黄色固体。ES-API:[M+H]
+＝284.1。
1H NMR(500MHz,DMSO-d
6):10.21(s,1H),7.87(d,J＝8.5Hz,1H),7.30-7.27(m,1H),7.23-7.20(m,1H),7.17(d,J＝2.5Hz,1H),7.11-7.09(m,1H),7.02(dd,J＝9.0,2.5Hz,1H)。
步骤三：向100mL圆底烧瓶中加入2-氯-4-(3-氟-2-(甲氧基-d
3)苯氧基)苯甲醛(64mg,0.22mmol)，(S)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(113mg,0.46mmol)，氢氧化钾(180mg,3.22mmol)和甲醇(6mL)。在室温下搅拌反应24小时。用2N盐酸(3mL)和水(20mL)淬灭反应，用乙酸乙酯萃取(50mLX3)。有机相用无水硫酸钠干燥，浓缩得(2S)-9-((2-氯-4-(3-氟-2-(甲氧基-d
3)苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,粗品)。ES-API:[M+H]
+＝530.2。
步骤四：0℃下，向圆底烧瓶中加入(2S)-9-((2-氯-4-(3-氟-2-(甲氧基-d
3)苯氧基)苯基)(羟基)甲基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(100mg,粗品)和四氢呋喃(5mL)。向其中加入2,3-二氯-5,6-二氰基苯醌(100mg,0.43mmol)。在室温下搅拌反应30分钟。饱和碳酸氢钠水溶液(20mL)淬灭反应，用二氯甲烷萃取(50mLX3)。有机相用无水硫酸钠干燥，浓缩，粗品经制备HPLC纯化得到(S)-9-(2-氯-4-(3-氟-2-(甲氧基-d
3)苯氧基)苯甲酰基)-2-(甲氧基甲基)-2-甲基-1,2,4,7-四氢-3H-吡咯并[3',2':5,6]吡啶并[3,4-b]吡嗪-3-酮(25mg,2步收率:21％)。ES-API:[M+H]
+＝528.2。
测试例1：BTK和BTK C481S酶学实验
使用DMSO配制1000X的化合物3倍梯度浓度储液，使用反应缓冲液(50mM HEPES,pH7.5,0.0015％Briji-35,2mM DTT,10mM MgCl
2)稀释100倍至10X化合物储液，转移10X化合物储液到384孔板中。用BTK Kinase Enzyme System(Promega Catalog#V2941)或BTK(C481S)Kinase Enzyme System(Promega Catalog#VA7033)来建立酶学反应。首先，用反应缓冲液配制2X酶液加入板内，酶液包含10nM BTK或10nM BTK C481S，与化合物孵育10分钟。然后，用反应缓冲液配制2.5X底物溶液加入板内，底物溶液包含ATP(125μM)，Poly(Glu4,Tyr1)(0.05μg/μL)，在20℃反应90分钟。最后，按照ADP-GloTM kinase Assay试剂盒(Promega,#V9101)提供的实验步骤来检测激酶活性,最终读取luminescence化学发光值。使用DMSO作为最大值信号值,不加酶作为最小值信号值。计算化合物的抑制率(％)＝(最大值信号值–化合物信号值)/(最大值信号值–最小值信号值)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的酶活抑制率，计算出IC
50值。从实验结果可知，本发明化合物对BTK或BTK(C481S)激酶具有较高的抑制 活性，IC
50值小于500nM(例如0.1nM至500nM)；部分化合物的IC
50值甚至小于100nM(例如0.1nM至100nM)或小于50nM(例如0.1nM至50nM)，更甚至小于10nM(例如0.1nM至10nM)。其中部分化合物的实验结果如表1所示。
表1
测试例2：p-BTK细胞实验
第一天：取对数生长期的HEK293细胞(ADDEXBIO,T0011001)，酶EDTA消化细胞收集计数并接种2E6个细胞于10cm培养皿中，培养过夜。第二天：使用1000μL Opti-MEM分别配制含6ug WT-BTK/C481S-BTK质粒和18μL FuGENE HD转染试剂的混合液，室温静置10分钟后，用移液枪把混合液缓慢加入到培养皿中，培养过夜。第三天：取出培养皿酶EDTA消化细胞收集计算并接种1E4个细胞于96孔细胞培养板中，培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，室温放置。第四天：取出配制好的1000X化合物储存液，使用培养基稀释200倍至5×化合物储液，每个细胞培养孔加入5×化合物储液，终浓度为1×，DMSO含量为0.1％。使用DMSO作为实验对照。加入化合物培养两小时之后，去除残留的培养基。每孔加入100μL细胞裂解缓冲液,冰上静置30分钟，冰水超声裂解5分钟。按比例稀释细胞裂解液后转移80μL混液至ELISA板中，空白孔则加入80μL细胞裂解缓冲液。37℃孵育箱中孵育2小时后，取出板子按 照PathScan P-Btk(Y223)Sandwich ELISA Kit(Cell signaling#23843CA)说明书完成抗体孵育以及显色终止操作，最后读取OD值。计算化合物的抑制率(％)＝(OD
对照–OD
化合物)/(OD
对照–OD
空白)×100％，使用Prism 8四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC
50值。从实验结果可知，本发明化合物对BTK或BTK(C481S)磷酸化水平具有较高的抑制活性，IC
50值小于500nM(例如0.1nM至500nM)；部分化合物的IC
50值甚至小于100nM(例如0.1nM至100nM)或小于50nM(例如0.1nM至50nM)。其中部分化合物的实验结果如表2所示。
表2
测试例3：TMD-8和OCI-LY10增殖抑制实验
TMD-8细胞为人弥漫性大B淋巴瘤(明舟生物，MZ-0832)，培养于10％FBS+1％PS1640培养基中；OCI-LY10为人弥漫性大B淋巴瘤(BeNa Culture Collection,BNCC337742),培养于10％FBS+1％PS IMDM。第一天，取对数生长期的细胞，计数并接种600个TMD-8或2000个OCI-LY10细胞于384孔细胞培养板中，培养过夜。第二天，使用DMSO配制400X的化合物3倍梯度浓度储液，使用培养基稀释40倍至10×化合物储液，每个细胞培养孔加入10×化合物储液，终浓度为1×，DMSO含量为0.25％。使用DMSO作为实验对照,培养基作为空白对照。加入化合物后继续培养三天。在第五天，每孔加入25μL ADP-Glo,混匀孵育10分钟后读取化学发光值(RLU值)。计算细胞增殖抑制率(％)＝(RLU
对照-RLU
化合物)/(RLU
对照-RLU
空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC
50值。从实验结果可知，本发明化合物对TMD-8或OCI-LY10具有较高的抑制活性，IC
50值小于500nM(例如0.1nM至500nM)；部分化合物的IC
50值甚至小于100nM(例如0.1nM至100nM)或小于50nM(例如0.1nM至50nM)。其中部分化合物的实验结果如表3所示。
表3
尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (13)
- 式(C)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
式中，R 1和R 2各自独立地选自：H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-20环烷基、3至20元杂环基、C 1-6烷氧基和C 1-6烷硫基；或者R 1和R 2与同它们相连的碳原子共同构成：C 3- 20环烷基、3至20元杂环基、C＝O或者C＝S；所述C 1-6烷基、所述C 2-6烯基、所述C 2-6炔基、所述C 3-20环烷基、所述3至20元杂环基、所述C 1-6烷氧基和所述C 1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；R 3和R 4各自独立地选自：H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-20环烷基和3至20元杂环基；或者R 3和R 4与同它们相连的碳原子共同构成：C 3-20环烷基、3至20元杂环基或者C＝O；所述C 1-6烷基、所述C 2-6烯基、所述C 2-6炔基、所述C 3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；n为0、1、2或3；E为NR 5、O或N；其中，R 5为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 1-4亚烷基-羟基、-C 1-4亚烷基-氰基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷基、-C 1-4亚烷基-氘代C 1-6烷基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-氘代C 1-6烷氧基、-C 1-4亚烷基-C 3-6单环环烷基、-C 1-4亚烷基-3至6元单环杂环基、-C 1-4亚烷基-NR aR b、-C 1-4亚烷基-C(O)NR aR b、-C 1-4亚烷基-C(O)OC 1-6烷基、-C 1-4亚烷基-SO 2C 1-3烷基、-C 1-4亚烷基-羧基或C 3-6单环环烷基；其中，所述-C 1-4亚烷基-为未取代的，或者所述-C 1-4亚烷基-上的1个或2个氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基和氘代C 1-6烷基的基团所取代，或者所述-C 1-4亚烷基-上同一个碳原子上的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C 3-6单环环烷基和所述3至6元单环杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基和氘代C 1-6烷氧基；当E为NR 5或O时，则与E连接的表示单键；
当E为N时，则与E连接的表示双键且R 2为无；
A为CR 6或N；其中，R 6为H、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基或-C 3-6环烷基；B为CR 7或N；其中，R 7为H、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基或-C 3-6环烷基；G 1为C 6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C 6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；G 2为C 6-14芳基、5或6元单环杂芳基或8至10元双环杂芳基；且所述C 6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；L为一根键、CR 8R 9、O、NH、NHC(O)、C 1-2亚烷基-NHC(O)或NHC(O)-C 1-2亚烷基-；其中，R 8和R 9各自独立地为H、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 3-6单环环烷基、-C 1-4亚烷基-羟基、-C 1-4亚烷基-氰基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-C 3-6单环环烷基、-C 1-4亚烷基-NR aR b、-C 1-4亚烷基-C(O)NR aR b、-C 1-4亚烷基-SO 2C 1-3烷基或-C 1-4亚烷基-羧基；i为0或1；所述S1和S2组的基团各自独立地选自：氘、卤素、氰基、羟基、羧基、硝基、C 1- 6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、C 3-20环烷基、卤代C 3-20环烷基、-O-C 3-20环烷基、3至20元杂环基、-O-3至20元杂环基、C 6-14芳基、-O-C 6-14芳基、5或6元单环杂芳基、-O-5或6元单环杂芳基、8至10元双环杂芳基、-O-8至10元双环杂芳基、-C 1-4亚烷基-羟基、-C 1-4亚烷基-氰基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷基、-C 1-4亚烷基-氘代C 1-6烷基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-氘代C 1-6烷氧基、-C 1-4亚烷基-C 3-20环烷基、-C 1-4亚烷基-O-C 3-20环烷基、-C 1-4亚烷基-3至20元杂环基、-C 1-4亚烷基-O-3至20元杂环基、-C 1-4亚烷基-C 6-14芳基、-C 1-4亚烷基-O-C 6-14芳基、-C 1-4亚烷基-5或6元单环杂芳基、-C 1-4亚烷基-O-5或6元单环杂芳基、-C 1-4亚烷基-8至10元双环杂芳基、-C 1-4亚烷基-O-8至10元双环杂芳基、-C 1-4亚烷基-NR aR b、-C 1-4亚烷基-C(O)NR aR b、-C 1-4亚烷基-NR dC(O)R c、-C 1-4亚烷基-NR dC(O)NR aR b、-C 1-4亚烷基-SO 2R c、-C 1-4亚烷基-NR dSO 2R c、-C 1-4亚烷基- SO 2NR aR b、-C 1-4亚烷基-NR dSO 2NR aR b、-C 1-4亚烷基-羧基、-C(O)C 1-6烷基、-C(O)卤代C 1- 6烷基、-C(O)氘代C 1-6烷基、-C(O)C 3-20环烷基、-C(O)3至20元杂环基、-C(O)C 6-14芳基、-C(O)5或6元单环杂芳基、-C(O)8至10元双环杂芳基、-C(O)NR aR b、-NR dC(O)R c、-NR dC(O)NR aR b、-SO 2R c、-NR dSO 2R c、-SO 2NR aR b、-NR dSO 2NR aR b、-NR aR b和-OR c；所述-C 1-4亚烷基-为未取代的，或者所述-C 1-4亚烷基-上的氢原子各自独立地被选自卤素、氰基、羟基、C 1-6烷基、卤代C 1-6烷基和氘代C 1-6烷基的基团所取代，或者所述-C 1-4亚烷基-上同一个碳原子的两个氢原子同时被-(CH 2) j-取代进而形成环烷基，其中j为2、3、4、5或6；所述C 3-20环烷基、所述3至20元杂环基、所述C 6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基各自独立地任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基和氘代C 1-6烷氧基；上述各基团中，R a和R b各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 3-6单环环烷基、-C 1-4亚烷基-C 3-6单环环烷基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-氘代C 1-6烷氧基、3至6元单环杂环基、-C 1-4亚烷基-3至6元单环杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4亚烷基-C 6- 14芳基、-C 1-4亚烷基-5或6元单环杂芳基、-C 1-4亚烷基-8至10元双环杂芳基或C(O)C 1- 6烷基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述C 6-14芳基、所述5或6元单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1- 6烷氧基和氘代C 1-6烷氧基；或上述各基团中，R a、R b与和它们相连的氮原子共同形成3至6元含氮杂环基；且所述3至6元含氮杂环基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基和氘代C 1- 6烷氧基；上述各基团中，R c各自独立地为H、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷基、-C 1-4亚烷基-氘代C 1-6烷基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-氘代C 1-6烷氧基、C 3-6单环环烷基、-C 1-4亚烷基-C 3-6单环环烷基、3至6元单环杂环基、-C 1-4亚烷基-3至6元单环杂环基、C 6-14芳基、5或6元单环杂芳基、8至10元双环杂芳基、-C 1-4亚烷基-C 6-14芳基、-C 1-4亚烷基-5或6元单环杂芳基或-C 1-4亚烷基-8至10元双环杂芳基；所述C 3-6单环环烷基、所述3至6元单环杂环基、所述C 6-14芳基、所述5或6元 单环杂芳基和所述8至10元双环杂芳基任选地被1或2个选自下组的基团所取代：卤素、羟基、羧基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1- 6烷氧基和氘代C 1-6烷氧基；上述各基团中，R d各自独立地为H、C 1-6烷基或氘代C 1-6烷基；“*”处标记的碳原子为手性碳原子或非手性碳原子。 - 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 1和R 2各自独立地选自：H、C 1-6烷氧基和C 1-6烷硫基；或者R 1和R 2与同它们相连的碳原子共同构成：C＝O或者C＝S；所述C 1-6烷氧基和所述C 1-6烷硫基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；和/或，R 3和R 4各自独立地选自：C 1-6烷基和C 3-20环烷基；或者R 3和R 4与同它们相连的碳原子共同构成：C 3-20环烷基或3至20元杂环基，所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；所述C 1-6烷基、所述C 3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1、2、3或4个独立选自S1组的基团取代；和/或，n为0；和/或，E为NR 5或O；和/或，R 5为H、C 1-6烷基、氘代C 1-6烷基、-C 1-4亚烷基-羟基、-C 1-4亚烷基-C 1-6烷氧基或-C 1-4亚烷基-NR aR b；和/或，A为CR 6；其中，R 6为H、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基或-C 3-6环烷基；和/或，B为CR 7；其中，R 7为H、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基或-C 3-6环烷基；和/或，G 1为C 6-14芳基或5或6元单环杂芳基；所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子，且所述C 6-14芳基和所述5或6元单环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；和/或，G 2为C 6-14芳基或5或6元单环杂芳基；所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子，且所述C 6-14芳基和所述5或6元单环杂芳基为未取代的或被1、2、3或4个独立选自S2组的基团取代；和/或，L为CR 8R 9或O；其中，R 8和R 9各自独立地为H、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 3-6单环环烷基、-C 1-4亚烷基-羟基、-C 1-4亚烷基-氰基、-C 1-4亚烷基-C 1-6烷氧基、-C 1-4亚 烷基-卤代C 1-6烷基、-C 1-4亚烷基-卤代C 1-6烷氧基、-C 1-4亚烷基-C 3-6单环环烷基、-C 1-4亚烷基-NR aR b、-C 1-4亚烷基-C(O)NR aR b、-C 1-4亚烷基-SO 2C 1-3烷基或-C 1-4亚烷基-羧基；和/或，所述S1组的基团选自：氘、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、-C 1-4亚烷基-羟基、-C(O)C 1-6烷基、-C(O)C 3-20环烷基、3至20元杂环基、-O-C 3-6单环环烷基、-NR aR b和-OR c，其中所述3至20元杂环基具有1、2或3个选自N、O和S的杂原子作为环原子；和/或，所述S2组的基团选自：卤素、氰基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、C 3-20环烷基、卤代C 3-20环烷基、-O-C 3-20环烷基、-NR aR b和-OR c；和/或，R a和R b各自独立地为C 1-6烷基；和/或，R c为-C 1-4亚烷基-C 1-6烷氧基或被1或2个卤素取代的C 3-6单环环烷基。
- 如权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 1和R 2中，所述C 1-6烷氧基各自独立地为C 1-3烷氧基，例如甲氧基；和/或，R 1和R 2中，所述C 1-6烷硫基各自独立地为C 1-3烷硫基，例如甲硫基或乙硫基；和/或，R 1和R 2中，所述C 1-6烷氧基和所述C 1-6烷硫基各自独立地为未取代的；和/或，R 3和R 4中，所述C 1-6烷基各自独立地为C 1-3烷基，例如甲基或乙基；和/或，R 3和R 4中，所述C 3-20环烷基各自独立地为C 3-6单环环烷基，例如环丙基；和/或，当R 3和R 4与同它们相连的碳原子共同构成C 3-20环烷基时，则所述C 3-20环烷基为C 3-6单环环烷基，例如环丙基、环戊基、环己基；和/或，当R 3和R 4与同它们相连的碳原子共同构成3至20元杂环基时，则所述3至20元杂环基为3至6元单环杂环基，其中所述3至6元单环杂环基具有1或2个选自N和O的杂原子作为环原子，例如氧杂环丁基、氮杂环丁基、四氢吡咯、四氢呋喃、四氢吡喃或哌啶；和/或，R 3和R 4中，所述C 1-6烷基、所述C 3-20环烷基和所述3至20元杂环基各自独立地为未取代的或被1或2个选自S1组的基团取代；和/或，R 5中，所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基，例如甲基或乙基；和/或，R 5中，所述氘代C 1-6烷基为氘代C 1-3烷基，例如氘代甲基；和/或，R 5中，所述-C 1-4亚烷基-羟基为-C 1-2亚烷基-羟基，例如-CH 2CH 2OH；和/或，R 5中，所述-C 1-4亚烷基-C 1-6烷氧基为-C 1-2亚烷基-C 1-3烷氧基，例如-CH 2CH 2OCH 3；和/或，R 5中，-C 1-4亚烷基-NR aR b为-C 1-2亚烷基-NR aR b，例如-CH 2CH 2N(CH 3) 2；和/或，A为CH；和/或，B为CH；和/或，G 1中，所述C 6-14芳基为苯基；和/或，G 1中，所述5或6元单环杂芳基为吡啶基、嘧啶基、呋喃基、吡咯基、噻唑基、吡唑基或噻吩基，例如吡啶基、呋喃基或噻吩基；和/或，G 1中，所述C 6-14芳基和所述5或6元单环杂芳基为未取代的或被1、2或3个独立选自S2组的基团取代；和/或，G 1中，所述S2组的基团选自：卤素、氰基、-C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基、C 3-20环烷基、卤代C 3-20环烷基、-O-C 3-20环烷基、-NR aR b和-OR c，例如氟、氯、溴、碘、氰基、甲基、异丙基、三氟甲基、甲氧基、三氟甲氧基、环丙基、-O-环丙基、-O-环戊基、-N(CH 3) 2和-OCH 2CH 2OCH 3；和/或，G 2中，所述C 6-14芳基为苯基；和/或，G 2中，所述5或6元单环杂芳基为吡啶基、嘧啶基、呋喃基、吡咯基、噻唑基或吡唑基，例如吡啶基或吡唑基；和/或，G 2中，所述C 6-14芳基和所述5或6元单环杂芳基为未取代的或被1、2或3个独立选自S2组的基团取代；和/或，G 2中，所述S2组的基团选自：卤素、氰基、-C 1-6烷基、卤代C 1-6烷基、C 1- 6烷氧基、氘代C 1-6烷氧基和C 3-20环烷基，例如氟、氯、氰基、甲基、三氟甲基、甲氧基、氘代甲氧基和环丙基；和/或，L中，所述CR 8R 9为CH 2；和/或，所述S1组的基团中，所述卤素各自独立地为氟或氯；和/或，所述S1组的基团中，所述C 1-6烷基各自独立地为C 1-3烷基，例如甲基；和/或，所述S1组的基团中，所述C 1-6烷氧基各自独立地为C 1-3烷氧基，例如甲氧基或乙氧基；和/或，所述S1组的基团中，所述卤代C 1-6烷氧基各自独立地为卤代C 1-3烷氧基，例如二氟甲氧基或三氟甲氧基；和/或，所述S1组的基团中，所述氘代C 1-6烷氧基各自独立地为氘代C 1-3烷氧基，例 如氘代甲氧基；和/或，所述S1组的基团中，所述C 1-4亚烷基-羟基各自独立地为C 1-2亚烷基-羟基，例如-CH 2OH；和/或，所述S1组的基团中，所述-C(O)C 1-6烷基各自独立地为-C(O)C 1-3烷基，例如-C(O)CH 3；和/或，所述S1组的基团中，所述-C(O)C 3-20环烷基各自独立地为-C(O)C 3-6单环环烷基，例如-C(O)-环丙基；和/或，所述S1组的基团中，所述3至20元杂环基各自独立地为3至6元单环杂环基，其中所述3至6元单环杂环基具有1或2个选自N和O的杂原子作为环原子，例如吗啉基；和/或，所述S1组的基团中，所述-NR aR b各自独立地为-N(CH 3) 2；和/或，所述S1组的基团中，所述-OR c各自独立地为-OCH 2CH 2OCH 3或-CH 2CH 2OCH 2CH 3；和/或，所述S2组的基团中，所述卤素各自独立地为氟、氯、溴或碘；和/或，所述S2组的基团中，所述C 1-6烷基各自独立地为C 1-3烷基，例如甲基或异丙基；和/或，所述S2组的基团中，所述卤代C 1-6烷基各自独立地为卤代C 1-3烷基，例如三氟甲基；和/或，所述S2组的基团中，所述氘代C 1-6烷基各自独立地为氘代C 1-3烷基，例如氘代甲基；和/或，所述S2组的基团中，所述C 1-6烷氧基各自独立地为C 1-3烷氧基，例如甲氧基；和/或，所述S2组的基团中，所述卤代C 1-6烷氧基各自独立地为卤代C 1-3烷氧基，例如二氟甲氧基或三氟甲氧基；和/或，所述S2组的基团中，所述氘代C 1-6烷氧基各自独立地为氘代C 1-3烷氧基，例如氘代甲氧基；和/或，所述S2组的基团中，所述C 3-20环烷基各自独立地为C 3-6单环环烷基，例如环丙基；和/或，所述S2组的基团中，所述卤代C 3-20环烷基各自独立地为卤代C 3-6单环环烷基，例如卤代环丙基；和/或，所述S2组的基团中，所述-O-C 3-20环烷基各自独立地为-O-C 3-6单环环烷基， 例如-O-环丙基或-O-环戊基；和/或，所述S2组的基团中，所述-NR aR b各自独立地为-N(CH 3) 2；和/或，所述S2组的基团中，所述-OR c各自独立地为-OCH 2CH 2OCH 3或-OCH 2CH 2OCH 2CH 3；和/或，R a和R b各自独立地为C 1-3烷基，例如甲基；和/或，R c中，所述-C 1-4亚烷基-C 1-6烷氧基各自独立地为-C 1-2亚烷基-C 1-3烷氧基，例如-CH 2CH 2OCH 3或-CH 2CH 2OCH 2CH 3；和/或，R c中，所述被1或2个卤素取代的C 3-6单环环烷基中的卤素为氟、氯或溴；和/或，R c中，所述被1或2个卤素取代的C 3-6单环环烷基中的C 3-6单环环烷基为环丙基；和/或，当“*”处标记的碳原子为手性碳原子时，所述碳原子为R构型、S构型或其混合。
- 如权利要求1至3中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 1和R 2各自独立地选自：H、甲氧基、甲硫基和乙硫基；或者R 1和R 2与同它们相连的碳原子共同构成：C＝O或者C＝S；和/或，R 3和R 4各自独立地选自：-CH 3、-CH 2CH 3、环丙基、三氟甲基(CF 3)、氘代甲基(CD 3)、-CH 2OH、-CH 2OCH 3、-CH 2OCF 3、-CH 2OCHF 2、-CH 2OCD 3、-CH 2OCH 2CH 3、-CH 2OCH 2CH 2OCH 3、-CH 2CH 2OCH 2CH 3、-CH 2O-环丙基、-CH 2N(CH 3) 2、-CH(OH)CH 3和-CH 2CH 3OCH 3；例如R 3选自：-CH 3、-CH 2CH 3、三氟甲基、氘代甲基和环丙基，R 4选自：-CH 3、-CH 2OH、-CH 2OCH 3、-CH 2OCF 3、-CH 2OCHF 2、-CH 2OCF 3、-CH 2OCHF 2、-CH 2OCD 3、-CH 2OCH 2CH 3、-CH 2OCH 2CH 2OCH 3、-CH 2CH 2OCH 2CH 3、-CH 2O-环丙基、-CH 2N(CH 3) 2、-CH(OH)CH 3和-CH 2CH 3OCH 3；或者R 3和R 4与同它们相连的碳原子共同构成：
和/或，R 5为H、甲基、乙基、氘代甲基、-CH 2CH 2OH、-CH 2CH 2OCH 3或-CH 2CH 2N(CH 3) 2；和/或，G 1为苯基、2-氯苯基、2-氟苯基、2-三氟甲基苯基、2-氯-6-氟苯基、2-氯-3,4-二氟苯基、2-氯-3-氟-4-甲氧基苯基、2-氯-4-环戊氧基苯基、2-氯-4-(2-甲氧基乙基)苯基、 2-氯-4-二甲氨基苯基、2-氯-4-环丙氧基苯基、2-氯-4-甲氧基苯基、2-氯-4-异丙基苯基、2-氯-4-环丙基苯基、2-氯-4-甲基苯基、2-氯呋喃基、呋喃基、噻吩基、2-溴噻吩基、2-氯噻吩基、吡啶基、3-氯吡啶基、2-甲基苯基、2-氯-4氰基苯基、2-氯-4氟苯基、2-碘苯基、2-氯-5-氟苯基、2-氯-3氟苯基、2-氯-三氟甲氧基苯基、2-氯-4溴苯基或2,4-二氯苯基；和/或，G 2为苯基、2-氟苯基、3-氟苯基、4-三氟甲基吡啶基、3-甲基吡啶基、3-三氟甲基吡啶基、4-甲基吡啶基、4-环丙基吡啶基、4,6-二甲基吡啶基、4-氯-6-甲基吡啶基、2-甲基-6-氯吡啶基、3-氰基苯基、3-氟-4-甲基吡啶基、吡啶基、3-氟吡啶基、2-甲氧基苯基、2-氯苯基、3-甲氧基苯基、2-氟-6-甲氧基苯基、吡唑基、3-甲基吡唑基、2-甲氧基-3-氟苯基、2-氟-3-氘代甲氧基苯基、2,4-二甲基吡啶基、2-氯吡啶基、2-甲氧基-3氟苯基或2-氘代甲氧基-3-氟苯基；和/或，L为CH 2或O；和/或，所述S1组的基团选自：氘、氟、氰基、羟基、甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氘代甲氧基、-CH 2OH、-C(O)CH 3、-C(O)-环丙基、吗啉基、-O-环丙基、-N(CH 3) 2、-OCH 2CH 2OCH 3和-CH 2CH 2OCH 2CH 3；和/或，所述S2组的基团选自：氟、氯、溴、碘、氰基、甲基、氘代甲基、异丙基、三氟甲基、甲氧基、三氟甲氧基、氘代甲氧基、环丙基、-O-环丙基、-O-环戊基、-N(CH 3) 2和-OCH 2CH 2OCH 3。 - 如权利要求1至4中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，i、G 1、L、G 2具有以下任一种定义：(1)i为0，G 1为苯基、吡啶基、呋喃基或噻吩基；所述苯基、所述吡啶基、所述呋喃基和所述噻吩基为未取代的或被1、2、3或4个独立选自S2组的基团取代；(2)i为1，L为CR 8R 9或O，G 1为苯基或吡啶基，G 2为苯基、吡啶基或吡唑基；所述苯基、所述吡啶基和所述吡唑基为未取代的或被1、2、3或4个独立选自S2组的基团取代；(3)i为1，L为CR 8R 9，G 1为苯基，G 2为吡唑基；所述苯基和所述吡唑基为未取代的或被1、2、3或4个独立选自S2组的基团取代；(4)i为1，L为O，G 1为苯基或吡啶基，G 2为苯基或吡啶基；所述苯基和所述吡啶基为未取代的或被1、2、3或4个独立选自S2组的基团取代。
- 如权利要求1至5中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，结构单元选自：
- 如权利要求1至6中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物具有以下任一结构：
各式中，A、B、R 1、R 3、R 4、R 5、L、G 1、G 2、“*”如权利要求1至6中任一项所定义。 - 如权利要求1至7中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物具有以下任一结构：
各式中，R 1、R 3、R 4、R 5、G 1、G 2、“*”如权利要求1至7中任一项所定义。 - 如权利要求7或8所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 1为C 1-6烷氧基或C 1-6烷硫基。
- 如权利要求1至8中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物具有以下任一结构：
- 一种药物组合物，所述药物组合物包括如权利要求1至10中任一项所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。
- 如权利要求1至10中任一项所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备预防和/或治疗疾病或病症的药物中的用途；所述疾病或病症与BTK相关和/或与B细胞活化异常相关。
- 如权利要求12所述的用途，其特征在于，所述疾病或病症选自下组：异种免疫疾病、自身免疫疾病、炎性疾病和癌症；优选地，所述异种免疫疾病、自身免疫疾病和炎性疾病选自下组：风湿性疾病、肾小球肾炎、Goodpasture综合征、动脉粥样硬化、自身免疫性血液病、自身免疫性胃炎、自身免疫性炎性肠病、肠易激综合征、同种异体移植排斥、慢性甲状腺炎、格雷夫斯病、舍格伦病、硬皮病、糖尿病、肝炎、胰腺炎、原发性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮、牛皮癣、特应性皮炎、皮肌炎、接触性皮炎、湿疹、血管炎、慢性肾功能不全、Stevens-Johnson综合征、炎性疼痛、特发性腹泻、恶病质、结节病、Guillain-Barre综合征、葡萄膜炎、结膜炎、中耳炎、牙周病、帕金森氏病、阿尔茨海默氏病、败血性休克、肺间质纤维化、哮喘、支气管炎、鼻炎、鼻窦炎、尘肺、肺功能不全综合征、肺气肿、肺纤维化、慢性炎性肺病和气道上的其他炎性或阻塞性疾病。
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| CN107344940A (zh) * | 2016-05-06 | 2017-11-14 | 广东东阳光药业有限公司 | Btk抑制剂及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023174300A1 (zh) * | 2022-03-15 | 2023-09-21 | 劲方医药科技(上海)有限公司 | Btk抑制剂的晶型及其酸式盐和其酸式盐的晶型 |
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| EP4223753A1 (en) | 2023-08-09 |
| CN116234550A (zh) | 2023-06-06 |
| TW202214633A (zh) | 2022-04-16 |
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