WO2024099440A1 - 一种稠环化合物、其用途及含其的药物组合物 - Google Patents
一种稠环化合物、其用途及含其的药物组合物 Download PDFInfo
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- WO2024099440A1 WO2024099440A1 PCT/CN2023/131053 CN2023131053W WO2024099440A1 WO 2024099440 A1 WO2024099440 A1 WO 2024099440A1 CN 2023131053 W CN2023131053 W CN 2023131053W WO 2024099440 A1 WO2024099440 A1 WO 2024099440A1
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- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 1
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- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
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- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
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- RJMHIBOUKAMBIK-UHFFFAOYSA-N methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate Chemical compound COC(=O)c1cc(Br)c2ncnn2c1 RJMHIBOUKAMBIK-UHFFFAOYSA-N 0.000 description 1
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- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
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- 238000002525 ultrasonication Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a condensed ring compound, application thereof and a pharmaceutical composition containing the condensed ring compound.
- Cancer is one of the leading causes of death worldwide and is mainly caused by genetic and epigenetic changes. These changes affect the gene expression or signaling pathways of normal cells, leading to the transformation of normal cells into malignant tumor cells.
- Cancer genome sequencing results of tumor samples found that subunit genes of the human ATP-dependent chromatin remodeling complex SWI/SNF are mutated in >20% of human tumors, and most of them are loss-of-function mutations.
- BRM Protein brahma homolog
- BRG1 Protein brahma homolog 1
- ATPase hydrolyzes ATP to provide energy for the SWI/SNF complex, enabling it to regulate gene expression and key cellular processes, and plays an important role in maintaining cell vitality.
- the BRG1 gene (SMARCA4) is highly mutated in many types of cancer, including but not limited to melanoma, endometrial cancer, non-small cell lung cancer, esophageal and gastric adenocarcinoma, urothelial bladder cancer, and colorectal cancer.
- the BRM gene (SMARCA2) rarely mutates.
- BRM and BRG1 are complementary and redundant in their functions related to cell viability, such as participating in the regulation of cell cycle and hormone action pathways, DNA damage repair response, etc. Therefore, in tumor cells with BRG1 gene defects, BRM can compensate for the functional loss of BRG1 and maintain the function of the SWI/SNF complex to support cell viability.
- BRM and BRG1 have been verified in in vitro and in vivo disease models of various types of tumor cells: degradation of BRM or silencing of BRM gene expression in BRG1 gene-deficient cells will inhibit tumor cell proliferation in vitro and tumor growth in vivo; BRG1 gene-deficient tumor cells are extremely sensitive to shRNA of the BRM gene; inhibiting the ATPase activity of BRM can inhibit the in vivo growth of BRG1 gene-deficient tumors... Therefore, in BRG1 gene mutant tumors, BRM is a potential drug treatment target.
- BRG1 Compared with BRG1, drug interference with BRM has a lower risk of toxicity.
- the ATPase activity and chromatin remodeling ability of the BRM-SWI/SNF complex are much lower than those of the BRG1-SWI/SNF complex.
- the SWI/SNF complex mainly relies on BRG1 to function. Homozygous knockout of the BRG1 gene does not cause embryonic lethality in mice or affect the reproductive capacity of adult mice, which is the opposite of the performance of homozygous knockout of the BRM gene.
- the present invention provides a condensed ring compound I or a pharmaceutically acceptable salt thereof.
- the condensed ring compound has a strong inhibitory effect on BRM ATPase and has a good application prospect in BRG1 gene mutation tumors.
- the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,
- Y is C or N
- R1 is Hydroxyl, cyano, halogen, amino, deuterium, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-3 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 1-4 , or 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 1-5 ; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R 1-1 is C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-1-1 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more deuterium, or -NR 1-1-2 R 1-1-3 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen or a C 1 -C 6 alkyl group which is unsubstituted or substituted with one or more deuteriums;
- Each R 1-1-1 is independently OR 1-1-1-1 , C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;
- R 1-1-1-1 is hydrogen or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- R 1-1-2 and R 1-1-3 are independently hydrogen or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- Each R 1-3 is independently hydroxy, cyano, halogen, amino, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;
- R 1-4 and R 1-5 is independently hydroxy, deuterium, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen, deuterium, halogen, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- R 1-8 is hydrogen or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , a C4-C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 , or a C6 - C10 aryl group which is unsubstituted or substituted by one or more R2-4 ;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3. and S, with one or more heteroatoms, 1, 2 or 3;
- Each R 2-1 is independently deuterium, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-1-1 , oxo ( ⁇ O), or two R 2-1 and the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more deuterium;
- Each R 2-2 is independently deuterium, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-2-1 , oxo ( ⁇ O), or two R 2-2 and the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more deuterium;
- Each R 2-3 is independently deuterium, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-3-1 , oxo ( ⁇ O), or two R 2-3 and the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more deuterium;
- Each R 2-4 is independently deuterium, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-4-1 , oxo ( ⁇ O), or two R 2-4 and the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more deuterium;
- R 2-1-1 , R 2-2-1 , R 2-3-1 and R 2-4-1 are independently deuterium or hydroxyl;
- A is a C 6 -C 10 arylene group which is unsubstituted or substituted by one or more deuteriums, a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more deuteriums, or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more deuteriums;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linking bond, a C 2 -C 6 alkenylene group which is unsubstituted or substituted by one or more deuterium groups, or a C 1 -C 6 alkylene group which is unsubstituted or substituted by one or more deuterium groups;
- Q is a C 6 -C 10 arylene group which is unsubstituted or substituted by one or more R 3-1 , a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more R 3-1 , or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R 3-1 ;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen or deuterium
- R 4 is C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-1 , C 2 -C 6 alkenyl which is unsubstituted or substituted by one or more R 4-2 , C 2 -C 6 alkynyl which is unsubstituted or substituted by one or more R 4-3 , C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 4-4 , 4-12 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 4-5 , 5-12 membered heteroaryl which is unsubstituted or substituted by one or more R 4-6 , C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 4-7 , or -NR 4-9 R 4-8 ; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S
- Each R 4-1 is independently deuterium, halogen, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by 1 or more deuterium, or C 1 -C 6 alkoxy which is unsubstituted or substituted by 1 or more deuterium;
- Each R 4-2 is independently deuterium, halogen, hydroxyl, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- Each R 4-3 is independently deuterium, halogen, hydroxyl, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- Each R 4-4 is independently deuterium, halogen, hydroxyl, or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- Each R 4-5 is independently deuterium, halogen, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted with one or more R 4-5-1 , -NR 4-5- 2 R 4-5-3 , or C 1 -C 6 alkoxy which is unsubstituted or substituted with one or more deuterium;
- Each R 4-5-1 is independently deuterium, hydroxyl or halogen
- R 4-5-2 and R 4-5-3 are independently hydrogen or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more deuteriums;
- Each R 4-6 is independently deuterium, halogen, cyano, hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by 1 or more deuterium, or C 1 -C 6 alkoxy which is unsubstituted or substituted by 1 or more deuterium;
- Each R 4-7 is independently deuterium, halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by 1 or more deuterium, or C 1 -C 6 alkoxy which is unsubstituted or substituted by 1 or more deuterium;
- R 4-9 and R 4-8 are independently hydrogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-8-1, or 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more deuteriums; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- Each R 4-8-1 is independently deuterium, hydroxy, C 1 -C 6 alkoxy which is unsubstituted or substituted by one or more R 4-8-1-1 , or OR 4-8-1-2 ;
- Each R 4-8-1-1 is independently deuterium or a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;
- Each R 4-8-1-2 is independently a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted with one or more deuterium groups.
- the plurality is 2, 3, 4, 5, 6 or 7.
- the C 1 -C 6 alkyl group is methyl, ethyl, propyl, isopropyl or isobutyl.
- the C 3 -C 6 cycloalkyl group in the "C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by one or more R 1-4 ", the C 3 -C 6 cycloalkyl group is cyclobutyl, for example,
- the heteroatom in the 3-6-membered heterocycloalkyl group is N, O or S, preferably O, and the number of heteroatoms in the 3-6-membered heterocycloalkyl group is preferably 1.
- the 3-6 membered heterocycloalkyl group in the “3-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R 1-5 ”, is a 4 membered heterocycloalkyl group, for example,
- R 1-1 in R 1-1 , the “C 1 -C 6 alkyl group which is unsubstituted or substituted with one or more R 1-1-1 ”; the “plurality” is 2.
- the C 1 -C 6 alkyl group is methyl, ethyl or propyl.
- the C 3 -C 6 cycloalkyl group is cyclopropyl.
- the C 1 -C 6 alkyl group is methyl.
- the C 1 -C 6 alkyl group is methyl.
- the C 1 -C 6 alkyl group is methyl.
- the halogen is F, Cl or Br, preferably F.
- R 1-3 the “C 1 -C 6 alkyl group which is unsubstituted or substituted with one or more deuteriums”; the “plurality” is 2 or 3.
- the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
- the C 1 -C 6 alkyl group is methyl.
- the C 1 -C 6 alkyl group is methyl.
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3.
- R2 and R3 in the “ R2 and R3 and the atoms to which they are connected form a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 ", the 5-6-membered heteroaryl group is a 5-membered heteroaryl group, for example,
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is preferably 1 or 2.
- the 4-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, for example,
- R 2 and R 3 in the “R 2 and R 3 and the atoms to which they are attached form a C 4 -C 6 cycloalkyl group which is unsubstituted or substituted with one or more R 2-3 ", the C 4 -C 6 cycloalkyl group is cyclopentane.
- the C 6 -C 10 aryl group is phenyl
- the halogen is F, Cl or Br, preferably F.
- the C 1 -C 6 alkyl group is a methyl group or an ethyl group.
- the halogen is F, Cl or Br, preferably F.
- the C 3 -C 6 cycloalkyl group is cyclopropyl.
- the arylene group is a phenylene group.
- the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3.
- the 5-12-membered heteroarylene is a 6-membered heteroarylene, a 6-membered heteroarylene and a 5-membered heteroarylene, or a 6-membered heteroarylene and a 6-membered heteroarylene, for example,
- the heteroatom in the 5-12-membered heterocycloalkylene group is independently N; the number of the heteroatom is preferably 1.
- the 5-12 membered heterocycloalkylene is a 6-membered heteroarylene and a 6-membered heterocycloalkylene, for example,
- the C 2 -C 6 alkenylene group is vinyl, for example,
- the C 6 -C 10 arylene group is a phenylene group.
- the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3.
- the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of the heteroatoms is 1, 2 or 3.
- the 5-12 membered heterocycloalkylene is a 6-membered heteroarylene and a 6-membered heterocycloalkylene, for example,
- the halogen is F, Cl or Br, preferably F.
- the C 1 -C 6 alkyl group in the "C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 4-1 ", is ethyl, for example,
- the C 2 -C 6 alkynyl group is ethynyl.
- R 4 the “C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 4-4 ”; the plurality is two.
- the heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is preferably 1 or 2.
- the 4-12 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R 4-5 ; the plurality is two.
- the 4-12 membered heterocycloalkyl is a 4-7 membered heterocycloalkyl or a 7-9 membered double bridged ring, for example,
- the heteroatom in the 5-12 membered heteroaryl group is N, and the number of heteroatoms is preferably 1 or 2.
- R 4 the “5-12 membered heteroaryl group which is unsubstituted or substituted by one or more R 4-6 ”; the plurality is two.
- the C 1 -C 6 alkoxy group is an ethoxy group, for example,
- the C 1 -C 6 alkoxy group is a methoxy group.
- the halogen is F, Cl or Br, preferably F.
- the C 1 -C 6 alkyl group is methyl.
- the C 1 -C 6 alkoxy group is a methoxy group.
- the C 1 -C 6 alkyl group is methyl.
- the halogen is F, Cl or Br, preferably F.
- the C 1 -C 6 alkyl group is methyl.
- the C 1 -C 6 alkyl group in R 4-9 and R 4-8 is methyl or ethyl.
- the heteroatom in the 4-6-membered heterocycloalkyl group is O, and the number of the heteroatom is preferably 1.
- the 4-6-membered heterocycloalkyl is a 5-membered or 6-membered heterocycloalkyl.
- the C 3 -C 6 cycloalkyl group is cyclopropyl.
- Y is C or N; preferably C.
- R1 is C 1 -C 6 alkyl substituted by one or more R 1-3 , C 3 -C 6 cycloalkyl unsubstituted or substituted by one or more R 1-4 , or 3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-5 ;
- the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably C 1 -C 6 alkyl substituted by one or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by one or more R 1-4 ; further preferably or a C 1 -C 6 alkyl group substituted by one or more R 1-3 ; more preferably
- R 1-1 is C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 1-1-1 , unsubstituted C 3 -C 6 cycloalkyl, or -NR 1-1-2 R 1-1-3 ; preferably C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 1-1-1 , or -NR 1-1-2 R 1-1-3 ; further preferably C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 1-1-1 ; further preferably unsubstituted C 1 -C 6 alkyl .
- R 1-2 is O or NR 1-2-1 ; preferably, it is O.
- R 1-2-1 is hydrogen
- each R 1-1-1 is independently OR 1-1-1-1 , unsubstituted C 1 -C 6 alkyl or unsubstituted C 1 -C 6 alkoxy; preferably OR 1-1-1-1 or unsubstituted C 1 -C 6 alkyl; more preferably unsubstituted C 1 -C 6 alkyl.
- R 1-1-1-1 is hydrogen or unsubstituted C 1 -C 6 alkyl; preferably, it is unsubstituted C 1 -C 6 alkyl.
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl.
- each R 1-3 is independently hydroxyl, cyano, halogen, amino, unsubstituted C 1 -C 6 alkyl or deuterium; preferably hydroxyl, cyano, halogen, unsubstituted C 1 -C 6 alkyl or deuterium; further preferably hydroxyl, cyano, halogen or unsubstituted C 1 -C 6 alkyl; further preferably hydroxyl or halogen.
- each R 1-3 is independently hydroxyl, halogen, unsubstituted C 1 -C 6 alkyl or deuterium; preferably hydroxyl, halogen or unsubstituted C 1 -C 6 alkyl.
- each of R 1-4 and R 1-5 is independently hydroxy.
- X is -CR 1-6 R 1-7 - or -NR 1-8 -; preferably -CR 1-6 R 1-7 -.
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl; preferably hydrogen.
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group.
- R2 and R3 and the atoms to which they are connected form a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 , or an unsubstituted C6- C10 aryl group; preferably, a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6- membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 ; further preferably, a 5-6-membere
- each R 2-1 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl or oxo ( ⁇ O) with one or more R 2-1-1 ; preferably halogen or unsubstituted C 1 -C 6 alkyl; more preferably unsubstituted C 1 -C 6 alkyl.
- each R 2-2 is independently halogen, unsubstituted C 1 -C 6 alkyl or oxo ( ⁇ O); preferably halogen.
- R 2-1-1 is hydroxy
- A is an unsubstituted C 6 -C 10 arylene group, an unsubstituted 5-12 membered heterocycloalkylene group or an unsubstituted 5-12 membered heteroarylene group; preferably an unsubstituted 5-12 membered heteroarylene group;
- the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
- L is a linker or an unsubstituted C 2 -C 6 alkenylene; preferably, it is a linker.
- Q is an unsubstituted C 6 -C 10 arylene group, an unsubstituted or substituted 5-12 -membered heteroarylene group, or an unsubstituted 5-12-membered heterocycloalkylene group; preferably, an unsubstituted or substituted 5-12 -membered heteroarylene group, or an unsubstituted 5-12-membered heterocycloalkylene group; further preferably, an unsubstituted 5-12-membered heteroarylene group, or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
- each R 3-1 is independently halogen.
- R4 is C1 - C6 alkyl which is unsubstituted or substituted by one or more R4-1 , unsubstituted C2 - C6 alkynyl, C3 - C6 cycloalkyl which is unsubstituted or substituted by one or more R4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R4-6 , unsubstituted C1- C6 alkoxy or -NR4-9R4-8 ; preferably C1 - C6 alkyl which is substituted by one or more R4-1 , unsubstituted C2 -C6 alkynyl , unsubstituted C3 - C6 cycloalkyl, 4-12-membered heterocycloalkyl which is unsubstituted or
- each R 4-1 is independently an unsubstituted C 1 -C 6 alkoxy group.
- each R 4-4 is independently halogen.
- each R 4-5 is independently hydroxyl, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-5-1 , -NR 4-5-2 R 4-5-3 , or unsubstituted C 1 -C 6 alkoxy; preferably C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-5-1 , or unsubstituted C 1 -C 6 alkoxy; further preferably unsubstituted C 1 -C 6 alkoxy.
- each R 4-5-1 is independently hydroxyl.
- R 4-5-2 and R 4-5-3 are independently unsubstituted C 1 -C 6 alkyl.
- each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl; preferably cyano or unsubstituted C 1 -C 6 alkyl.
- R 4-9 and R 4-8 are independently C 1 -C 6 alkyl or unsubstituted 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 4-8-1 ; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
- each R 4-8-1 is independently OR 4-8-1-2 .
- each R 4-8-1-2 is independently an unsubstituted C 3 -C 6 cycloalkyl.
- Y is C or N
- R1 is C 1 -C 6 alkyl substituted by one or more R 1-3 , C 3 -C 6 cycloalkyl unsubstituted or substituted by one or more R 1-4 , or 3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-5 , wherein the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R 1-1 is C 1 -C 6 alkyl, unsubstituted C 3 -C 6 cycloalkyl or -NR 1-1-2 R 1-1- 3 which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen;
- Each R 1-1-1 is independently OR 1-1-1-1 , an unsubstituted C 1 -C 6 alkyl group or an unsubstituted C 1 -C 6 alkoxy group;
- R 1-1-1-1 is hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, cyano, halogen, amino, unsubstituted C 1 -C 6 alkyl or deuterium;
- R 1-4 and R 1-5 are independently hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 , or an unsubstituted C6 - C10 aryl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
- Each R 2-1 is independently halogen, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 2-1-1 , or oxo ( ⁇ O);
- R 2-1-1 is a hydroxyl group
- A is an unsubstituted C 6 -C 10 arylene group, an unsubstituted 5-12-membered heterocycloalkylene group or an unsubstituted 5-12-membered heteroarylene group;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted C 6 -C 10 arylene group, an unsubstituted or one or more R 3-1 substituted 5-12-membered heteroarylene group, or an unsubstituted 5-12-membered heterocycloalkylene group;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R 4 is C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-1 , unsubstituted C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl which is unsubstituted or substituted by one or more R 4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R 4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R 4-6 , unsubstituted C 1 -C 6 alkoxy or -NR 4-9 R 4-8 ; the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or
- Each R 4-1 is independently an unsubstituted C 1 -C 6 alkoxy group
- Each R 4-4 is independently halogen
- Each R 4-5 is independently hydroxy, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 4-5-1 , -NR 4-5-2 R 4-5-3 or unsubstituted C 1 -C 6 alkoxy;
- Each R 4-5-1 is independently hydroxyl
- R 4-5-2 and R 4-5-3 are independently unsubstituted C 1 -C 6 alkyl groups
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl; preferably cyano or unsubstituted C 1 -C 6 alkyl;
- R 4-9 and R 4-8 are independently C 1 -C 6 alkyl or unsubstituted 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R 4-8-1 ; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- Each R 4-8-1 is independently OR 4-8-1-2 ;
- Each R 4-8-1-2 is independently an unsubstituted C 3 -C 6 cycloalkyl group.
- Y is C or N
- R1 is C 1 -C 6 alkyl substituted by 1 or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by 1 or more R 1-4 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 or -NR 1-1-2 R 1-1-3 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen;
- Each R 1-1-1 is independently OR 1-1-1-1 or an unsubstituted C 1 -C 6 alkyl group;
- R 1-1-1-1 is hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, cyano, halogen, unsubstituted C 1 -C 6 alkyl or deuterium;
- Each R 1-4 is hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 ;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are N or O, and the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently halogen or unsubstituted C 1 -C 6 alkyl
- A is an unsubstituted 5-12-membered heteroarylene group, wherein the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is a 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R 3-1 ;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R 4 is a C 1 -C 6 alkyl group substituted by one or more R 4-1 , an unsubstituted C 2 -C 6 alkynyl group, an unsubstituted C 3 -C 6 cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R 4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R 4-6 , or an unsubstituted C 1 -C 6 alkoxy group;
- the heteroatoms in the 4-12-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is a C 1 -
- R 4-1 is independently an unsubstituted C 1 -C 6 alkoxy group
- Each R 4-5 is independently a C 1 -C 6 alkyl group or an unsubstituted C 1 -C 6 alkoxy group which is unsubstituted or substituted by one or more R 4-5-1 ;
- Each R 4-5-1 is independently hydroxyl
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl.
- Y is C or N
- R1 is C 1 -C 6 alkyl substituted by 1 or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by 1 or more R 1-4 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 or -NR 1-1-2 R 1-1-3 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen;
- Each R 1-1-1 is independently OR 1-1-1-1 or an unsubstituted C 1 -C 6 alkyl group;
- R 1-1-1-1 is an unsubstituted C 1 -C 6 alkyl group
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, cyano, halogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-4 is hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 ;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are N or O, and the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group, wherein the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is a 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R 3-1 ;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R 4 is a C 1 -C 6 alkyl group substituted by one or more R 4-1 , an unsubstituted C 2 -C 6 alkynyl group, an unsubstituted C 3 -C 6 cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R 4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R 4-6 , or an unsubstituted C 1 -C 6 alkoxy group;
- the heteroatoms in the 4-12-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is a C 1 -
- R 4-1 is independently an unsubstituted C 1 -C 6 alkoxy group
- Each R 4-5 is independently a C 1 -C 6 alkyl group or an unsubstituted C 1 -C 6 alkoxy group which is unsubstituted or substituted by one or more R 4-5-1 ;
- Each R 4-5-1 is independently hydroxyl
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl.
- Y is C or N
- R1 is C 1 -C 6 alkyl substituted by 1 or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by 1 or more R 1-4 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 or -NR 1-1-2 R 1-1-3 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen;
- Each R 1-1-1 is independently OR 1-1-1-1 or an unsubstituted C 1 -C 6 alkyl group;
- R 1-1-1-1 is an unsubstituted C 1 -C 6 alkyl group
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, cyano, halogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-4 is hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or a C4 - C6 cycloalkyl group which is unsubstituted or substituted by one or more R2-3 ;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are N or O, and the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group, wherein the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is a 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R 3-1 ;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R 4 is a C 1 -C 6 alkyl group substituted by one or more R 4-1 , an unsubstituted C 2 -C 6 alkynyl group, an unsubstituted C 3 -C 6 cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R 4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R 4-6 , or an unsubstituted C 1 -C 6 alkoxy group;
- the heteroatoms in the 4-12-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is a C 1 -
- R 4-1 is independently an unsubstituted C 1 -C 6 alkoxy group
- Each R 4-5 is independently a C 1 -C 6 alkyl group or an unsubstituted C 1 -C 6 alkoxy group which is unsubstituted or substituted by one or more R 4-5-1 ;
- Each R 4-5-1 is independently hydroxyl
- Each of R 4-6 is independently cyano or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is C 1 -C 6 alkyl substituted by 1 or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by 1 or more R 1-4 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 or -NR 1-1-2 R 1-1-3 ;
- R 1-2 is O or NR 1-2-1 ;
- R 1-2-1 is hydrogen;
- Each R 1-1-1 is independently an unsubstituted C 1 -C 6 alkyl group
- R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy or halogen
- Each R 1-4 is hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen or unsubstituted C 1 -C 6 alkyl
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or an unsubstituted C4 - C6 cycloalkyl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or both of N and S, and the number of heteroatoms is 1 or 2;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are N or
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group;
- the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R4-5 , a 5-12-membered heteroaryl substituted by one or more R4-6 , or an unsubstituted C1 - C6 alkoxyl group;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, a 4-6 -membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each of R 4-6 is independently cyano or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is C 1 -C 6 alkyl substituted by 1 or more R 1-3 or C 3 -C 6 cycloalkyl unsubstituted or substituted by 1 or more R 1-4 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O
- Each R 1-1-1 is independently an unsubstituted C 1 -C 6 alkyl group
- Each R 1-3 is independently halogen
- Each R 1-4 is hydroxyl
- X is -CR 1-6 R 1-7 - or -NR 1-8 -;
- R 1-6 and R 1-7 are independently hydrogen
- R 1-8 is an unsubstituted C 1 -C 6 alkyl group
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or an unsubstituted C4 - C6 cycloalkyl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl group is N or O, and the number of heteroatoms is 1 or
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R4-5 , a 5-12-membered heteroaryl substituted by one or more R4-6 , or an unsubstituted C1 - C6 alkoxyl group;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, a 4-6 -membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each of R 4-6 is independently cyano or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is or C 1 -C 6 alkyl which is unsubstituted or substituted by one or more R 1-3 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O
- Each R 1-1-1 is independently OR 1-1-1-1 ;
- R 1-1-1-1 is hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, halogen, unsubstituted C 1 -C 6 alkyl or deuterium;
- X is -CR 1-6 R 1-7 -;
- R 1-6 and R 1-7 are independently hydrogen
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or an unsubstituted C4 - C6 cycloalkyl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O; the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently halogen or unsubstituted C 1 -C 6 alkyl
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R 4 is an unsubstituted C 2 -C 6 alkynyl, an unsubstituted C 3 -C 6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R 4-5 , a 5-12-membered heteroaryl substituted by one or more R 4-6 , or an unsubstituted C 1 -C 6 alkoxy;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-6-membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is or a C 1 -C 6 alkyl group substituted by one or more R 1-3 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O
- Each R 1-1-1 is independently OR 1-1-1-1 ;
- R 1-1-1-1 is hydrogen or unsubstituted C 1 -C 6 alkyl
- Each R 1-3 is independently hydroxy, halogen, unsubstituted C 1 -C 6 alkyl or deuterium;
- X is -CR 1-6 R 1-7 -;
- R 1-6 and R 1-7 are independently hydrogen
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or an unsubstituted C4 - C6 cycloalkyl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O; the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently a halogen or an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group, wherein the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1. The number of atoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R4-5 , a 5-12-membered heteroaryl substituted by one or more R4-6 , or an unsubstituted C1 - C6 alkoxyl group;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, a 4-6 -membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is or a C 1 -C 6 alkyl group substituted by one or more R 1-3 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O
- Each R 1-1-1 is independently OR 1-1-1-1 ;
- R 1-1-1-1 is an unsubstituted C 1 -C 6 alkyl group
- Each R 1-3 is independently hydroxy, halogen or unsubstituted C 1 -C 6 alkyl
- X is -CR 1-6 R 1-7 -;
- R 1-6 and R 1-7 are independently hydrogen
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2 , or an unsubstituted C4 - C6 cycloalkyl group;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O; the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- Each R 2-2 is independently halogen
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- Each R 3-1 is independently halogen
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R4-5 , a 5-12-membered heteroaryl substituted by one or more R4-6 , or an unsubstituted C1 - C6 alkoxyl group;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, a 4-6 -membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each R 4-6 is independently cyano, halogen or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R1 is or a C 1 -C 6 alkyl group substituted by one or more R 1-3 ;
- R 1-1 is a C 1 -C 6 alkyl group which is unsubstituted or substituted by one or more R 1-1-1 ;
- R 1-2 is O
- Each R 1-1-1 is independently OR 1-1-1-1 ;
- R 1-1-1-1 is an unsubstituted C 1 -C 6 alkyl group
- Each R 1-3 is independently hydroxy, halogen or unsubstituted C 1 -C 6 alkyl
- X is -CR 1-6 R 1-7 -;
- R 1-6 and R 1-7 are independently hydrogen
- R2 and R3 and the atoms connected thereto form a 5-6 membered heteroaryl group, an unsubstituted 4-6 membered heterocycloalkyl group or an unsubstituted C4 - C6 cycloalkyl group, which is unsubstituted or substituted by one or more R2-1 ;
- the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-6 membered heteroaryl group are N or O, the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is O, the number of heteroatoms is 1 or 2;
- Each R 2-1 is independently an unsubstituted C 1 -C 6 alkyl group
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;
- L is a linker or an unsubstituted C 2 -C 6 alkenylene group
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R4-5 , a 5-12-membered heteroaryl substituted by one or more R4-6 , or an unsubstituted C1 - C6 alkoxyl group;
- the heteroatoms in the 4-12-membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- the heteroatoms in the 5-12-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, a 4-6 -membered heterocycloal
- Each R 4-5 is independently an unsubstituted C 1 -C 6 alkyl group
- Each of R 4-6 is independently cyano or unsubstituted C 1 -C 6 alkyl.
- Y is C
- R 1-1 is an unsubstituted C 1 -C 6 alkyl group
- R 1-2 is O
- X is -CR 1-6 R 1-7 -;
- R 1-6 and R 1-7 are independently hydrogen
- R2 and R3 and the atoms to which they are connected form an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4 - C6 cycloalkyl;
- the heteroatom in the 4-6 membered heterocycloalkyl is independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O; the number of heteroatoms is 1;
- A is an unsubstituted 5-12-membered heteroarylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12-membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;
- Q is an unsubstituted 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatoms in the 5-12-membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; the heteroatom in the 5-6-membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12-membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3 - C6 cycloalkyl, or a 5-12-membered heteroaryl substituted by one or more R4-6 ;
- the heteroatom in the 5-12-membered heteroaryl is independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
- R4 is an unsubstituted C2 - C6 alkynyl, an unsubstituted C3- C6 cycloalkyl, or a 5-6 -membered heteroaryl substituted by one or more R4-6 ;
- the heteroatom in the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1;
- Each of R 4-6 is independently cyano or unsubstituted C 1 -C 6 alkyl.
- R1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- X is methylene
- R4 is
- the present invention provides the following compound or a pharmaceutically acceptable salt thereof:
- the present invention also provides the use of the compound shown above or its pharmaceutically acceptable salt in the preparation of BRM ATPase inhibitors.
- the present invention also provides a pharmaceutical composition, which comprises the compound shown above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention also provides the use of the compound shown above or its pharmaceutically acceptable salt in the preparation of a drug for treating BRM ATPase-related diseases.
- the present invention also provides the use of the compound shown above or a pharmaceutically acceptable salt thereof in preparing a drug for treating melanoma, endometrial cancer, non-small cell lung cancer, esophageal gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.
- alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 1 -C 6 ); for example, C 1 -C 6 alkyl.
- alkynyl refers to a straight or branched monovalent hydrocarbon radical of two to twenty-two carbon atoms having at least one site of unsaturation, ie, a carbon-carbon sp triple bond; for example, C2 - C6 alkynyl.
- cycloalkyl refers to a saturated monocyclic group having a specified number of ring carbon atoms (e.g., C 3 - C 6 or C 4 -C 6 ), wherein the ring atoms consist only of carbon atoms, for example, C 3 - C 6 cycloalkyl or C 4 -C 6 cycloalkyl.
- heterocycloalkyl refers to a saturated monocyclic ring (e.g., 3-6, 4-6, or 4-12) with a specified number of ring atoms (e.g., 1, 2, or 3), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom or heteroatom group (1, 2, or 3 of N, O, and S). ), spirocyclic ring (e.g., ) or bridge ring (e.g. ), unsaturated and cyclic
- heterocycloalkylene refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as the term “heterocycloalkyl”.
- heteroaryl refers to a cyclic group with a specified number of ring atoms (e.g., 5-12 members or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (e.g., one, two, or more of N, O, and S), which is monocyclic or bicyclic.
- Monocyclic heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazole, furazolidinyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, for example,
- Bicyclic heteroaryl groups include, but are not limited to, 5-membered heteroarylene and 6-membered heteroarylene or 6-membered heteroarylene and 5-membered heteroarylene; for example,
- aryl refers to an aromatic group having a specified number of ring carbon atoms (eg, C 6 -C 10 ). Examples of aryl groups include, but are not limited to, phenyl.
- arylene refers to a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "aryl”.
- halogen refers to F, Cl or Br.
- heteroarylene refers to a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term “heteroaryl”.
- alkenyl refers to a linear or branched monovalent hydrocarbon group of two to twenty-two carbon atoms (eg, C 1 -C 6 alkenyl) having at least one site of unsaturation, ie, a carbon-carbon sp 2 double bond.
- alkenylene refers to a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term “alkenyl”.
- alkoxy refers to the group R X -O-, wherein R X is alkyl as defined above.
- the reagents and raw materials used in the present invention are commercially available.
- the positive and progressive effect of the present invention is that the compounds of the present invention have a strong inhibitory effect on BRM ATPase and have good application prospects in BRG1 gene mutation tumors.
- step 1
- EVO33109-A1 (257 mg, 1.0 mmol), Pd(dppf)Cl 2 -DCM (81 mg, 0.1 mmol), TEA (303 mg, 3.0 mmol), DMF (6 mL) and MeOH (3 mL) were added to a single-mouth bottle in sequence, and the reaction system was replaced with CO 3 times, and heated at 80°C with stirring overnight. After the reaction was completed, the system was cooled to room temperature, and water (30 mL) and EA (30 mL) were added.
- EVO33109-C1 160 mg, 0.68 mmol was suspended in MeOH (10 mL), H 2 O (10 mL) and CH 3 CN (10 mL), solid Oxone (1.24 g, 2.03 mmol) was added, and the reaction system was stirred at room temperature overnight. After the reaction, the reaction system was concentrated, and water (30 mL) and EA (30 mL) were added. The aqueous phase was extracted once with EA. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- EVO33109-C2 (20 mg, 0.075 mmol) was suspended in MeOH (1 mL), H 2 O (0.5 mL) and THF (1 mL), and solid LiOH ⁇ H 2 O (9 mg, 0.22 mmol) was added.
- the reaction system changed from a white turbid liquid to a light yellow turbid liquid, and then to a dark green clear liquid.
- EVO33109-C3 (20 mg, 0.078 mmol) and intermediate 1-A1 (22 mg, 0.063 mmol) were dissolved in DMF (3 mL), and TEA (40 mg, 0.39 mmol) and HATU (45 mg, 0.12 mmol) were added in sequence, and the reaction system was stirred at room temperature for 1 hour.
- step 1
- EVO33109-A1 180 mg, 0.70 mmol was dissolved in TFA (5 mL), and Et 3 SiH (406 mg, 3.50 mmol) was added. The reaction system was stirred at room temperature overnight. After the reaction was completed, it was concentrated, and EA (30 mL) and water (30 mL) were added to dilute it. The organic phase was washed with saturated NaHCO 3 solution, water and saturated sodium chloride solution once each, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product. The crude product was purified by medium-pressure normal phase column chromatography to obtain a colorless oil EVO33127-A1 (150 mg, yield: 88%), which turned into a white solid after long standing.
- EVO33127-A1 150 mg, 0.62 mmol was dissolved in CH 3 CN (6 mL) and H 2 O (6 mL), and Oxone (1.13 g, 1.85 mmol) was added, and solid precipitated.
- the reaction system was stirred at room temperature overnight. After the reaction was completed, it was concentrated, and EA (30 mL) and water (30 mL) were added to dilute it, and the aqueous phase was extracted once with EA.
- EVO33127-A2 (90 mg, 0.33 mmol), Pd(OAc) 2 (7 mg, 0.033 mmol), DCCP-2HBF 4 (20 mg, 0.033 mmol), K 2 CO 3 (135 mg, 0.99 mmol), H 2 O (0.1 mL) and DMSO (3 mL) were added to a single-mouth bottle in sequence.
- the reaction system was replaced with CO 3 times, and then heated to 100°C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature and filtered, and the filter cake was washed with water twice.
- EVO33127-A3 15 mg, 0.062 mmol
- intermediate 1-A1 22 mg, 0.062 mmol
- TEA 32 mg, 0.31 mmol
- HATU 35 mg, 0.093 mmol
- the reaction system was stirred at room temperature for 1 hour.
- the reaction system was quenched with water, extracted twice with EA, and the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- step 1
- EVO33168-A2 (380 mg, 1.23 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL) solution, solid Oxone (1.60 g, 2.46 mmol) was added, and the reaction was stirred overnight.
- step 1
- EVO33070-A1 (1 g, 3.17 mmol), CH 3 CN (50 mL) and NaSCH 3 (222 mg, 3.17 mmol) were added to the reaction flask and stirred overnight. After the reaction system was concentrated, EA (50 mL) and water (50 mL) were added for dilution, and the liquid was separated.
- EVO33070-A2 600 mg, 1.75 mmol
- CH 3 OH 6 mL
- THF 6 mL
- NaBH 4 133 mg, 3.50 mmol
- Cs 2 CO 3 (953 mg, 2.92 mmol), TBAB (47 mg, 0.15 mmol) and CH 3 CN (50 mL) were added to the reaction flask and heated to 85°C. Then, a CH 3 CN (5 mL) solution of EVO33070-A3 (440 mg, 1.46 mmol) was added dropwise to the reaction system. After the addition was completed, the mixture was stirred in an oil bath at 90°C overnight.
- EVO33070-A5 140 mg, 0.45 mmol
- Pd(OAc) 2 10 mg, 0.045 mmol
- DCCP-2HBF 4 27 mg, 0.045 mmol
- K 2 CO 3 185 mg, 1.34 mmol
- DMSO 5 mL
- H 2 O 0.2 mL
- the aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M), extracted three times with DCM/MeOH (10/1), the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- EVO33070-A6 (20 mg, 0.072 mmol) and intermediate 1-A1 (25 mg, 0.072 mmol) were dissolved in DMF (2 mL), and TEA (36 mg, 0.36 mmol) and HATU (55 mg, 0.14 mmol) were added in sequence.
- the reaction system was stirred at room temperature for 2 hours. Water was added to the reaction system to quench, and EA was extracted twice. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product. After purification by Prep-HPLC, EVO33070 (5 mg, yield: 11%) was obtained by freeze drying.
- step 1
- EVO33137-A1 (3.5 g, 14.76 mmol), Pd 2 (dba) 3 (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.95 mmol), Cs 2 CO 3 (14.44 g, 44.29 mmol), t-BuOH (6 mL) and toluene (60 mL) were added to a single-mouth bottle in sequence. After replacing with argon for 3 times, methyl thioacetate (6.65 g, 73.81 mmol) was added, and then replaced with argon once. The reaction system was heated to 100°C and stirred overnight.
- EVO33137-A2 (1 g, 4.90 mmol) was suspended in CH 3 CN (30 mL) and H 2 O (30 mL), and Oxone (8.99 g, 14.69 mmol) was added, and the reaction system was stirred at room temperature overnight.
- EVO33137-A4 130 mg, 0.58 mmol was dissolved in pyridine (3 mL), and Tf 2 O (495 mg, 1.75 mmol) was slowly added dropwise. After the addition was completed, the reaction system was warmed to room temperature and stirred overnight.
- EVO33137-A5 120 mg, 0.34 mmol
- Pd(OAc) 2 7.6 mg, 0.034 mmol
- DCCP-2HBF 4 21 mg, 0.034 mmol
- K 2 CO 3 140 mg, 1.02 mmol
- H 2 O 0.1 mL
- DMSO 3 mL
- EVO33137-A6 25 mg, 0.1 mmol
- intermediate 1-A1 35 mg, 0.1 mmol
- TEA 51 mg, 0.5 mmol
- HATU 76 mg, 0.2 mmol
- EVO33111-A1 (1.00 g, 3.36 mmol), sodium sulfite (667.74 mg, 5.38 mmol), sodium bicarbonate (451.74 mg, 5.38 mmol), water (10 mL) and 1,4-dioxane (10 mL) were added to the reaction flask and heated to 80°C in an oil bath. After the reaction was completed, EVO33111-A2 (1.20 g, yield: >99%) was prepared by medium pressure reverse phase.
- EVO33111-A2 (1.10 g, 1.93 mmol) and DMF (5 mL) were added to the reaction flask, and CH 3 I (821.50 mg, 5.79 mmol) was added dropwise at room temperature. After the reaction was completed, EVO33111-A3 (290 mg, yield: 27.1%) was prepared under medium pressure.
- EVO33111-A3 (290.00 mg, 1.05 mmol), palladium acetate (23.49 mg, 0.10 mmol), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) (63.86 mg, 0.10 mmol), potassium carbonate (433.88 mg, 3.14 mmol), DMSO (3 mL) and water (0.3 mL) were added to the reaction flask, CO was replaced 3 times, and the temperature was raised to 80°C. After the reaction was completed, EVO33111-A4 (20 mg, yield: 7.9%) was prepared under medium pressure.
- EVO33111-A4 (20.00 mg, 0.08 mmol), intermediate 1-A1 (28.85 mg, 0.08 mmol), HATU (47.09 mg, 0.12 mmol) and DMF (5 mL) were added to the reaction flask.
- DIPEA 42.68 mg, 0.33 mmol was added. After the reaction was completed, it was purified by Prep-HPLC and freeze-dried to obtain EVO33111 (13 mg, yield: 27.5%).
- step 1
- EVO33138-A1 100 mg, 0.46 mmol was dissolved in DMF (3 mL), and NaSCH 3 (479.44 mg, 1.37 mmol, 20% purity in H 2 O) was added, and the reaction system was stirred at room temperature overnight. The reaction system was quenched with water, extracted with EA, and the organic phases were combined, washed with water and saturated sodium chloride solution once each, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude colorless oil EVO33138-A2 (100 mg).
- EVO33138-A3 50 mg, 0.18 mmol
- Pd(OAc) 2 4 mg, 0.018 mol
- DCCP-2HBF 4 11 mg, 0.018 mmol
- K 2 CO 3 74 mg, 0.54 mmol
- H 2 O 0.1 mL
- DMSO 3 mL
- the aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M), and then extracted with DCM/MeOH (10/1) for 3 times.
- the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- EVO33138-A4 (16 mg, 0.065 mmol) and intermediate 1-A1 (23 mg, 0.065 mmol) were dissolved in DMF (3 mL), and TEA (33 mg, 0.33 mol) and HATU (50 mg, 0.13 mmol) were added in sequence. The reaction was stirred at room temperature for 1 hour.
- step 1
- EVO33173-A1 180 mg, 0.91 mmol
- hexamethyltin 596 mg, 1.82 mmol
- Pd(PPh 3 ) 4 105 mg, 0.091 mmol
- 1,4-dioxane 5 mL
- EVO33127-A3 (20 mg, 0.083 mmol) and EVO33173-A4 (23 mg, 0.083 mol) were dissolved in DMF (3 mL), and TEA (42 mg, 0.42 mmol) and HATU (63 mg, 0.17 mmol) were added in sequence, and the reaction system was stirred at room temperature for 1 hour.
- step 1
- intermediate 2 100 mg, 340.62 ⁇ mol
- EVO33174-A1 54 mg, 283.85 ⁇ mol
- freshly dried Cs 2 CO 3 solid (277 mg, 851.55 ⁇ mol)
- Ruphos 26 mg, 56.77 ⁇ mol
- Ruphos-pd-G 3 24 mg, 28.39 ⁇ mol
- anhydrous dioxane 5 mL
- the reference compound EVO33138 was prepared by prep-HPLC and lyophilized to obtain yellow solid EVO33163 (30 mg, yield: 75%).
- LCMS (ESI) m/z 604.4 [M+H] + . Purity: 99.20%.
- step 1
- EVO33110-A1 (1.2 g, 5.06 mmol) was dissolved in THF (20 mL), potassium tert-butoxide (1.70 g, 15.19 mmol) was added, and after the reaction was completed, it was washed with saturated sodium chloride solution (20 mL), and the organic phase was concentrated and EVO33110-A2 (400 mg, yield: 36.41%) was prepared under medium pressure.
- EVO33110-A2 (240 mg, 1.11 mmol) was dissolved in DMF (5 mL), sodium thiomethoxide (116.26 mg, 1.66 mmol) was added, and the temperature was raised to 120°C overnight. After the reaction was completed, water (50 mL) was added, EA (3*30 mL) was extracted, the organic phase was concentrated, and EVO33110-A3 (184 mg, yield: 67.88%) was prepared under medium pressure.
- EVO33110-A3 (184 mg, 750.60 ⁇ mol) was dissolved in acetonitrile (10 mL) and water (10 mL), and Oxone (460.87 mg, 750.60 ⁇ mol) was added, and the mixture was kept at 30°C overnight. After the reaction was completed, the mixture was filtered, acetonitrile was evaporated, water (50 mL) was added, and EA (3*30 mL) was added for extraction. The organic phase was concentrated to obtain EVO33110-A4 (110 mg, yield: 52.88%), and the crude product was used directly in the next step.
- EVO33110-A4 110 mg, 396.92 ⁇ mol was dissolved in DMSO (5 mL) and water (0.5 mL), and palladium acetate (17.82 mg, 79.38 ⁇ mol), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) (48.44 mg, 79.38 ⁇ mol) and potassium carbonate (164.57 mg, 1.19 mmol) were added, and the mixture was heated at 110 ° C overnight under CO atmosphere. After the reaction, EVO33110-A5 (41 mg, yield: 42.64%) was prepared by reverse phase.
- EVO33110-A5 (20 mg, 82.56 ⁇ mol) was dissolved in DMF (2 mL), and then intermediate 1-A1 (28.85 mg, 82.56 ⁇ mol), triethylamine (41.69 mg, 412.80 ⁇ mol) and HATU (69.06 mg, 181.63 ⁇ mol) were added and stirred overnight.
- water 50 mL was added to the reaction solution, and EA (3*30 mL) was used for extraction.
- the organic phase was concentrated and prepared under high pressure to obtain EVO33110 (14 mg, yield: 29.56%).
- LCMS (ESI) m/z 574.01 [M+H] + . Purity: 99.25%.
- step 1
- EVO33115-A1 (8 g, 30.42 mmol) was dissolved in methanol (150 mL) and concentrated sulfuric acid (14.92 g, 152.08 mmol) and refluxed overnight. After the reaction was completed, the solvent was evaporated, water (100 mL) was added, EA (3*50 mL) was extracted, the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, the organic phase was concentrated, and EVO33115-A2 (8.5 g, yield: 96.01%) was prepared under medium pressure.
- EVO33115-A2 (8.5 g, 29.20 mmol) was dissolved in anhydrous THF (50 mL), and lithium aluminum tetrahydride (2.44 g, 64.25 mmol) was added. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was filtered. Water (100 mL) was added to the filtrate, and the mixture was extracted with EA (3*50 mL). The organic phase was concentrated and EVO33115-A3 (4.5 g, yield: 65.56%) was prepared under medium pressure.
- EVO33115-A3 (4.6 g, 19.57 mmol) was dissolved in dichloromethane (50 mL), and manganese dioxide (8.17 g, 93.94 mmol) was added. After the raw material disappeared, the mixture was filtered, and the filtrate was taken. Triethylsilane (6.83 g, 58.71 mmol) and trifluoroacetic acid (10.71 g, 93.94 mmol) were added. After 2 hours, the reaction was completed. After evaporating the solvent, water (100 mL) was added, and EA (3*50 mL) was used for extraction. The organic phase was concentrated and EVO33115-A4 (3.6 g, yield: 84.76%) was prepared under medium pressure.
- EVO33115-A4 (220 mg, 1.01 mmol) was dissolved in DMF (5 mL), sodium thiomethoxide (355.24 mg, 5.07 mmol) was added, and the reaction temperature was raised to 100 ° C. After 2 hours, the reaction was completed, water (30 mL) was added, and EA (3*50 mL) was extracted. The organic phase was evaporated to dryness to obtain EVO33115-A5 (90 mg, yield: 36.22%), which was directly used in the next step.
- EVO33115-A5 (260 mg, 1.06 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and Oxone (3.26 g, 5.30mmol), then heated to 60°C. After 1 hour, the reaction was completed, acetonitrile was evaporated, water (30mL) was added, and EA (3*50mL) was extracted. The organic phase was evaporated to dryness to obtain EVO33115-A6 (290mg, yield: 98.66%), which was directly used in the next step.
- EVO33115-A6 (90 mg, 324.75 ⁇ mol) was added with DMSO (5 mL), water (0.5 mL), palladium acetate (14.58 mg, 64.95 ⁇ mol), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) (39.64 mg, 64.95 ⁇ mol) and potassium carbonate (134.65 mg, 974.26 ⁇ mol), and reacted at 100 °C overnight under CO atmosphere. After completion, EVO33115-A7 (10 mg, yield: 12.71%) was prepared by reverse phase.
- step 1
- EVO33124-A4 (176 mg, 0.604 mmol), Pd(OAc) 2 (14 mg, 0.06 mmol), DCCP-2HBF 4 (74 mg, 0.121 mmol), K 2 CO 3 (167 mg, 1.21 mmol), H 2 O (0.1 mL) and DMSO (3 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with CO 3 times, and then heated to 100°C and stirred overnight.
- step 1
- EVO33240-A1 130 mg, 454.28 ⁇ mol
- (2S, 6R)-2,6-dimethyl-4-(6-vinyl-2-pyridyl)morpholine 99.17 mg, 454.28 ⁇ mol
- Pd(OAc) 2 10.20 mg, 45.43 ⁇ mol
- tri-o-tolylphosphine 27.65 mg, 90.86 ⁇ mol
- triethylamine 137.91 mg, 1.36 mmol
- DMF 2 mL
- EVO33240-A2 50 mg, 118.05 ⁇ mol
- DCM 5 mL
- TFA 40.38 mg, 354.15 ⁇ mol
- the reaction was completed after monitoring by LC-MS.
- the mixture was concentrated under reduced pressure to remove most of the TFA and freeze-dried to obtain a yellow oil EVO33240-A3 (50 mg, crude product) which was directly used in the next step.
- LCMS (ESI) m/z 324.1 [M+H] + .
- step 1
- EVO33338-A5 565 mg, 2.19 mmol
- CH 3 CN 18 mL
- isoamyl nitrite 384.38 mg, 3.28 mmol, 439.29 ⁇ L
- LC-MS showed that the reaction was complete.
- the mixture was dried by spin-drying, MTBE (30 mL) was added, and the mixture was stirred for a while after ultrasonication. The mixture was filtered by suction, washed with a small amount of MTBE, and the filter cake was collected.
- intermediate 1-A1 25.95 mg, 67.26 ⁇ mol
- EVO33338-A8 (20 mg, 74.27 ⁇ mol)
- DMF 3 mL
- DIPEA 95.99 mg, 742.73 ⁇ mol, 129.37 ⁇ L
- HATU 33.89 mg, 89.13 ⁇ mol
- EA was added, and the mixture was washed with water and saturated sodium chloride solution in turn, and the organic phase was spin-dried.
- step 1
- EVO33341-A2 (30 mg, 0.109 mmol) and intermediate 1-A1 (38 mg, 0.109 mmol) were dissolved in DMF (3 mL), and DIPEA (42 mg, 0.326 mmol) and HATU (62 mg, 0.163 mmol) were added in sequence.
- the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction system was quenched with water, extracted twice with EA, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
- step 1
- compound 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester 800 mg, 3.12 mmol
- ethyl thio S-methyl ester (1.41 g, 15.62 mmol)
- tris(dibenzylideneacetone)dipalladium 286 mg, 312 ⁇ mol
- 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (361 mg, 624 ⁇ mol)
- potassium phosphate (1.99 g, 9.37 mmol) were added to a mixed solution of tert-butyl alcohol (0.5 mL) and toluene (5 mL) and reacted at 110° C.
- EVO33349-A4 25 mg, 0.103 mmol
- intermediate 1-A1 36 mg, 0.103 mmol
- DIPEA 40 mg, 0.311 mmol
- HATU 59 mg, 0.155 mmol
- step 1
- EVO33383-A1 400 mg, 1.54 mmol
- benzyl mercaptan 230.14 mg, 1.85 mmol
- DIPEA 598.67 mg, 4.63 mmol, 806.84 ⁇ L
- anhydrous 1,4-dioxane 5 mL
- Xantphos 178.69 mg, 308.82 ⁇ mol
- Pd 2 (dba) 3 141.39 mg, 154.41 ⁇ mol
- EVO33383-A3 60 mg, 215.31 ⁇ mol
- TEA 0.2 mL
- DCM 2 mL
- methylamine solution 0.2 mL, 2 M in THF
- EVO33383-A4 36 mg, 131.74 ⁇ mol
- MeOH 1.5 mL
- LiOH.H 2 O 22.11 mg, 526.97 ⁇ mol
- H 2 O 1.5 mL
- Methanol was removed by concentration under reduced pressure, and water (0.5 mL) was added.
- the pH was adjusted to 3 with 1N dilute hydrochloric acid to precipitate a white solid, which was filtered, and the filter cake was washed with water (1 mL*3).
- EVO33383-A5 21 mg, 81.01 ⁇ mol
- intermediate 1-A1 28.31 mg, 81.01 ⁇ mol
- DIPEA 52.35 mg, 405.04 ⁇ mol, 70.55 ⁇ L
- HATU 46.20 mg, 121.51 ⁇ mol
- anhydrous DMF 2 mL
- step 1
- EVO33500-A1 850 mg, 4.21 mmol
- SOCl 2 10 mL
- EVO33500-A2 700 mg, 3.46 mmol
- (2S, 6R)-2,6-dimethyl-4-(6-(trimethyltinyl)pyridin-2-yl)morpholine 1.2 g, 3.46 mmol
- Pd(dppf)Cl 2 253 mg, 0.34 mmol
- anhydrous 1,4-dioxane 10 mL
- the reaction was monitored by LC-MS. Water was added to quench, extracted with EA (50 mL x 3), and concentrated under reduced pressure.
- EVO33500-A3 (480 mg, 1.33 mmol), potassium N-tert-butylcarbonylmethyl trifluoroborate (474 mg, 2 mmol), cataCXium A-Pd-G2 (87 mg, 0.13 mmol), K 3 PO 4 (564 mg, 2.66 mmol), 1,4-dioxane (10 mL) and water (1 mL) were stirred in an oil bath at 80°C. LC-MS monitored the completion of the reaction, with a small amount of raw materials remaining. Water was added to quench, and EA (50 mL x 3) was used for extraction.
- EVO33500-A5 60 mg, 0.17 mmol
- EVO33138-A4 41 mg, 0.17 mmol
- DMF 3 mL
- EDCl 65 mg, 0.34 mmol
- HOBt 46 mg, 0.34 mmol
- DIEA 44 mg, 0.34 mmol
- step 1
- EVO33389-A1 (364 mg, 1.73 mmol) and anhydrous DCM (10 mL) were added to the reaction flask, and the temperature was cooled to -10°C in a cold bath; PBr 3 (937.57 mg, 3.46 mmol, 325.55 ⁇ L) was added with a temperature control of ⁇ 5°C, and the temperature was naturally raised to room temperature and stirred for 2 hours after the addition.
- EVO33389-A2 (322 mg, 1.18 mmol), anhydrous ACN (10 mL) and TMSCN (233.97 mg, 2.36 mmol, 295.04 ⁇ L) were added to the reaction flask, the ice-water bath was cooled to 0-5°C, TBAF solution (1.0 M in THF, 2.5 mL) was slowly added dropwise, and the temperature was naturally raised to room temperature for 2 hours.
- EVO33389-A3 50 mg, 228.11 ⁇ mol
- MeOH (1 mL) and H 2 O (1 mL) were added to the reaction flask and stirred at room temperature for 16 hours.
- EVO33389-A4 21 mg, 102.36 ⁇ mol
- EVO33070A7 35.77 mg, 102.36 ⁇ mol
- anhydrous DMF 2 mL
- TEA 51.79 mg, 511.78 ⁇ mol, 71.33 ⁇ L
- HATU 58.38 mg, 153.53 ⁇ mol
- step 1
- EVO33381-B1 124 mg, 415.67 ⁇ mol
- THF 3 mL
- a methanol solution of NaOMe 5.4 M in methanol, 623.51 ⁇ mol
- the mother liquor was directly used in the next reaction.
- EVO33392-A3 29 mg, 105.74 ⁇ mol
- intermediate 1-A1 36.95 mg, 105.74 ⁇ mol
- anhydrous DMF 2 mL
- DIPEA 68.33 mg, 528.72 ⁇ mol, 92.09 ⁇ L
- HATU 60.31 mg, 158.62 ⁇ mol
- step 1
- EVO33522-A2 (30 mg, 84.55 ⁇ mol), DMSO (1.0 mL), methylhydrazine sulfate (243 mg, 1.69 mmol), K 2 CO 3 (350 mg, 2.54 mmol), and water (1.0 mL) were added to the microwave tube, and the tube was sealed. Eight batches of materials were added. Stir for 0.5 h, and then heated to 110 ° C and stirred for 48 hours. After cooling to room temperature, methylhydrazine sulfate (243 mg, 1.69 mmol) and K 2 CO 3 (350 mg, 2.54 mmol) were added to each microwave tube, and the tube was sealed.
- EVO33522-A1 56 mg, 137.40 ⁇ mol
- DMF 1 mL
- DIPEA 88 mg, 687.00 ⁇ mol
- 7-ethylsulfonebenzo[d][1,3]dioxo-5-carboxylic acid 28 mg, 109.92 ⁇ mol
- stirring was continued for 10 minutes
- EDCI 53 mg, 275.00 ⁇ mol
- HOBt (19 mg, 140.74 ⁇ mol
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Abstract
一种稠环化合物、其用途及含其的药物组合物,该化合物对BRM ATPase有较强的抑制作用,在BRG1基因突变肿瘤中有很好的应用前景。
Description
本发明涉及一种稠环化合物、其用途及含其的药物组合物。
癌症是全球人类死亡的主要原因之一,主要由遗传和表观遗传改变引起。这些改变会影响正常细胞的基因表达或信号通路,导致正常细胞转化为恶性肿瘤细胞。肿瘤样本的癌症基因组测序结果发现,人类ATP依赖性染色质重塑复合物SWI/SNF的亚基基因在>20%的人类肿瘤中发生突变,且多为功能丧失型突变。
BRM(Protein brahma homolog)为SWI/SNF复合物的ATPase亚基,与同是ATPase亚基的BRG1(Protein brahma homolog 1)相互排斥。ATPase水解ATP为SWI/SNF复合物提供能量,使其行使调控基因表达和关键细胞过程的功能,对维持细胞活力具有重要作用。
BRG1基因(SMARCA4)在多癌症种类中发生高突变,包括但不限于黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌、结直肠癌。相比之下,BRM基因(SMARCA2)很少发生突变。BRM与BRG1在参与调控细胞周期与激素作用通路、DNA损伤修复应答等细胞活力相关的功能方面存在互补和冗余,因此在BRG1基因缺陷的肿瘤细胞中,BRM可以补偿BRG1的功能损失,维持SWI/SNF复合物的功能,以支持细胞活力。
BRM与BRG1的合成致死性,在多种类型的肿瘤细胞的体外和体内疾病模型中都得到了验证:在BRG1基因缺陷的细胞中降解BRM、或沉默BRM基因表达,均会抑制体外肿瘤细胞增殖和体内肿瘤生长;BRG1基因缺陷的肿瘤细胞对BRM基因的shRNA极为敏感;抑制BRM的ATPase活性,能够抑制BRG1基因缺陷肿瘤的体内生长…因此,在BRG1基因突变肿瘤中,BRM是一个有潜力的药物治疗靶点。
相比BRG1,药物干扰BRM毒性风险更低。BRM-SWI/SNF复合物的ATPase酶活性和染色质重塑能力远低于BRG1-SWI/SNF复合物,在正常细胞中,SWI/SNF复合物主要依赖BRG1行使功能。纯合敲除BRG1基因不会引起小鼠胚胎致死和影响成年小鼠的生殖能力,这与纯合敲除BRM基因的表现相反。
因此,靶向抑制BRM ATPase活性有潜力成为BRG1基因突变肿瘤的新型治疗方案。
目前还未有BRM ATPase抑制剂药物进入临床阶段,但已有BRM ATPase抑制剂正在临床前研发过程中,Foghorn近期披露的专利WO2022103899中公开了多个高选择性的BRM ATPase抑制剂,结构示例如下:
发明内容
本发明所要解决的技术问题是现有的BRM ATPase抑制剂种类较少,为此,本发明提供了一种稠环化合物I或其药学上可接受的盐。该稠环化合物对BRM ATPase有较强的抑制作用,在BRG1基因突变肿瘤中有很好的应用前景。
本发明提供了一种如式I所示的化合物或其药学上可接受的盐,
其中,
Y为C或N;
R1为羟基、氰基、卤素、氨基、氘、未取代或被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基;所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代或被1个或多个氘取代的C3-C6的环烷基或-NR1-1-2R1-1-3;
R1-2为O或NR1-2-1;R1-2-1为氢或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R1-1-1独立地为OR1-1-1-1、未取代或被1个或多个氘取代的C1-C6的烷基或氘;
R1-1-1-1为氢或未取代或被1个或多个氘取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R1-3独立地为羟基、氰基、卤素、氨基、未取代或被1个或多个氘取代的C1-C6的烷基或氘;
各个R1-4和R1-5独立地为羟基、氘或未取代或被1个或多个氘取代的C1-C6的烷基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢、氘、卤素或未取代或被1个或多个氘取代的C1-C6的烷基;
R1-8为氢或未取代或被1个或多个氘取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代或被1个或多个R2-4取代的C6-C10的芳基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O
和S中的一种或多种,杂原子数为1个、2个或3个;
各个R2-1独立地为氘、卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-1和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;
各个R2-2独立地为氘、卤素、未取代或被1个或多个R2-2-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;
各个R2-3独立地为氘、卤素、未取代或被1个或多个R2-3-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-3和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;
各个R2-4独立地为氘、卤素、未取代或被1个或多个R2-4-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-4和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;
R2-1-1、R2-2-1、R2-3-1和R2-4-1独立地为氘或羟基;
A为未取代或被1个或多个氘取代的C6-C10的亚芳基、未取代或被1个或多个氘取代的5-12元的亚杂芳基或未取代或被1个或多个氘取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
L为连接健、未取代或被1个或多个氘取代的C2-C6的亚烯基或未取代或被1个或多个氘取代的C1-C6的亚烷基;
Q为未取代或被1个或多个R3-1取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代或被一个或多个R3-1取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素或氘;
R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代或被一个或多个R4-2取代的C2-C6的烯基、未取代或被一个或多个R4-3取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代或被一个或多个R4-7取代的C1-C6的烷氧基或-NR4-9R4-8;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R4-1独立地为氘、卤素、羟基、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;
各个R4-2独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R4-3独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R4-4独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R4-5独立地为氘、卤素、羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5-
2R4-5-3或未取代或被1个或多个氘取代的C1-C6的烷氧基;
各个R4-5-1独立地为氘、羟基或卤素;
R4-5-2和R4-5-3独立地为氢或未取代或被1个或多个氘取代的C1-C6的烷基;
各个R4-6独立地为氘、卤素、氰基、羟基、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;
各个R4-7独立地为氘、卤素、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;
R4-9和R4-8独立地为氢、未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代或被1个或多个氘取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R4-8-1独立地为氘、羟基、未取代或被一个或多个R4-8-1-1取代的C1-C6的烷氧基或OR4-8-1-2;
各个R4-8-1-1独立地为氘或未取代或被1个或多个氘取代的C3-C6的环烷基;
各个R4-8-1-2独立地为未取代或被1个或多个氘取代的C3-C6的环烷基。
某一优选方案中,如式I化合物中,某些基团的定义可如下所述,其他基团的定义可如其他任一方案所述(以下简称“在某一方案中”)。
在某一方案中,R1中,所述多个为2个、3个、4个、5个、6个或7个。
在某一方案中,R1中,所述C1-C6的烷基为甲基、乙基、丙基、异丙基或异丁基。
在某一方案中,R1中,所述“未取代或被1个或多个R1-4取代的C3-C6的环烷基”中;所述C3-C6的环烷基为环丁基,例如,
在某一方案中,R1中,所述3-6元的杂环烷基中的杂原子为N、O或S,优选为O,所述3-6元的杂环烷基中的杂原子数优选为1个。
在某一方案中,R1中,所述“未取代或被1个或多个R1-5取代的3-6元的杂环烷基”中;所述3-6元的杂环烷基为4元杂环烷基,例如,
在某一方案中,R1-1中,所述“未取代或被1个或多个R1-1-1取代的C1-C6的烷基”中;所述多个为2个。
在某一方案中,R1-1中,所述C1-C6的烷基为甲基、乙基或丙基。
在某一方案中,R1-1中,所述C3-C6的环烷基为环丙基。
在某一方案中,R1-1-1中,所述C1-C6的烷基为甲基。
在某一方案中,R1-1-1-1中,所述C1-C6的烷基为甲基。
在某一方案中,R1-1-2和R1-1-3中,所述C1-C6的烷基为甲基。
在某一方案中,R1-3中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R1-3中,所述“未取代或被1个或多个氘取代的C1-C6的烷基”中;所述多个为2个或3个。
在某一方案中,R1-3中,所述C1-C6的烷基为甲基或乙基。
在某一方案中,R1-6和R1-7中,所述C1-C6的烷基为甲基。
在某一方案中,R1-8中,所述C1-C6的烷基为甲基。
在某一方案中,R2和R3中,所述5-6元的杂芳基中的杂原子独立地选自N、O和S的一种或两种,杂原子数为1个、2个或3个。
在某一方案中,R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基”中;所述5-6元的杂芳基为5元的杂芳基,例如,
在某一方案中,R2和R3中,所述4-6元的杂环烷基中的杂原子独立地选自N或O中的一种或两种,杂原子数优选为1个或2个。
在某一方案中,R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-2取代的4-6元的杂环烷基”中;所述4-6元的杂环烷基为5-6元的杂环烷基,例如,
在某一方案中,R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-3取代的C4-C6的环烷基”中;所述C4-C6的环烷基为环戊烷。
在某一方案中,R2和R3中,所述C6-C10的芳基为苯基。
在某一方案中,R2-1中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R2-1中,所述C1-C6的烷基为甲基或乙基。
在某一方案中,R2-2中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R2-2中,所述C3-C6的环烷基为环丙基。
在某一方案中,A中,所述亚芳基为亚苯基。
在某一方案中,A中,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个。
在某一方案中,A中,所述5-12元的亚杂芳基为6元亚杂芳基、6元亚杂芳基并5元亚杂芳基或6元亚杂芳基并6元亚杂芳基,例如,
在某一方案中,A中,所述5-12元的亚杂环烷基中的杂原子独立地为N;杂原子数优选为1个。
在某一方案中,A中,所述5-12元的亚杂环烷基为6元亚杂芳基并6元亚杂环烷基,例如,
在某一方案中,L中,所述C2-C6的亚烯基为乙烯基,例如,
在某一方案中,Q中,所述C6-C10的亚芳基为亚苯基。
在某一方案中,Q中,所述5-12元的亚杂芳基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个。
在某一方案中,Q中,所述“未取代或被一个或多个R3-1取代的5-12元的亚杂芳基”中;所述5-12元的亚杂芳基为6元亚杂芳基、5元亚杂芳基并6元亚芳基或6元亚杂芳基并5元亚杂芳基,例如,
在某一方案中,Q中,所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个。
在某一方案中,Q中,所述5-12元的亚杂环烷基为6元亚杂芳基并6元亚杂环烷基,例如,
在某一方案中,R3-1中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R4中,所述“未取代或被一个或多个R4-1取代的C1-C6的烷基”中;所述C1-C6的烷基为乙基,例如,
在某一方案中,R4中,所述C2-C6的炔基为乙炔基。
在某一方案中,R4中,所述“未取代或被一个或多个R4-4取代的C3-C6的环烷基”中;所述多个为两个。
在某一方案中,R4中,所述“未取代或被一个或多个R4-4取代的C3-C6的环烷基”中;所述C3-C6的环烷基为环丙基或环丁基,例如,
在某一方案中,R4中,所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或两种,杂原子数优选为1个或2个。
在某一方案中,R4中,所述未取代或被一个或多个R4-5取代的4-12元的杂环烷基中;所述多个为两个。
在某一方案中,R4中,所述“未取代或被一个或多个R4-5取代的4-12元的杂环烷基”中;所述
4-12元的杂环烷基为4-7元的杂环烷基或7-9元双桥环,例如,
在某一方案中,R4中,所述5-12元的杂芳基中的杂原子为N,杂原子数优选为1个或2个。
在某一方案中,R4中,所述“未取代或被一个或多个R4-6取代的5-12元的杂芳基”中;所述多个为两个。
在某一方案中,R4中,所述“未取代或被一个或多个R4-6取代的5-12元的杂芳基”中;所述5-12元的杂芳基为5元或6元杂芳基,例如,
在某一方案中,R4中,所述C1-C6的烷氧基为乙氧基,例如,
在某一方案中,R4-1中,所述C1-C6的烷氧基为甲氧基。
在某一方案中,R4-4中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R4-5中,所述C1-C6的烷基为甲基。
在某一方案中,R4-5中,所述C1-C6的烷氧基为甲氧基。
在某一方案中,R4-5-2和R4-5-3中,所述C1-C6的烷基为甲基。
在某一方案中,R4-6中,所述卤素为F、Cl或Br,优选为F。
在某一方案中,R4-6中,所述C1-C6的烷基为甲基。
在某一方案中,R4-9和R4-8中所述C1-C6的烷基为甲基或乙基。
在某一方案中,R4-9和R4-8中,所述4-6元的杂环烷基中的杂原子为O,杂原子数优选为1个。
在某一方案中,R4-9和R4-8中,所述4-6元的杂环烷基为5元或6元杂环烷基。
在某一方案中,R4-8-1-2中,所述C3-C6的环烷基为环丙基。
在某一方案中,Y为C或N;较佳地为C。
在某一方案中,R1为被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基;所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;进一步较佳地为或被1个或多个R1-3取代的C1-C6的烷基;更进一步较佳地为
在某一方案中,R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代的C3-C6的环烷基或-NR1-1-2R1-1-3;较佳地为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;进一步较佳地为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;更进一步较佳地为未取代的C1-C6的烷基。
在某一方案中,R1-2为O或NR1-2-1;较佳地为O。
在某一方案中,R1-2-1为氢。
在某一方案中,各个R1-1-1独立地为OR1-1-1-1、未取代的C1-C6的烷基或未取代的C1-C6的烷氧基;较佳地为OR1-1-1-1或未取代的C1-C6的烷基;进一步较佳地为未取代的C1-C6的烷基。
在某一方案中,R1-1-1-1为氢或未取代的C1-C6的烷基;较佳地为未取代的C1-C6的烷基。
在某一方案中,R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基。
在某一方案中,各个R1-3独立地为羟基、氰基、卤素、氨基、未取代的C1-C6的烷基或氘;较佳地为羟基、氰基、卤素、未取代的C1-C6的烷基或氘;进一步较佳地为羟基、氰基、卤素或未取代的C1-C6的烷基;更进一步较佳地为羟基或卤素。
在某一方案中,各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;较佳地为羟基、卤素或未取代的C1-C6的烷基。
在某一方案中,各个R1-4和R1-5独立地为羟基。
在某一方案中,X为-CR1-6R1-7-或-NR1-8-;较佳地为-CR1-6R1-7-。
在某一方案中,R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;较佳地为氢。
在某一方案中,R1-8为未取代的C1-C6的烷基。
在某一方案中,R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代的C6-C10的芳基;较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;进一步较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;更进一步较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;还可更进一步较佳地为未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个。
在某一方案中,各个R2-1独立地为卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基或氧代基(=O);较佳地为卤素或未取代的C1-C6的烷基;进一步较佳地为未取代的C1-C6的烷基。
在某一方案中,各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-
2和与之相连的碳原子形成C3-C6的环烷基;较佳地为氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;进一步较佳地为氧代基(=O)。
在某一方案中,各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);较佳地为卤素。
在某一方案中,各个R2-3独立地为氧代基(=O)。
在某一方案中,R2-1-1为羟基。
在某一方案中,A为未取代的C6-C10的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基;较佳地为未取代的5-12元的亚杂芳基;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个。
在某一方案中,L为连接健或未取代的C2-C6的亚烯基;较佳地为连接健。
在某一方案中,Q为未取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;较佳地为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;进一步较佳地为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个。
在某一方案中,各个R3-1独立地为卤素。
在某一方案中,R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代的C1-C6的烷氧基或-NR4-9R4-8;较佳地为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;进一步较佳地为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;更进一步较佳地为未取代的C2-C6的炔基、未取代的C3-C6的环烷基或被一个或多个R4-6取代的5-12元的杂芳基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个。
在某一方案中,各个R4-1独立地为未取代的C1-C6的烷氧基。
在某一方案中,各个R4-4独立地为卤素。
在某一方案中,各个R4-5独立地为羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5-2R4-5-3或未取代的C1-C6的烷氧基;较佳地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;进一步较佳地为未取代的C1-C6的烷氧基。
在某一方案中,各个R4-5-1独立地为羟基。
在某一方案中,R4-5-2和R4-5-3独立地为未取代的C1-C6的烷基。
在某一方案中,各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;较佳地为氰基或未取代的C1-C6的烷基。
在某一方案中,R4-9和R4-8独立地为未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个。
在某一方案中,各个R4-8-1独立地为OR4-8-1-2。
在某一方案中,各个R4-8-1-2独立地为未取代的C3-C6的环烷基。
在某一方案中,
Y为C或N;
R1为被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基,所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代的C3-C6的环烷基或-NR1-1-2R1-1-
3;
R1-2为O或NR1-2-1;R1-2-1为氢;
各个R1-1-1独立地为OR1-1-1-1、未取代的C1-C6的烷基或未取代的C1-C6的烷氧基;
R1-1-1-1为氢或未取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、氰基、卤素、氨基、未取代的C1-C6的烷基或氘;
各个R1-4和R1-5独立地为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代的C6-C10的芳基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R2-1独立地为卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基或氧代基(=O);
各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;
各个R2-3独立地为氧代基(=O);
R2-1-1为羟基;
A为未取代的C6-C10的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代的C1-C6的烷氧基或-NR4-9R4-8;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R4-1独立地为未取代的C1-C6的烷氧基;
各个R4-4独立地为卤素;
各个R4-5独立地为羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5-2R4-5-3或未取代的C1-C6的烷氧基;
各个R4-5-1独立地为羟基;
R4-5-2和R4-5-3独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;较佳地为氰基或未取代的C1-C6的烷基;
R4-9和R4-8独立地为未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
各个R4-8-1独立地为OR4-8-1-2;
各个R4-8-1-2独立地为未取代的C3-C6的环烷基。
在某一方案中,
Y为C或N;
R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;
R1-2为O或NR1-2-1;R1-2-1为氢;
各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;
R1-1-1-1为氢或未取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、氰基、卤素、未取代的C1-C6的烷基或氘;
各个R1-4为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;
各个R2-1独立地为卤素或未取代的C1-C6的烷基;
各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;
各个R2-3独立地为氧代基(=O);
A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;
R4-1独立地为未取代的C1-C6的烷氧基;
各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;
各个R4-5-1独立地为羟基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基。
在某一方案中,
Y为C或N;
R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;
R1-2为O或NR1-2-1;R1-2-1为氢;
各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;
R1-1-1-1为未取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、氰基、卤素或未取代的C1-C6的烷基;
各个R1-4为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;
各个R2-3独立地为氧代基(=O);
A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的
杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;
R4-1独立地为未取代的C1-C6的烷氧基;
各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;
各个R4-5-1独立地为羟基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基。
在某一方案中,
Y为C或N;
R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;
R1-2为O或NR1-2-1;R1-2-1为氢;
各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;
R1-1-1-1为未取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、氰基、卤素或未取代的C1-C6的烷基;
各个R1-4为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;
各个R2-3独立地为氧代基(=O);
A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;
R4-1独立地为未取代的C1-C6的烷氧基;
各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;
各个R4-5-1独立地为羟基;
各个R4-6独立地为氰基或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;
R1-2为O或NR1-2-1;R1-2-1为氢;
各个R1-1-1独立地为未取代的C1-C6的烷基;
R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基或卤素;
各个R1-4为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元的杂芳基中的杂原子独立地选自N和S中的一种或两种;杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
各个R2-2独立地为氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;
R1-2为O;
各个R1-1-1独立地为未取代的C1-C6的烷基;
各个R1-3独立地为卤素;
各个R1-4为羟基;
X为-CR1-6R1-7-或-NR1-8-;
R1-6和R1-7独立地为氢;
R1-8为未取代的C1-C6的烷基;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元的杂芳基中的杂原子为N;杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
各个R2-2独立地为氧代基(=O);
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为或未取代或被1个或多个R1-3取代的C1-C6的烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;
R1-2为O;
各个R1-1-1独立地为OR1-1-1-1;
R1-1-1-1为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;
X为-CR1-6R1-7-;
R1-6和R1-7独立地为氢;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O;杂原子数为1个或2个;
各个R2-1独立地为卤素或未取代的C1-C6的烷基;
各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为或被1个或多个R1-3取代的C1-C6的烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;
R1-2为O;
各个R1-1-1独立地为OR1-1-1-1;
R1-1-1-1为氢或未取代的C1-C6的烷基;
各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;
X为-CR1-6R1-7-;
R1-6和R1-7独立地为氢;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O;杂原子数为1个或2个;
各个R2-1独立地为卤素火或未取代的C1-C6的烷基;
各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);
A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂
原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为或被1个或多个R1-3取代的C1-C6的烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;
R1-2为O;
各个R1-1-1独立地为OR1-1-1-1;
R1-1-1-1为未取代的C1-C6的烷基;
各个R1-3独立地为羟基、卤素或未取代的C1-C6的烷基;
X为-CR1-6R1-7-;
R1-6和R1-7独立地为氢;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O;杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
各个R2-2独立地为卤素;
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
各个R3-1独立地为卤素;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为或被1个或多个R1-3取代的C1-C6的烷基;
R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;
R1-2为O;
各个R1-1-1独立地为OR1-1-1-1;
R1-1-1-1为未取代的C1-C6的烷基;
各个R1-3独立地为羟基、卤素或未取代的C1-C6的烷基;
X为-CR1-6R1-7-;
R1-6和R1-7独立地为氢;
R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元的杂芳基中的杂原子为N或
O,杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个或2个;
各个R2-1独立地为未取代的C1-C6的烷基;
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;
L为连接健或未取代的C2-C6的亚烯基;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-5独立地为未取代的C1-C6的烷基;
各个R4-6独立地为氰基或未取代的C1-C6的烷基。
在某一方案中,
Y为C;
R1为
R1-1为未取代的C1-C6的烷基;
R1-2为O;
X为-CR1-6R1-7-;
R1-6和R1-7独立地为氢;
R2和R3与其相连的原子形成未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O;杂原子数为1个;
A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;
L为连接健;
Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;
R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、或被一个或多个R4-6取代的5-12元的杂芳基;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、或被一个或多个R4-6取代的5-6元的杂芳基;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;
各个R4-6独立地为氰基或未取代的C1-C6的烷基。
在某一方案中,R1为
在某一方案中,X为亚甲基、
在某一方案中,为
在某一方案中,A为
在某一方案中,L为
在某一方案中,Q为
在某一方案中,R4为
本发明提供了如下的化合物或其药学上可接受的盐:
本发明还提供了如上所示的化合物或其药学上可接受的盐在制备BRM ATPase抑制剂中的用途。
本发明还提供了一种药物组合物,其包含如上所示的化合物或其药学上可接受的盐、以及药学上可接受的载体。
本发明还提供了如上所示的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗BRM ATPase相关的疾病。
本发明还提供了如上所示的化合物或其药学上可接受的盐在制备药物中用途,所述药物用于治疗黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌或结直肠癌。
如本文所述,术语“药学上可接受的盐”是指本发明的化合物的药学上可接受的有机或无机盐。
术语“烷基”是指具有指定碳原子数(例如,C1-C6)的、直链或支链的、饱和的一价烃基;例如,C1-C6的烷基。
术语“炔基”是指具有至少一个不饱和位置即碳-碳sp三键的二到二十二个碳原子的直链或支链的一价烃基;例如,C2-C6的炔基。
术语“环烷基”是指具有指定的环碳原子数(例如,C3-C6或C4-C6)、环原子仅由碳原子组成的饱和的单环基团。例如,C3-C6的环烷基或C4-C6的环烷基。
术语“杂环烷基”是指具有指定环原子数(例如3-6元、4-6元或4-12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子或杂原子基团种类(N、O和S中的1种、2种或3种)的饱和单环(例如,)、螺环(例如,)或桥环(例如,),不饱和并环
术语“亚杂环烷基”是指二价基团,其通过两个单键与分子其余部分相连,其余定义同术语“杂环烷基”。术语“杂芳基”是指具有指定环原子数(例如,5-12元或5-6元)的、指定杂原子数(例如,1个、2个或3个)的、指定杂原子种类(例如,N、O和S中的一种、两种或多种)的环状基团,其为单环或双环。单环杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、三氮唑、呋咱噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基,例如,
双环杂芳基包括但不限于5元亚杂芳基并6元亚芳基或6元亚杂芳基并5元亚杂芳基;例如,
术语“芳基”是指具有指定环碳原子数(例如,C6-C10)的芳香基团。芳基的实例包括不限于苯基。
术语“亚芳基”是指二价基团,其通过两个单键与分子其余部分相连,其余定义同术语“芳基”。
术语“卤素”是指F、Cl或Br。
术语“亚杂芳基”是指二价基团,其通过两个单键与分子其余部分相连,其余定义同术语“杂芳基”。
术语“烯基”是指具有至少一个不饱和位置即碳-碳sp2双键的二到二十二个碳原子的直链或支链的一价烃基(例如,C1~C6烯基)。
术语“亚烯基”是指二价基团,其通过两个单键与分子其余部分相连,其余定义同术语“烯基”。
术语“烷氧基”是指基团RX-O-,其中,RX为上文所定义的烷基。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明化合物对BRM ATPase有较强的抑制作用,在BRG1基因突变肿瘤中有很好的应用前景。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1 EVO33109
第1步:
室温下,将5-溴-7-氟-1-茚酮(1g,4.37mmol)溶于DMF(15mL)中,加入NaSCH3(2.29g,6.55mmol,20%purity)的水溶液,反应体系在室温下搅拌过夜。反应体系中加水稀释,EA萃取1次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=5-50%)得白色固体EVO33109-A1(700mg,收率:62%)。
第2步:
室温下,单口瓶中依次加入EVO33109-A1(257mg,1.0mmol),Pd(dppf)Cl2-DCM(81mg,0.1mmol),TEA(303mg,3.0mmol),DMF(6mL)和MeOH(3mL),反应体系用CO置换3次,80℃加热搅拌过夜。反应结束后,体系冷却到室温,加入水(30mL)和EA(30mL),水相用EA萃取1次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=10-50%)得白色固体EVO33109-C1(160mg,收率:67%),LCMS(ESI)m/z=237.1[M+H]+。
第3步:
室温下,将EVO33109-C1(160mg,0.68mmol)悬浮在MeOH(10mL),H2O(10mL)和CH3CN(10mL)中,加入固体Oxone(1.24g,2.03mmol),反应体系在室温下搅拌过夜。反应结束后,反应体系浓缩,加入水(30mL)和EA(30mL),水相用EA萃取1次,有机相合并后,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(DCM/EA=0-10%)得白色固体EVO33109-C2(150mg,收率:82%),1H NMR(400MHz,CDCl3)δ8.72(s,1H),8.42(s,1H),4.00(s,3H),3.45(s,3H),3.31-3.28(m,2H),2.90-2.87(m,2H)。
第4步:
室温下,将EVO33109-C2(20mg,0.075mmol)悬浮于MeOH(1mL)、H2O(0.5mL)和THF(1mL)中,加入固体LiOH·H2O(9mg,0.22mmol),反应体系从白色浑浊液,慢慢变为淡黄色浑浊液,再变为深绿色澄清液,反应体系在室温下搅拌1小时。反应结束后,反应体系用稀HCl(1M)调pH=3–5,反应体系浓缩后得黑色固体EVO33109-C3(25mg,粗品),LCMS(ESI)m/z=253.1[M-H]-。
第5步:
室温下,将中间体1(30mg,0.067mmol)溶于1,4-二氧六环(0.5mL)中,再加入氯化氢的1,4-二氧六环溶液(3mL),反应体系在室温下搅拌1小时。反应体系浓缩得粗品黄色固体中间体1-A1(22mg,收率:95%),LCMS(ESI)m/z=350.4[M+H]+。
第6步:
室温下,将EVO33109-C3(20mg,0.078mmol)和中间体1-A1(22mg,0.063mmol)溶于DMF(3mL)中,依次加入TEA(40mg,0.39mmol)和HATU(45mg,0.12mmol),反应体系在室温下搅拌1小时。反应加水淬灭,用EA萃取2次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩,中压正相柱层析纯化(DCM/EA=10-50%;然后DCM/10%MeOH=10-30%)得粗品,再用Prep-HPLC制备,冻干得淡黄色固体EVO33109(7mg,收率:15%),LCMS(ESI)m/z=586.1[M+H]+,纯度:99.3%,1H NMR(400MHz,DMSO-d6)δ9.75(t,J=5.8Hz,1H),9.41(s,1H),8.70-8.60(m,2H),8.50-8.47(m,2H),7.90(d,J=7.4Hz,2H),7.84(s,1H),7.78–7.72(m,1H),7.03(d,J=8.8Hz,1H),4.84(d,J=5.8Hz,2H),4.31(d,J=12.4Hz,2H),3.72-3.62(m,2H),3.47(s,3H),3.30-3.25(m,4H),2.87-2.82(m,2H),1.21(d,J=6.2Hz,6H)。
实施例2 EVO33127
第1步:
室温下,将EVO33109-A1(180mg,0.70mmol)溶于TFA(5mL)中,再加入Et3SiH(406mg,3.50mmol)。反应体系在室温下搅拌过夜。反应结束后,浓缩,加入EA(30mL)和水(30mL)稀释,有机相用饱和NaHCO3溶液、水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化得无色油状物EVO33127-A1(150mg,收率:88%),久置变为白色固体。1H NMR(400MHz,CDCl3)δ7.14(s,1H),7.04(s,1H),2.91(t,J=7.2Hz,2H),2.77(t,J=7.2Hz,2H),2.46
(s,3H),2.12-2.05(m,2H)。
第2步:
室温下,将EVO33127-A1(150mg,0.62mmol)溶于CH3CN(6mL)和H2O(6mL),再加入Oxone(1.13g,1.85mmol),有固体析出。反应体系在室温下搅拌过夜。反应结束后,浓缩,加入EA(30mL)和水(30mL)稀释,水相用EA萃取1次。有机相合并后,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品白色固体EVO33127-A2(140mg,收率:82%),1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.61(s,1H),3.22(t,J=7.6Hz,2H),3.04(s,3H),2.97(t,J=7.6Hz,2H),2.21-2.13(m,2H)。
第3步:
室温下,向单口瓶中依次加入EVO33127-A2(90mg,0.33mmol),Pd(OAc)2(7mg,0.033mmol),DCCP-2HBF4(20mg,0.033mmol),K2CO3(135mg,0.99mmol),H2O(0.1mL)和DMSO(3mL),反应体系用CO置换3次后,加热到100℃搅拌过夜。反应结束后,反应体系冷却到室温并过滤,滤饼用水洗涤2次。滤液用EA萃取1次,有机相丢弃,水相用稀HCl(1M)调pH=3,用DCM/MeOH=10/1萃取3次,有机相合并,浓缩得粗品,用中压反相柱层析纯化(H2O/CH3CN=0-50%),冻干得淡粉色固体EVO33127-A3(60mg,收率:80%),LCMS(ESI)m/z=239.2[M-H]-。
第4步:
室温下,将EVO33127-A3(15mg,0.062mmol)和中间体1-A1(22mg,0.062mmol)溶于DMF(3mL)中,依次加入TEA(32mg,0.31mmol)和HATU(35mg,0.093mmol),反应体系在室温下搅拌1小时。反应体系加水淬灭,用EA萃取2次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,Prep-HPLC制备后,冻干得淡黄色固体EVO33127(15mg,收率:42%),LCMS(ESI)m/z=572.37[M+H]+。纯度:99.17%。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=5.9Hz,1H),9.39(s,1H),8.70-8.60(m,2H),8.28(s,1H),8.18(s,1H),7.90(d,J=7.4Hz,1H),7.80(s,1H),7.77-7.71(m,1H),7.03(d,J=8.5Hz,1H),4.80(d,J=5.8Hz,2H),4.31(d,J=11.9Hz,2H),3.72-3.63(m,2H),3.30-3.25(m,4H),3.23(s,3H),3.02(t,J=7.6Hz,2H),2.20-2.10(m,2H),1.21(d,J=6.2Hz,6H)。
实施例3 EVO33314
参照化合物EVO33127,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33314(15mg,收率:38%),LCMS(ESI)m/z=586.4[M+H]+,纯度:99.13%,1H NMR(400MHz,DMSO-d6)δ9.47(t,J=5.9Hz,1H),9.39(s,1H),8.69-8.59(m,2H),8.23(s,1H),8.19(s,1H),7.90(d,J=7.2Hz,1H),7.80(s,1H),7.74(t,J=8.0Hz,1H),7.02(d,J=8.6Hz,1H),4.80(d,J=5.8Hz,2H),4.31(d,J=12.6Hz,2H),
3.73-3.61(m,2H),3.30-3.21(m,4H),3.03(t,J=7.4Hz,2H),2.56-2.50(m,2H),2.18-2.08(m,2H),1.21(d,J=6.2Hz,6H),1.13(t,J=7.4Hz,3H)。
实施例4 EVO33319
参照化合物EVO33127,经高效液相制备柱分离,再冷冻干燥得到得黄色固体EVO33319(25mg,收率:46%),LCMS(ESI)m/z=600.5[M+H]+,纯度:97.9%,1H NMR(400MHz,DMSO-d6)δ9.49(t,J=5.6Hz,1H),9.39(s,1H),8.67-8.61(m,2H),8.20(d,J=3.6Hz,2H),7.90(d,J=7.6Hz,1H),7.80(s,1H),7.74(t,J=7.2Hz,1H),7.03(d,J=8.4Hz,1H),4.80(d,J=5.6Hz,2H),4.31(d,J=10.8Hz,2H),3.70-3.64(m,2H),3.48-3.41(m,1H),3.24(t,J=8.8Hz,2H),3.02(d,J=7.2Hz,2H),2.53-2.51(m,2H),2.15-2.08(m,2H),1.22-1.18(m,12H)。
实施例5 EVO33168
第1步:
Ar保护下,化合物5-溴-7-氟吲唑(1.03g,4.80mmol)和甲硫醇钠(0.93g,12mmol)的DMF(5mL)溶液在80℃下反应12小时。反应液加冰水淬灭,加入EA萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得到白色固体EVO33168-A1(1.28g,收率:98%),LCMS(ESI)m/z=245.04[M+H]+。
第2步:
Ar保护,冰水浴条件下,向化合物EVO33168-A1(300mg,1.23mmol)的DMF(5mL)溶液中加入NaH(200mg,4.94mmol),搅拌10分钟,再滴入CH3I(350mg,2.46mmol),继续搅拌15分钟。反应液加冰水淬灭,加入EA萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得到白色固体
EVO33168-A2(380mg,收率:98%),LCMS(ESI)m/z=259.07[M+H]+。
第3步:
室温下,将EVO33168-A2(380mg,1.23mmol)溶于乙腈(5mL)和水(5mL)溶液中,加入固体Oxone(1.60g,2.46mmol),反应搅拌过夜。将反应液浓缩,加入EA和水,分层萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得粗品,中压正相柱层析纯化(PE/EA=3/1),得到白色固体EVO33168-A3(210mg,收率:60%),LCMS(ESI)m/z=291.10[M+H]+。
第4步:
室温下,向反应瓶中加入化合物EVO33168-A3(195mg,0.68mmol)、Pd(OAc)2(15mg,0.068mmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(41mg,0.068mmol)、K2CO3(281mg,2.04mmol)、DMSO(2mL)和水(0.2mL),CO置换3次后,反应液在100℃下搅拌4小时。反应液中加入水,过滤,少量水洗涤滤饼,滤液酸化至pH=1-2,EA萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得到淡黄色固体EVO33168-A4(140mg,收率:80%),LCMS(ESI)m/z=255.17[M+H]+。
第5步:
室温下,向化合物中间体1-A1(40mg,0.11mmol)的DCM(5mL)溶液中加入化合物EVO33168-A4(42mg,0.15mmol)、HOBt(22mg,0.16mmol)、EDCI(31mg,0.16mmol)和DIPEA(28.7mg,0.22mmol),反应搅拌1小时。依次用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩,粗品经Prep-HPLC制备,冷冻干燥得到黄色固体EVO33168(25.6mg,收率:42%),纯度:97%,LCMS(ESI)m/z=586.44[M+H]+,1H NMR(400MHz,DMSO-d6)δ9.59(t,J=6.0Hz,1H),9.43(s,1H),8.89(d,J=1.6Hz,1H),8.72-8.62(m,3H),8.56(s,1H),7.93(d,J=7.6Hz,1H),7.87(s,1H),7.78(t,J=7.9Hz,1H),7.06(d,J=7.0Hz,1H),4.88(d,J=5.7Hz,2H),4.49(s,3H),4.37-4.29(m,2H),3.75-3.65(m,2H),3.57(s,3H),2.57-2.46(m,2H),1.24(d,J=6.2Hz,6H)。
实施例6 EVO33135
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33135(15.5mg,收率:16.3%),LCMS(ESI)m/z=571.05[M+H]+,1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),9.47-9.40(m,1H),9.40(s,1H),8.70-8.59(m,3H),8.29(d,J=1.6Hz,1H),7.89(d,J=7.4Hz,1H),7.82(s,1H),7.72(t,J=8.0Hz,1H),7.61-7.56(m,1H),7.02(d,J=8.5Hz,1H),6.85-6.79(m,1H),4.83(d,J=5.8Hz,2H),4.35-4.26(m,2H),3.72-3.61(m,2H),3.35(s,3H),3.33-3.31(m,2H),1.21(d,J=6.2Hz,6H)。
实施例7 EVO33136
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33136(13.58mg,收率:31%),LCMS(ESI)m/z=585.46[M+H]+,1H NMR(400MHz,DMSO-d6)δ9.47-9.42(m,1H),9.39(s,1H),8.70-8.59(m,3H),8.43(d,J=1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.82(s,1H),7.74-7.70(m,1H),7.63(d,J=3.2Hz,1H),7.03-7.00(m,1H),6.86(d,J=3.2Hz,1H),4.83(d,J=5.6Hz,2H),4.34-4.27(m,2H),4.23(s,3H),3.71-3.63(m,2H),3.51(s,3H),2.53–2.50(m,2H),1.21(d,J=6.4Hz,6H)。
实施例8 EVO33165
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33165(5.6mg,收率:12%,纯度:97.3%),LCMS(ESI)=572.43[M+H]+,1H NMR(400MHz,DMSO-d6)δ13.86(s,1H),9.61(t,J=5.6,1H),9.44(s,1H),8.90(d,J=1.2,1H),8.73-8.62(m,2H),8.57(s,1H),8.53(d,J=1.6Hz,1H),7.93(d,J=7.2,1H),7.87(s,1H),7.79-7.71(m,1H),7.05(d,J=8.5Hz,1H),4.88(d,J=5.6,2H),4.38-4.29(m,2H),3.75-3.65(m,2H),3.45(s,3H),2.58-2.46(m,2H),1.24(d,J=6.2,6H)。
实施例9 EVO33070
第1步:
室温下,往反应瓶中加入二氟溴乙酸乙酯(7.96g,39.20mmol)和DMSO(50mL),溶清后加入Cu(2.49g,39.20mmol),反应液在室温下搅拌1小时,再加入2,6-二氟-4-溴碘苯(5g,16mmol),油浴75℃搅拌过夜。反应体系冷却到室温,加入EA(300mL)和水(300mL),有大量固体析出,过滤,滤饼用EA洗涤,分液,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-15%)得无色油状物EVO33070-A1(4g,收率:81%),1H NMR(400MHz,DMSO-d6)δ7.78–7.75(m,2H),4.37(q,J=6.8Hz,2H),1.24(t,J=7.2Hz,3H)。
第2步:
室温下,反应瓶中加入EVO33070-A1(1g,3.17mmol)、CH3CN(50mL)和NaSCH3(222mg,3.17mmol),搅拌过夜。反应体系浓缩后,加入EA(50mL)和水(50mL)稀释,分液,水相用EA萃取2次,有机相合并,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-10%)得无色油状物EVO33070-A2(600mg,收率:55%),1H NMR(400MHz,CDCl3)δ7.13(s,1H),7.09–7.06(m,1H),4.11(t,J=13.2Hz,2H),2.47(t,J=4.4Hz,3H)。
第3步:
室温下,反应瓶中加入EVO33070-A2(600mg,1.75mmol)、CH3OH(6mL)和THF(6mL),在0℃搅拌5-10分钟后,加入NaBH4(133mg,3.50mmol),继续搅拌1小时后,升至室温搅拌过夜。反应体系加水淬灭,浓缩,用EA萃取2次,有机相合并,无水Na2SO4干燥,过滤,浓缩,中压正相柱层析纯化(PE/DCM=50%-70%)得白色固体EVO33070-A3(440mg,收率:83%),1H NMR(400MHz,DMSO-d6)δ7.58(d,J=5.6Hz,1H),7.49(s,1H),4.34(q,J=7.2Hz,2H),2.55(s,3H),1.23(t,J=6.8Hz,3H)。
第4步:
室温下,反应瓶中加入Cs2CO3(953mg,2.92mmol)、TBAB(47mg,0.15mmol)和CH3CN(50mL),加热到85℃,然后向反应体系中滴加EVO33070-A3(440mg,1.46mmol)的CH3CN(5mL)溶液,滴毕,油浴90℃搅拌过夜。反应体系冷却到室温,过滤,滤液浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-2%)得白色固体EVO33070-A4(160mg,收率:39%),1H NMR(400MHz,DMSO-d6)δ7.14(q,J=1.6Hz,1H),7.06(d,J=1.2Hz,1H),4.81(t,J=16.8Hz,2H),2.57(s,3H)。
第5步:
室温下,反应瓶中加入EVO33070-A4(160mg,0.57mmol)、CH3OH(5mL)和H2O(5mL),然后加入Oxone(1.05g,1.71mmol),反应液在室温下搅拌2-4小时。反应体系加水稀释,用EA萃取2次,合并有机相,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-50%)得白色固体EVO33070-A5(140mg,收率:78%),1H NMR(400MHz,CDCl3)δ7.82(d,J=1.2Hz,1H),7.43(q,J=1.6Hz,1H),4.74(t,J=16.0Hz,2H),3.19(s,3H)。
第6步:
室温下,依次向单口瓶中加入EVO33070-A5(140mg,0.45mmol),Pd(OAc)2(10mg,0.045mmol),DCCP-2HBF4(27mg,0.045mmol),K2CO3(185mg,1.34mmol),DMSO(5mL)和H2O(0.2mL),反应体系用CO置换3次,加热到100℃搅拌过夜。反应体系冷却到室温,过滤,滤饼用水洗涤,水相用EA萃取1次,有机相丢弃,水相用稀HCl(1M)调pH=3-5,用DCM/MeOH(10/1)萃取3次,有机相合并,无水Na2SO4干燥,过滤,浓缩得粗品,反相柱层析纯化(H2O/CH3CN=5-50%),冷冻干燥得白色固体EVO33070-A6(65mg,收率:52%),LCMS(ESI)m/z=277.0[M-H]-。
第7步:
室温下,将EVO33070-A6(20mg,0.072mmol)和中间体1-A1(25mg,0.072mmol)溶于DMF(2mL)中,依次加入TEA(36mg,0.36mmol)和HATU(55mg,0.14mmol)。反应体系在室温下搅拌2小时。反应体系加入水淬灭,用EA萃取2次,有机相合并,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,用Prep-HPLC纯化后,冷冻干燥得EVO33070(5mg,收率:11%)。LCMS(ESI)m/z=610.34[M+H]+,纯度:98%,1H NMR(400MHz,DMSO-d6)δ9.67(t,J=5.6Hz,1H),9.40(s,1H),8.68-8.61(m,2H),8.16(d,J=1.2Hz,1H),8.03(d,J=1.2Hz,1H),7.91-7.90(m,1H),7.84(s,1H),7.77-7.73(m,1H),7.03(d,J=8.4Hz,1H),5.00(t,J=17.0Hz,2H),4.82(d,J=6.0Hz,2H),4.31(d,J=12.4Hz,2H),3.70-3.65(m,2H),3.31-3.29(m,3H),2.53–2.46(m,2H),1.21(d,J=6.0Hz,6H)。
实施例10 EVO33074
参照化合物EVO33070,经高效液相制备柱分离,再冷冻干燥得到淡黄色固体EVO33074(10mg,收率:35%),LCMS(ESI)m/z=589.9[M+H]+,纯度:88.7%,1H NMR(400MHz,DMSO-d6)δ9.68(t,J=6.0Hz,1H),9.40(s,1H),8.77(d,J=4.0Hz,1H),8.68-8.61(m,3H),8.49(d,J=1.2Hz,1H),7.89(d,J=7.2Hz,1H),7.85(s,1H),7.75-7.71(m,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=6.0Hz,2H),4.33-4.29(m,2H),3.69-3.64(m,2H),3.38(s,3H),2.53–2.46(m,2H),1.21(d,J=6.0Hz,6H)。
实施例11 EVO33137
第1步:
室温下,将1-溴-3-羟基萘(3.8g,17.04mmol)溶于CH3CN(80mL)中,依次加入K2CO3(7.05g,51.11mmol)和CH3I(7.36g,51.11mmol),反应体系在室温下搅拌过夜。反应体系过滤,滤液浓缩后,加水稀释,用EA萃取,有机相用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品棕色油状物EVO33137-A1(4g),1H NMR(400MHz,DMSO-d6)δ8.02(d,J=8.8Hz,1H),7.89(d,J=8.4Hz,1H),7.58-7.48(m,3H),7.43(d,J=2.4Hz,1H),3.89(s,3H)。
第2步:
室温下,向单口瓶中依次加入EVO33137-A1(3.5g,14.76mmol),Pd2(dba)3(1.35g,1.48mmol),Xantphos(1.71g,2.95mmol),Cs2CO3(14.44g,44.29mmol),t-BuOH(6mL)和toluene(60mL),用氩气置换3次后,加入硫代乙酸甲酯(6.65g,73.81mmol),再用氩气置换1次,反应体系加热到100℃搅拌过夜。反应体系过滤,滤饼用EA洗涤,滤液浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-
5%)得无色油状物EVO33137-A2(2g,收率:66%),1H NMR(400MHz,DMSO-d6)δ7.98(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.51-7.47(m,1H),7.41-7.37(m,1H),7.13(d,J=2.4Hz,1H),6.98(d,J=2.4Hz,1H),3.87(s,3H),2.57(s,3H)。
第3步:
室温下,将EVO33137-A2(1g,4.90mmol)悬浮于CH3CN(30mL)和H2O(30mL)中,再加入Oxone(8.99g,14.69mmol),反应体系在室温下搅拌过夜。反应体系浓缩后,加水稀释,用EA萃取1次,有机相用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品淡黄色固体EVO33137-A3(1g,收率:86%),1H NMR(400MHz,DMSO-d6)δ8.51(d,J=8.4Hz,1H),7.82(d,J=8.8Hz,1H),7.80-7.77(m,2H),7.67-7.58(m,2H),3.95(s,3H),3.36(s,3H)。
第4步:
在充满氩气的三口瓶中,加入EVO33137-A3(200mg,0.85mmol)和DCM(5mL),反应体系冷却到-70℃,缓慢滴加BBr3(2.54mL,2.54mmol,1M in DCM),滴毕,反应体系缓慢升温到室温,搅拌2小时。反应体系冷却到0℃,加水淬灭,用DCM萃取2次,合并有机相,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(DCM/10%MeOH=0-30%)得淡黄色固体EVO33137-A4(130mg,收率:69%),LCMS(ESI)m/z=221.1[M-H]-。
第5步:
在0℃下,将EVO33137-A4(130mg,0.58mmol)溶于吡啶(3mL)中,再缓慢滴加Tf2O(495mg,1.75mmol),滴毕,反应体系升到室温,搅拌过夜。反应体系浓缩后,加入EA稀释,用饱和NaHCO3溶液、水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=0-50%)得无色油状物EVO33137-A5(120mg,收率:58%),1HNMR(400MHz,DMSO-d6)δ8.68-8.66(m,2H),8.32(d,J=8.0Hz,1H),7.19(d,J=2.4Hz,1H),7.95-7.91(m,1H),7.88-7.84(m,1H),3.47(s,3H)。
第6步:
室温下,向单口瓶中依次加入EVO33137-A5(120mg,0.34mmol),Pd(OAc)2(7.6mg,0.034mmol),DCCP-2HBF4(21mg,0.034mmol),K2CO3(140mg,1.02mmol),H2O(0.1mL)和DMSO(3mL),反应体系用CO置换3次后,加热到100℃搅拌过夜。反应体系过滤,滤饼用水洗涤,滤液用EA萃取1次,有机相丢弃,水相用稀HCl(2M)调pH=3-5,用DCM/MeOH(10/1)萃取3次后,有机相合并,浓缩得粗品,中压反相柱层析纯化(H2O/CH3CN=5-50%),冻干得白色固体EVO33137-A6(60mg,收率:70%),LCMS(ESI)m/z=249.1[M-H]-。
第7步:
室温下,将EVO33137-A6(25mg,0.1mmol)和中间体1-A1(35mg,0.1mmol)溶于DMF(3mL)中,再依次加入TEA(51mg,0.5mmol)和HATU(76mg,0.2mmol),反应体系在室温下搅拌1小时。反应体系加水淬灭,用EA萃取1次,有机相用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,用Prep-HPLC制备,冻干得黄色固体EVO33137(25mg,收率:43%),LCMS
(ESI)m/z=582.4[M+H]+,纯度:98.6%,1H NMR(400MHz,DMSO-d6)δ9.73(t,J=5.6Hz,1H),9.42(s,1H),9.00(s,1H),8.75-8.61(m,4H),9.30(d,J=8.0Hz,1H),7.94-7.87(m,3H),7.84-7.71(m,2H),7.02(d,J=8.8Hz,1H),4.88(d,J=5.6Hz,2H),4.31(d,J=12.4Hz,2H),3.69-3.64(m,2H),3.41(s,3H),2.49-2.46(m,2H),1.20(d,J=6.0Hz,6H)。
实施例12 EVO33167
参照化合物EVO33168、EVO33137,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33167(20.11mg,收率:31.3%),LCMS(ESI)m/z=572.4[M+H]+,纯度:99.0%,1H NMR(400MHz,DMSO-d6)δ14.10(br,1H),9.70(t,J=6.0Hz,1H),9.41(s,1H),8.71-8.56(m,3H),8.46(s,1H),8.29(d,J=1.2Hz,1H),7.90(d,J=7.6Hz,1H),7.85(s,1H),7.73(t,J=8.0Hz,1H),7.02(d,J=8.4Hz,1H),4.86(d,J=5.6Hz,2H),4.31(dd,J1=2.4Hz,J2=12.8Hz,2H),3.71-3.63(m,2H),3.36(s,3H),2.56-2.45(m,2H),1.21(d,J=6.0Hz,6H)。
实施例13 EVO33111
第一步:
冰水浴条件下,反应瓶中加入5-溴-2,3-二氢苯并呋喃(1.00g,5.02mmol)和氯磺酸(2mL),2小时后,将反应液倒入冰水中,DCM(20mL*3)萃取,有机相浓缩,中压制备纯化得EVO33111-A1(1.00g,收率:67.1%)。
第二步:
室温下,反应瓶中加入EVO33111-A1(1.00g,3.36mmol),亚硫酸钠(667.74mg,5.38mmol),碳酸氢钠(451.74mg,5.38mmol),水(10mL)和1,4-二氧六环(10mL),油浴加热至80℃。反应结束后,中压反相制备得EVO33111-A2(1.20g,收率:>99%)。
第三步:
室温下,反应瓶中加入EVO33111-A2(1.10g,1.93mmol)和DMF(5mL),室温下滴加CH3I(821.50mg,5.79mmol)。反应结束后,中压制备得EVO33111-A3(290mg,收率:27.1%)。
第四步:
室温下,反应瓶中加入EVO33111-A3(290.00mg,1.05mmol),醋酸钯(23.49mg,0.10mmol),1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(63.86mg,0.10mmol),碳酸钾(433.88mg,3.14mmol),DMSO(3mL)和水(0.3mL),CO置换3次后,升温至80℃。反应结束后,中压制备得EVO33111-A4(20mg,收率:7.9%)。
第五步:
室温下,反应瓶中加入EVO33111-A4(20.00mg,0.08mmol),中间体1-A1(28.85mg,0.08mmol),HATU(47.09mg,0.12mmol)和DMF(5mL),室温下,加入DIPEA(42.68mg,0.33mmol)。反应结束后,用Prep-HPLC纯化,冷冻干燥得EVO33111(13mg,收率:27.5%),LCMS(ESI)m/z=574.36[M+H]+,纯度:99.80%,1H NMR(400MHz,DMSO-d6)δ9.41(d,J=6.5Hz,2H),8.72-8.61(m,2H),8.27–8.19(m,2H),7.93(d,J=7.4Hz,1H),7.83-7.73(m,2H),7.06(d,J=8.5Hz,1H),4.90(t,J=8.8Hz,2H),4.81(d,J=5.8Hz,2H),4.38-4.30(m,2H),3.71(m,2H),3.39(t,J=8.8Hz,2H),3.29(s,3H),2.57-2.47(m,2H),1.24(d,J=6.2Hz,6H)。
实施例14 EVO33138
第1步:
室温下,将5-溴-3-氟苯-1,2-二醇(1g,4.83mmol)溶于DMF(30mL)中,再依次加入K2CO3(3.34g,24.15mmol)和二溴甲烷(4.20g,24.15mmol),反应体系加热到80℃搅拌过夜。反应结束后,冷却
到室温,加入EA和水稀释,有机相用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=2-5%)得无色油状物EVO33138-A1(300mg,收率:28%),1H NMR(400MHz,DMSO-d6)δ7.16(dd,J1,J2=1.6Hz,9.6Hz,1H),7.12-7.11(m,1H),6.16(s,2H)。
第2步:
室温下,将EVO33138-A1(100mg,0.46mmol)溶于DMF(3mL)中,加入NaSCH3(479.44mg,1.37mmol,20%purity in H2O),反应体系在室温下搅拌过夜。反应体系加水淬灭,用EA萃取,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品无色油状物EVO33138-A2(100mg)。
第3步:
室温下,将EVO33138-A2(100mg,0.40mol)悬浮于CH3CN(3mL)和H2O(3mL)中,再加入Oxone(745mg,1.21mmol),反应体系在室温下搅拌过夜。反应体系浓缩后,用EA和水稀释,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(PE/DCM=20-50%,DCM/10%MeOH=10%)得白色固体EVO33138-A3(50mg,收率:44%)。
第4步:
室温下,向单口瓶中依次加入EVO33138-A3(50mg,0.18mmol),Pd(OAc)2(4mg,0.018mol),DCCP-2HBF4(11mg,0.018mmol),K2CO3(74mg,0.54mmol),H2O(0.1mL)和DMSO(3mL),反应体系用CO置换3次后,加热到100℃搅拌过夜。反应体系冷却到室温,过滤,滤饼用水洗涤,滤液用EA洗涤1次,有机相丢弃,水相用稀HCl(1M)调pH=3-5,再DCM/MeOH(10/1)萃取3次,合并有机相,无水Na2SO4干燥,过滤,浓缩得粗品,用反相柱层析纯化(H2O/CH3CN=5-50%)后,冻干得白色固体EVO33138-A4(26mg,收率:59%),LCMS(ESI)m/z=243.1[M-H]-。
第5步:
室温下,将EVO33138-A4(16mg,0.065mmol)和中间体1-A1(23mg,0.065mmol)溶于DMF(3mL)中,再依次加入TEA(33mg,0.33mol)和HATU(50mg,0.13mmol)。反应在室温下搅拌1小时。反应体系用水淬灭后,用EA萃取2次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,中压正相柱层析纯化(DCM/EA=10-50%,DCM/10%MeOH=10-50%)后,冻干得黄色固体EVO33138(20mg,收率:53%),LCMS(ESI)m/z=576.0[M+H]+,纯度:98.6%,1H NMR(400MHz,DMSO-d6)δ9.41-9.39(m,2H),8.67-8.60(m,2H),7.93-7.89(m,2H),7.80-7.72(m,3H),7.03(d,J=8.4Hz,1H),6.37(s,2H),4.77(d,J=6.0Hz,2H),4.31(dd,J1,J2=2.4Hz,12.8Hz,2H),3.70-3.65(m,2H),3.31(s,3H),2.55–2.44(m,2H),1.21(d,J=6.4Hz,6H)。
实施例15 EVO33157
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33157(10mg,收率:36%),LCMS(ESI)m/z=590.1[M+H]+,纯度:99.94%,1H NMR(400MHz,DMSO-d6)δ9.42-9.38(m,2H),8.64(q,J=8.8Hz,2H),8.03(d,J=2.4Hz,1H),7.91-7.89(m,1H),7.85(d,J=2.0Hz,1H),7.76-7.72(m,2H),7.02(d,J=8.8Hz,1H),4.77(d,J=6.0Hz,2H),4.53-4.51(m,2H),4.42-4.40(m,2H),4.31(d,J=12.0Hz,2H),3.70-3.65(m,2H),3.30(s,3H),2.57-2.42(m,2H),1.21(d,J=6.4Hz,6H)。
实施例16 EVO33173
第1步:
室温下,向单口瓶中依次加入2,6-二溴吡啶(1g,4.22mmol),环丙基硼酸(725mg,8.44mmol),Pd(dppf)Cl2·DCM(345mg,0.42mmol),K2CO3(1.75g,12.66mmol)和1,4-二氧六环(20mL),反应体系用氩气置换3次后,加热到100℃搅拌过夜。反应体系过滤,滤饼用EA洗涤,滤液浓缩后,中压正相柱层析纯化(PE/DCM=1-5%)得无色油状物EVO33173-A1(500mg,收率:59%),LCMS(ESI)m/z=197.9/199.9[M+H]+。
第2步:
室温下,向单口瓶中依次加入EVO33173-A1(180mg,0.91mmol),六甲基二锡(596mg,1.82mmol),Pd(PPh3)4(105mg,0.091mmol)和1,4-二氧六环(5mL),反应体系用氩气置换3次后,加热到100℃搅拌3小时。反应结束后,将反应体系冷却到室温,加入KF(aq.)搅拌30分钟,过滤,滤饼用EA洗涤,分液,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品棕色油状物EVO33173-A2(300mg)。
第3步:
室温下,向单口瓶中依次加入中间体2(120mg,0.41mmol),EVO33173-A2(230mg,0.82mmol),Pd(PPh3)2Cl2(58mg,0.082mol)和1,4-二氧六环(5mL)。反应体系用氩气置换3次后,加热到110℃搅拌过夜。反应体系冷却到室温,浓缩得粗品,中压正相柱层析纯化(PE/EA=0-50%)得淡黄色油状物EVO33173-A3(100mg,收率:65%),LCMS(ESI)m/z=377.2[M+H]+。
第4步:
室温下,将EVO33173-A3(30mg,0.08mmol)溶于DCM(3mL)中,加入TFA(1.5mL),反应体系在室温下搅拌1小时。反应体系浓缩得粗品淡黄色油状物EVO33173-A4(25mg),LCMS(ESI)m/z=277.2[M+H]+。
第5步:
室温下,将EVO33127-A3(20mg,0.083mmol)和EVO33173-A4(23mg,0.083mol)溶于DMF(3mL)中,再依次加入TEA(42mg,0.42mmol)和HATU(63mg,0.17mmol),反应体系在室温下搅拌1小时。反应加水淬灭,用EA萃取1次,合并有机相,用水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,用Prep-HPLC制备,冻干得白色固体EVO33173(20mg,收率:48%),LCMS(ESI)m/z=499.0[M+H]+,纯度:99.68%,1H NMR(400MHz,DMSO-d6)δ9.47(t,J=6.0Hz,1H),9.40(s,1H),8.69-8.60(m,2H),8.33(d,J=8.0Hz,1H),8.27(s,1H),8.18(s,1H),7.86-7.81(m,2H),7.47-7.45(m,1H),4.80(d,J=6.0Hz,2H),3.29-3.28(m,2H),3.23(s,3H),3.02(t,J=7.6Hz,2H),2.26-2.20(m,1H),2.18-2.10(m,2H),1.12-1.02(m,4H)。
实施例17 EVO33175
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33175(17mg,收率:43%),LCMS(ESI)m/z=503.0[M+H]+,纯度:99.74%,1H NMR(400MHz,DMSO-d6)δ9.48(t,J=6.0Hz,1H),9.41(s,1H),8.72-8.61(m,2H),8.27(s,1H),8.20-8.18(m,2H),7.89(t,J=7.6Hz,1H),7.81(s,1H),6.97(d,J=8.2Hz,1H),4.80(d,J=5.6Hz,2H),4.51(q,J=6.8Hz,2H),3.29-3.26(m,2H),3.23(s,3H),3.02(t,J=7.6Hz,2H),2.18-2.11(m,2H),1.41(t,J=7.2Hz,3H)。
实施例18 EVO33174
第1步:
25mL反应瓶中,加入中间体2(100mg,340.62μmol),EVO33174-A1(54mg,283.85μmol),新烘干的Cs2CO3固体(277mg,851.55μmol),Ruphos(26mg,56.77μmol,Ruphos-pd-G3(24mg,28.39μmol),无水二氧六环(5mL),Ar气置换3次,油浴110℃反应2.5小时。冷却至室温,过滤,滤饼用EA淋洗,滤液减压浓缩过中压柱(PE:EA=0-30%),得淡黄色粘稠物EVO33174-A2(44mg,收率:34.6%),1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.44(d,J=9.2Hz,1H),8.30(d,J=9.2Hz,1H),7.54(t,J=6.0Hz,1H),7.46(s,1H),7.24(d,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),4.38-4.36(m,6H),3.54(m,1H),2.25-2.19(m,4H),1.97-1.91(m,1H),1.86-1.79(m,1H),1.43(s,9H)。
第2步:
25mL反应瓶,加入EVO33174-A2(39mg,87.15μmol),DCM(1.0mL),冰水浴,Ar保护,加入TFA(0.5mL),冰水浴搅拌20分钟,转室温搅拌1.5小时。减压浓缩,加入EA(10mL),用饱和碳酸氢钠溶液调pH=7~8,EA萃取(10mL*2),合并有机相,用水和饱和氯化钠溶液各洗1次,无水Na2SO4干燥,过滤,减压浓缩得淡黄色粘稠物EVO33174-A3(粗品36mg,收率:>99%),LCMS(ESI)m/z=348.2[M+H]+。
第3步:
50mL反应瓶,加入EVO33127-A3(21mg,87.40μmol),EVO33174-A3(30mg,87.40μmol),TEA(44mg,437.00μmol,60.91μL)和无水DMF(2mL),Ar保护,最后加入HATU(66mg,174.80μmol),室温搅拌1.5小时。向反应体系加水,用EA萃取(15mL*3),合并有机相,用水和饱和氯化
钠溶液各洗1次,无水Na2SO4干燥,过滤,滤液减压浓缩得黄色粘稠物,用Prep-HPLC纯化,冷冻干燥,得到类白色固体EVO33174(22mg,收率:44.2%),LCMS(ESI)m/z=570.0[M+H]+,纯度:93.9%,1H NMR(400MHz,DMSO-d6)δ9.42(t,J=2.0Hz,1H),9.10(s,1H),8.46(d,J=9.2Hz,1H),8.32(d,J=9.2Hz,1H),8.27(d,J=1.6Hz,1H),8.17(d,J=1.6Hz,1H),7.49(s,1H),7.24(d,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),4.73(d,J=6.0Hz,2H),4.40-4.26(m,4H),3.59-3.48(m,1H),3.28(t,J=7.2Hz,2H),3.23(s,3H),3.02(t,J=7.6Hz,2H),2.27-2.17(m,4H),2.17-2.09(m,2H),2.00-1.87(m,1H),1.87-1.76(m,1H)。
实施例19 EVO33071
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到淡黄色固体EVO33071(8mg,收率:17%),LCMS(ESI)m/z=629.9[M+H]+,纯度:97.9%,1H NMR(400MHz,DMSO-d6)δ9.61(t,J=6.0Hz,1H),9.11(s,1H),8.31(d,J=9.2Hz,1H),8.19(d,J=9.6Hz,1H),8.15(d,J=1.2Hz,1H),8.01(s,1H),7.53(s,1H),7.33(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),5.00(t,J=17.2Hz,2H),4.75(d,J=6.0Hz,2H),4.53-4.47(m,1H),4.41-4.29(m,2H),4.16-4.10(m,1H),3.28(s,3H),3.14-3.06(m,1H),2.09-1.98(m,1H),1.98-1.86(m,1H)。
实施例20 EVO33176
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33176(10mg,收率:21%),LCMS(ESI)m/z=554.0[M+H]+,纯度:93.4%,1H NMR(400MHz,DMSO-d6)δ9.40(t,J=6.0Hz,1H),9.05(s,1H),8.26(s,1H),8.18-8.16(m,2H),7.81(d,J=9.2Hz,1H),7.45-7.42(m,2H),6.96(d,J=7.6Hz,1H),4.71(d,J=6.0Hz,2H),4.13-4.02(m,2H),3.29-3.25(m,2H),3.22(s,3H),3.02(t,J=7.6Hz,2H),2.76(d,J=6.5Hz,2H),2.19-2.08(m,2H),2.03-1.89(m,3H),0.89-0.72(m,4H)。
实施例21 EVO33177
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到淡黄色固体EVO33177(6mg,收率:14%),LCMS(ESI)m/z=556.4[M+H]+,纯度:97.7%,1H NMR(400MHz,DMSO-d6)δ9.42(t,J=6.0Hz,1H),9.09(s,1H),8.31-8.26(m,2H),8.21-8.16(m,2H),7.47(s,1H),7.21(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),4.71(d,J=5.6Hz,2H),4.30-4.26(m,4H),3.29-3.25(m,2H),3.22(s,3H),3.02(t,J=7.6Hz,2H),2.19-2.08(m,2H),2.06-1.95(m,1H),0.90-0.75(m,4H)。
实施例22 EVO33321
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33321(21.52mg,收率44.9%),LCMS(ESI)m/z=568.42[M+H]+,HPLC纯度:99.65%,1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.48(d,J=9.2Hz,1H),8.19(s,1H),8.13–8.05(m,2H),7.75-7.65(m,2H),7.18(d,J=8.2Hz,1H),7.09(d,J=8.2Hz,1H),4.92(d,J=5.2Hz,2H),4.54–4.48(m,2H),4.43–4.36(m,2H),3.32(t,J=7.5Hz,2H),3.15(q,J=7.4Hz,2H),3.04(t,J=7.6Hz,2H),2.25-2.13(m,2H),2.06(s,3H),1.29(t,J=7.4Hz,3H)。
实施例23 EVO33162
参照化合物EVO33138,得黄色固体EVO33162(25mg,收率:49%)。LCMS(ESI)m/z=590.4[M+H]+。纯度:99.42%。1H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.64(q,J=8.8Hz,2H),7.91-7.89(m,2H),7.80-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.77(d,J=5.6Hz,2H),4.32(d,J=12.4Hz,2H),3.70-3.65(m,2H),3.38(q,J=7.2Hz,2H),2.53-2.46(m,2H),1.22-1.16(m,9H)。
实施例24 EVO33163
参照化合物EVO33138,用prep-HPLC制备后,冻干得黄色固体EVO33163(30mg,收率:75%)。LCMS(ESI)m/z=604.4[M+H]+。纯度:99.20%。1H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.64(q,J=8.8Hz,2H),7.92-7.86(m,2H),7.81-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.33(s,2H),4.77(d,J=5.6Hz,2H),4.32(d,J=12.4Hz,2H),3.70-3.65(m,2H),3.52-3.42(m,1H),2.53-2.47(m,2H),1.25-1.20(m,12H)。
实施例25 EVO33110
第1步:
室温下,4-溴-2,6-二氟苯乙酸(3g,11.95mmol,1.69mL)溶于THF(30mL),加入CDI(2.91g,17.93mmol),监测原料消失后,加入硼氢化钠(904.27mg,23.90mmol),搅拌过夜。反应结束后,加入甲醇淬灭反应,蒸干溶剂,加入水(50mL),EA(3*30mL)萃取,有机相浓缩中压制备得EVO33110-A1(1.6g,收率:56.84%)。1H NMR(400MHz,Chloroform-d)δ7.10-7.02(m,2H),3.82(t,J=6.7Hz,2H),2.90(d,J=1.3Hz,2H)。
第2步:
室温下,EVO33110-A1(1.2g,5.06mmol)溶于THF(20mL),加入叔丁醇钾(1.70g,15.19mmol),反应结束后,饱和氯化钠溶液(20mL)洗涤,有机相浓缩,中压制备得EVO33110-A2(400mg,收率:36.41%)。1H NMR(400MHz,Chloroform-d)δ6.77-6.71(m,2H),4.63(t,J=8.7Hz,2H),3.19(td,J=8.8,1.1Hz,2H)。
第3步:
室温下,EVO33110-A2(240mg,1.11mmol)溶于DMF(5mL),加入甲硫醇钠(116.26mg,1.66mmol),升温至120℃过夜。反应结束后,加入水(50mL),EA(3*30mL)萃取,有机相浓缩,中压制备得EVO33110-A3(184mg,收率:67.88%)。
第4步:
室温下,EVO33110-A3(184mg,750.60μmol)溶于乙腈(10mL)和水(10mL),加入Oxone(460.87mg,750.60μmol),30℃过夜。反应结束后,过滤,蒸出乙腈,加入水(50mL),EA(3*30mL)萃取,有机相浓缩得EVO33110-A4(110mg,收率:52.88%),粗品直接用于下一步。
第5步:
室温下,EVO33110-A4(110mg,396.92μmol)溶于DMSO(5mL)和水(0.5mL),再加入醋酸钯(17.82mg,79.38μmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(48.44mg,79.38μmol)和碳酸钾(164.57mg,1.19mmol),CO氛围下,110℃过夜。反应结束后,反相制备得EVO33110-A5(41mg,收率:42.64%)。
第6步:
室温下,EVO33110-A5(20mg,82.56μmol)溶于DMF(2mL),再加入中间体1-A1(28.85mg,82.56μmol)、三乙胺(41.69mg,412.80μmol)和HATU(69.06mg,181.63μmol),搅拌过夜。反应结束后,反应液中加入水(50mL),EA(3*30mL)萃取,有机相浓缩高压制备,得EVO33110(14mg,收率:29.56%)。LCMS(ESI)m/z=574.01[M+H]+。纯度:99.25%。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=6.0Hz,1H),9.39(s,1H),8.64(q,J=8.8Hz,2H),7.96(s,1H),7.91(d,J=7.2Hz,1H),7.79(s,1H),7.77-7.72(m,1H),7.67(s,1H),7.03(d,J=8.4Hz,1H),4.79(d,J=5.6Hz,2H),4.72(t,J=8.8Hz,2H),4.36-4.27(m,2H),3.72-3.63(m,2H),3.58(t,J=8.8Hz,2H),3.26(s,3H),2.53-2.47(m,2H),1.21(d,J=6.2Hz,6H)。
实施例26 EVO33357
参照化合物EVO33110,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33357(1.8mg,收率:5.45%),LCMS(ESI)m/z=588.41[M+H]+,纯度:92.5%。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=5.6Hz,1H),9.39(s,1H),8.64(q,J=8.8Hz,2H),7.91(t,J=4.4Hz,2H),7.80(s,1H),7.75(t,J=8.0Hz,1H),7.68(s,1H),7.03(d,J=8.4Hz,1H),4.79(d,J=5.6Hz,2H),4.71(t,J=8.8Hz,2H),4.38-4.27(m,2H),3.71-3.62(m,2H),3.56(t,J=8.8Hz,2H),3.38-3.37(m,2H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H),1.16(t,J=7.2Hz,3H)。
实施例27 EVO33115
第1步:
室温下,4-溴-2-氟-6-甲基苯甲酸(4g,17.16mmol)溶于水(40mL),再加入KMnO4(8.14g,51.49mmol)和NaOH(2.75g,68.66mmol),80℃过夜。反应结束后,过滤,滤液用1N盐酸酸化至pH=3,EA(3*50mL)萃取,合并有机相,无水Na2SO4干燥,过滤,蒸干滤液得EVO33115-A1(4g,收率:88.60%)。1H NMR(400MHz,DMSO-d6)δ7.95(dd,J=8.9,1.8Hz,1H),7.85(d,J=1.8Hz,1H).
第2步:
EVO33115-A1(8g,30.42mmol)溶于甲醇(150mL)和浓硫酸(14.92g,152.08mmol),回流过夜。反应结束后,蒸去溶剂后,加入水(100mL),EA(3*50mL)萃取,合并有机相,无水Na2SO4干燥,过滤,有机相浓缩,中压制备得EVO33115-A2(8.5g,收率:96.01%)。
第3步:
0℃下,EVO33115-A2(8.5g,29.20mmol)溶于无水THF(50mL),加入四氢铝锂(2.44g,64.25mmol),反应结束后,加水(5mL)淬灭,过滤,滤液加入水(100mL),EA(3*50mL)萃取,有机相浓缩,中压制备得EVO33115-A3(4.5g,收率:65.56%)。
第4步:
室温下,EVO33115-A3(4.6g,19.57mmol)溶于二氯甲烷(50mL),加入二氧化锰(8.17g,93.94mmol),原料消失后,过滤,取滤液,加入三乙基硅烷(6.83g,58.71mmol)和三氟乙酸(10.71g,93.94mmol),2小时后,反应结束,蒸去溶剂后,加入水(100mL),EA(3*50mL)萃取,有机相浓缩,中压制备得EVO33115-A4(3.6g,收率:84.76%)。
第5步:
室温下,EVO33115-A4(220mg,1.01mmol)溶于DMF(5mL),加入甲硫醇钠(355.24mg,5.07mmol),反应升温至100℃,2小时后反应结束,加入水(30mL),EA(3*50mL)萃取,有机相蒸干得EVO33115-A5(90mg,收率:36.22%),直接用于下一步。
第6步:
室温下,EVO33115-A5(260mg,1.06mmol)溶于乙腈(10mL)和水(10mL),加入Oxone(3.26g,
5.30mmol),然后升温至60℃,1小时后反应结束,蒸去乙腈,加入水(30mL),EA(3*50mL)萃取,有机相蒸干得EVO33115-A6(290mg,收率:98.66%),直接用于下一步。
第7步:
室温下,EVO33115-A6(90mg,324.75μmol),加入DMSO(5mL)、水(0.5mL)、醋酸钯(14.58mg,64.95μmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(39.64mg,64.95μmol)和碳酸钾(134.65mg,974.26μmol),CO氛围下,100℃反应过夜。结束后,反相制备得EVO33115-A7(10mg,收率:12.71%)。
第8步:
室温下,EVO33115-A7(10mg,41.28μmol)溶于DMF(2mL),再加入中间体1-A1(21.64mg,61.92μmol)、DIPEA(21.34mg,165.12μmol)和HATU(23.54mg,61.92μmol),搅拌过夜。反应结束后,加入水(50mL),EA(3*30mL)萃取,有机相浓缩高压制备,得EVO33115(14mg,收率:59.12%)。LCMS(ESI)m/z=574.4[M+H]+。纯度:98.4%。1H NMR(400MHz,DMSO-d6)δ9.58(t,J=6.0Hz,1H),9.40(s,1H),8.65(q,J=8.4Hz,2H),8.37(s,1H),8.25(s,1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.79-7.71(m,1H),7.03(d,J=8.4Hz,1H),5.35(t,J=2.0Hz,2H),5.14(s,2H),4.82(d,J=5.6Hz,2H),4.35-4.27(m,2H),3.71-3.62(m,2H),3.29(s,3H),2.54-2.47(m,2H),1.21(d,J=6.0Hz,6H)。
实施例28 EVO33369
参照化合物EVO33115,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33369(10mg,收率:36.34%),LCMS(ESI)m/z=588.4[M+H]+,纯度:95.8%。1H NMR(400MHz,DMSO-d6)δ9.59(t,J=6.0Hz,1H),9.40(s,1H),8.65(q,J=8.4Hz,2H),8.32(s,1H),8.27(s,1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.77-7.73(m,1H),7.03(d,J=8.4Hz,1H),5.32(s,2H),5.14(s,2H),4.82(d,J=5.6Hz,2H),4.34-4.28(m,2H),3.75-3.62(m,2H),3.38(q,J=7.2Hz,2H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H),1.15(t,J=7.2Hz,3H)。
实施例29 EVO33124
第1步:
将8-氟-2,3-二氢苯并吡喃-4-酮(900mg,5.42mmol)及三乙基硅烷(2.52g,21.67mmol)加入到三氟乙酸(5mL)中,在25℃下反应72小时。TLC监测反应完毕,反应液减压浓缩,中压正相快速柱层析得到无色油状物EVO33124-A1(670mg,收率:81%)。
第2步:
将化合物EVO33124-A1(530mg,3.49mmol)加入到乙酸(5mL)中,再加入溴素(613mg,3.84mmol),在25℃下反应15分钟。TLC监测反应完毕,反应液减压浓缩,中压正相快速柱层析得到无色油状物EVO33124-A2(450mg,收率:55%)。
第3步:
将化合物EVO33124-A2(176mg,0.76mmol)及甲硫醇钠(80mg,1.14mmol)加入到DMF(2mL)中,在50℃下反应2小时。反应完毕,将反应中加入EA和水,分层萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得粗品,中压正相柱层析纯化(PE/EA=50/1),得到产物EVO33124-A3(165mg,收率:83%)。1H NMR(400MHz,Chloroform-d)δ7.00(s,1H),6.97(s,1H),4.26(t,J=5.2Hz 2H),2.75(t,J=6.4Hz,2H),2.41(s,3H),2.05-1.94(m,2H).
第4步:
室温下,将EVO33124-A3(165mg,0.64mmol)溶于乙腈(2mL)和水(2mL)溶液中,加入固体Oxone(1.17g,1.91mmol),反应搅拌过夜。反应完毕,将反应液浓缩,加入EA和水,分层萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得粗品,中压正相柱层析纯化(PE/EA=10/1),得到产物EVO33124-A4(176mg,收率:94%)。
第5步:
室温下,向单口瓶中依次加入EVO33124-A4(176mg,0.604mmol),Pd(OAc)2(14mg,0.06mmol),DCCP-2HBF4(74mg,0.121mmol),K2CO3(167mg,1.21mmol),H2O(0.1mL)和DMSO(3mL),反应体系用CO置换3次后,加热到100℃搅拌过夜。反应结束后,用稀HCl(1M)调pH=3,用中压反相柱层析纯化(H2O/CH3CN=0-50%),冻干得白色固体EVO33124-A5(65mg,收率:41%),LCMS(ESI)m/z=255.2[M-H]-。
第6步:
室温下,将EVO33124-A5(23mg,0.089mmol)和中间体1-A1(31mg,0.089mmol)溶于DMF(3mL)中,依次加入DIPEA(35mg,0.267mmol)和HATU(51mg,0.134mmol),反应体系在室温下搅拌1小时。反应完毕,反应体系加水淬灭,用EA萃取2次,合并有机相,水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,Prep-HPLC制备后,冻干得淡黄色固体EVO33124(11mg,收率:20%),LCMS(ESI)m/z=588.1[M+H]+。纯度:99.67%。1H NMR(400MHz,DMSO-d6)δ9.39(s,2H),8.68-8.61(m,2H),8.27(s,1H),8.08(s,1H),7.90(d,J=7.2Hz,1H),7.76(s,1H),7.73(d,J=7.2Hz,1H),7.03(d,J=8.4Hz,1H),4.77(d,J=5.2Hz,2H),4.42(t,J=5.2Hz,2H),4.35-4.26(m,2H),3.72-3.63(m,2H),3.27(s,3H),2.94-2.87(d,J=6.4Hz,2H),2.56-2.52(m,2H),2.06-2.00(m,2H),1.21(d,J=6.0Hz,6H)。
实施例30 EVO33025
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33025(10mg,收率:43.4%),LCMS(ESI)m/z=586.1[M+H]+,纯度:99.3%。1H NMR(400MHz,DMSO-d6)δ9.57(t,J=6.0Hz,1H),9.41(s,1H),8.74(d,J=1.6Hz,1H),8.68-8.61(m,2H),8.54(s,1H),8.51(d,J=1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.83(s,1H),7.72(t,J=8.0Hz,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=5.6Hz,2H),4.31(d,J=12Hz,2H),4.20(s,3H),3.70-3.65(m,2H),3.51(s,3H),2.52-2.46(m,2H),1.21(d,J=6.4Hz,6H)。
实施例31 EVO33160
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33160(16.31mg,收率:29.1%),LCMS(ESI)m/z=600.6[M+H]+,纯度:90.5%。1H NMR(400MHz,DMSO-d6)δ9.60(t,J=5.9Hz,1H),9.40(s,1H),8.88(d,J=1.8Hz,1H),8.70–8.51(m,4H),7.92-7.82(m,2H),7.73(t,J=7.8Hz,1H),7.02(d,J=8.5Hz,1H),4.84(d,J=5.8Hz,2H),4.44(s,3H),4.31(d,J=12.7Hz,2H),3.73-3.55(m,4H),2.46-2.41(m,2H),1.23-1.17(m,9H)。
实施例32 EVO33232
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33232(21.4mg,收率:32.6%),LCMS(ESI)m/z=603.2[M+H]+,纯度:92.06%。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.72(t,J=6.0Hz,1H),9.41(s,1H),9.21(d,J=1.6Hz,1H),8.69-8.62(m,3H),7.92-7.87(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),4.86(d,J=5.6Hz,2H),4.31(d,J=12.8Hz,2H),3.78(t,J=7.2Hz,2H),3.71-3.63(m,2H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H),1.15(t,J=7.2Hz,3H)。
实施例33 EVO33281
参照化合物EVO331168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33281(2.3mg,收率:2.59%),LCMS(ESI)m/z=603.2[M+H]+,纯度:98.44%。1H NMR(400MHz,Chloroform-d)δ9.72(s,1H),9.30(s,1H),8.81(d,J=8.4Hz,1H),8.52-8.42(m,2H),8.25(s,1H),8.16(s,1H),8.09(d,J=7.2Hz,1H),7.86(s,1H),7.74(t,J=8.0Hz,1H),6.84(d,J=8.4Hz,1H),5.05(d,J=5.6Hz,2H),4.70(s,2H),4.21(d,J=12.4Hz,2H),3.83-3.75(m,2H),3.22(s,3H),2.69-2.59(m,2H),1.33(d,J=6.0Hz,6H)。
实施例34 EVO33313
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33313(15mg,收率:40%),LCMS(ESI)m/z=575.4[M+H]+,纯度:99.14%。1H NMR(400MHz,DMSO-d6)δ9.44-9.40(m,2H),8.64(q,J=8.4Hz,2H),8.53(d,J=1.6Hz,1H),8.40(s,1H),8.00(d,J=1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.82(s,1H),7.72(t,J=8.4Hz,1H),7.02(d,J=8.4Hz,1H),4.82(d,J=6.0Hz,2H),4.51(s,3H),4.31(d,J=12.4Hz,2H),3.69-3.64(m,2H),2.52-2.46(m,2H),1.97(s,6H),1.21(d,J=6.4Hz,6H)。
实施例35 EVO33323
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33323(81mg,收率:95%),LCMS(ESI)m/z=586.4[M+H]+,纯度:95.6%。1H NMR(400MHz,DMSO-d6)δ13.80(bs,1H),9.63(t,J=6.0Hz,1H),9.43(s,1H),8.91(d,J=1.6Hz,1H),8.70-8.63(m,2H),8.54(d,J=1.2
Hz,1H),8.50(d,J=1.2Hz,1H),7.92(d,J=7.2Hz,1H),7.87(s,1H),7.73-7.77(m,1H),7.04(d,J=8.4Hz,1H),4.88(d,J=1.4Hz,2H),4.34(d,J=2.4Hz,1H),4.31(d,J=2.4Hz,1H),3.65-3.73(m,2H),3.49-3.55(m,2H),2.48-2.54(m,2H),1.24(d,J=6.4Hz,6H),1.21(t,J=7.2Hz,3H)。
实施例36 EVO33324
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33324(30mg,收率:51%),LCMS(ESI)m/z=599.1[M+H]+,纯度:88.4%。1H NMR(400MHz,Chloroform-d)δ9.34(s,1H),8.89-8.87(m,1H),8.58-8.57(m,1H),8.54-8.52(m,1H),8.47-8.46(m,2H),8.29-8.23(m,1H),8.13-8.11(m,1H),7.78-7.74(m,1H),6.87(d,J=8.8Hz,1H).6.81-6.80(m,2H),5.16-5.14(m,2H),4.73-4.67(m,2H),4.22-4.19(m,2H),3.81-3.77(m,2H),3.38(s,3H),2.68-2.62(m,2H),1.50-1.58(m,3H),1.34(d,J=6.4Hz,6H)。
实施例37 EVO33326
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33326(17mg,收率:37%),LCMS(ESI)m/z=585.1[M+H]+,纯度:99.73%。1H NMR(400MHz,Chloroform-d)δ9.88(s,1H),9.24(s,1H),8.62-8.60(m,1H),8.47-8.46(m,1H),8.35-8.33(m,1H),8.15-8.14(m,1H),8.02-7.99(m,2H),7.69(t,J=8.4Hz,1H),7.63-7.61(m,1H),7.38-7.37(m,1H),6.76(d,J=8.4Hz,1H).6.73-6.71(m,1H),5.01(d,J=5.2Hz,2H),4.22-4.18(m,2H),3.81-3.76(m,2H),3.25-3.19(m,2H),2.64-2.59(m,2H),1.32(d,J=6.4Hz,6H),1.26(t,J=7.6Hz,3H)。
实施例38 EVO33327
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33327(5mg,收率:22%),LCMS(ESI)m/z=599.1[M+H]+,纯度:99.03%。1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.63-8.61(m,1H),8.50-8.49(m,1H),8.38-8.34(m,2H),8.02-8.00(m,2H),7.69(t,J=8.4Hz,1H),7.54-7.53(m,1H),7.17-7.16(m,1H),6.78-6.73(m,2H),5.02(d,J=5.6Hz,2H).4.24(s,3H),
4.23-4.19(m,2H),3.81-3.77(m,2H),3.39-3.33(m,2H),2.65-2.59(m,2H),1.37(d,J=7.2Hz,3H),1.32(d,J=6.4Hz,6H)。
实施例39 EVO33330
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33330(14.49mg,收率:25%),LCMS(ESI)m/z=586.4[M+H]+,纯度:98.6%。1H NMR(400MHz,DMSO-d6)δ9.65(t,J=6.0Hz,1H),9.43(s,1H),8.74-8.73(m,1H),8.72-8.62(m,2H),8.41(d,J=1.6Hz,1H),8.38(d,J=2.4Hz,1H),7.94-7.92(m,1H),7.87(s,1H),7.78-7.74(m,1H),7.36(d,J=2.0Hz,1H),7.05(d,J=8.4Hz,1H),4.87(d,J=6.0Hz,2H),4.36-4.32(m,2H),3.74-3.66(m,2H),3.56(q,J=7.6Hz,2H),2.56-2.48(m,2H),1.24(d,J=6.4Hz,6H),1.20(t,J=7.6Hz,3H)。
实施例40 EVO33331
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33331(9mg,收率:36%),LCMS(ESI)m/z=602.4[M+H]+,纯度:96.9%。1H NMR(400MHz,DMSO-d6)δ9.70(t,J=6Hz,1H),9.44(s,1H),8.92(d,J=1.6Hz,1H),8.73-8.61(m,2H),8.51(d,J=1.6Hz,1H),8.13(d,J=5.6Hz,1H),7.93(d,J=7.2Hz,1H),7.95-7.88(m,2H),7.82-7.73(m,2H),7.05(d,J=8.4Hz,1H),4.90(d,J=6.0Hz,2H),4.37-4.30(m,2H),3.76-3.64(m,2H),3.48(d,J=7.4Hz,2H),2.58-2.45(m,2H),1.24(d,J=6.0Hz,6H),1.17(t,J=7.2Hz,3H)。
实施例41 EVO33356
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33356(27.87mg,收率:30%),LCMS(ESI)m/z=586.4[M+H]+,纯度:98.4%。1H NMR(400MHz,DMSO-d6)δ9.64(t,J=6.0Hz,1H),9.41(s,1H),8.72-8.58(m,3H),8.46(d,J=2.0Hz,1H),8.42(d,J=1.2Hz,1H),7.90(d,J=7.6Hz,1H),7.86(s,1H),7.75-7.71(m,1H),7.35-7.34(m,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=5.6Hz,2H),4.33-4.29(m,2H),3.71-3.63(m,2H),3.41(q,J=7.6Hz,2H),2.56-2.48(m,2H),1.21(d,J=6.4Hz,6H),1.14(t,J=7.2Hz,3H)。
实施例42 EVO33395
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33395(9.8mg,收率:48.8%),LCMS(ESI)m/z=600.4[M+H]+,纯度:99.9%。1H NMR(400MHz,DMSO-d6)δ9.53(t,J=5.8Hz,1H),9.40(s,1H),8.68-8.60(m,2H),8.59(d,J=1.6Hz,1H),8.45(d,J=1.6Hz,1H),7.90(d,J=7.2Hz,1H),7.82(s,1H),7.72(t,J=7.6Hz,1H),7.02(d,J=8.4Hz,1H),4.84(d,J=6.0Hz,2H),4.31(d,J=12.4Hz,2H),4.14(s,3H),3.70-3.65(m,2H),3.50(s,3H),2.65(s,3H),2.52-2.47(m,2H),1.21(d,J=6.4Hz,6H)。
实施例43 EVO33362
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33362(15mg,收率:53%),LCMS(ESI)m/z=520.9[M+H]+,纯度:99.89%。1H NMR(400MHz,DMSO-d6)δ9.44-9.41(m,2H),8.72-8.61(m,2H),8.20(d,J=7.6Hz,1H),7.92-7.88(m,2H),7.81-7.80(m,2H),6.98(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.51(q,J=7.2Hz,2H),3.38(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H),1.18(t,J=7.2Hz,3H)。
实施例44 EVO33363
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33363(9mg,收率:32%),LCMS(ESI)m/z=516.9[M+H]+,纯度:99.77%。1H NMR(400MHz,DMSO-d6)δ9.44-9.41(m,2H),8.70-8.60(m,2H),8.34(d,J=7.6Hz,1H),7.90-7.80(m,4H),7.47(d,J=8.0Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),3.38(q,J=7.2Hz,2H),2.26-2.20(m,1H),1.18(t,J=7.2Hz,3H),1.12-1.03(m,4H)。
实施例45 EVO33364
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33364(10.8mg,收率:20.5%),LCMS(ESI)m/z=588.4[M+H]+,纯度:92.7%。1H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.63(q,J=8.0Hz,2H),7.93-7.87(m,2H),7.82-7.77(m,2H),7.73(t,J=8.0Hz,1H),6.91(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.49(s,2H),4.00(d,J=12.4Hz,2H),3.38(q,J=7.2Hz,2H),3.07-3.03(m,2H),1.93-1.74(m,4H),1.18(t,J=7.2Hz,3H)。
实施例46 EVO33390
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33390(18.8mg,收率:12.6%),LCMS(ESI)m/z=556.7[M+H]+,纯度:99.95%。1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.75(d,J=8.7Hz,1H),8.45(d,J=8.7Hz,1H),8.16(s,1H),8.09(d,J=7.4Hz,1H),7.83-7.73(m,2H),7.71(d,J=1.8Hz,1H),7.38(d,J=1.8Hz,1H),6.85(d,J=8.4Hz,1H),6.09(s,2H),5.04(d,J=5.5Hz,2H),4.29-4.20(m,2H),3.88-3.78(m,2H),2.72-2.63(m,2H),1.67(s,6H),1.38(d,J=6.2Hz,6H)。
实施例47 EVO33396
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33396(17.4mg,收率:38%),LCMS(ESI)m/z=590.4[M+H]+,纯度:99.49%。1H NMR(400MHz,DMSO-d6)δ9.45-9.34(m,2H),8.70-8.58(m,2H),7.92-7.87(m,2H),7.81(d,J=1.6Hz,1H),7.79-7.78(m,1H),7.75-7.71(m,1H),7.01(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.12-4.05(m,2H),3.76(d,J=3.2Hz,1H),3.72(d,J=3.6Hz,1H),3.42-3.33(m,4H),1.25-1.14(m,9H)。
实施例48 EVO33397
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33397(13.09mg,收率:12%),LCMS(ESI)m/z=590.2[M+H]+,纯度:96.6%。1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.68-8.66(m,1H),8.40-8.37(m,1H),8.02-8.00(m,2H),7.82-7.81(m,1H),7.72-7.68(m,2H),7.61-7.56(m,1H),6.76(d,J=8.4Hz,1H),6.24(s,2H),4.98(d,J=5.2Hz,2H),4.22-4.18(m,2H),3.80-3.76(m,2H),3.81-3.77(m,2H),3.36-3.26(m,2H),1.35-1.30(m,9H)。
实施例49 EVO33399
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33399(24.5mg,收率:52%),LCMS(ESI)m/z=576.4[M+H]+,纯度:99.33%。1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J=8.8Hz,1H),8.38(d,J=8.8Hz,1H),8.06-8.01(m,2H),7.83(d,J=1.6Hz,1H),7.75-7.63(m,3H),6.75(d,J=8.4Hz,1H),6.24(s,2H),4.98(d,J=5.2Hz,2H),4.47-4.41(m,1H),4.12-4.00(m,2H),3.89-3.81(m,2H),3.73-3.65(m,1H),3.39-3.25(m,3H),1.37-1.30(m,6H)。
实施例50 EVO33402
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33402(4.18mg,收率:9.7%),LCMS(ESI)m/z=556.3[M+H]+,纯度:98.4%。1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.61-8.60(m,1H),8.39(d,J=8.8Hz,1H),8.17-8.10(m,2H),8.08(s,1H),7.98-7.95(m,1H),7.83(d,J=1.6Hz,1H),7.70(d,J=1.6Hz,1H),7.66(s,1H),7.59(t,J=7.6Hz,1H),7.44(d,J=2.4Hz,1H),6.67(d,J=2.4Hz,1H),6.24(s,2H),4.99(d,J=5.2Hz,2H),4.00(s,3H),3.29(q,J=7.6Hz,2H),1.34(t,J=7.2Hz,3H)。
实施例51 EVO33404
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33404(18.2mg,收率:47%),LCMS(ESI)m/z=573.4[M+H]+,纯度:98.10%。1H NMR(400MHz,Chloroform-d)δ9.53-9.33(m,1H),8.53-8.30(m,2H),8.05-7.94(m,1H),7.87-7.74(m,2H),7.69-7.30(m,5H),6.22
(s,2H),5.10(d,J=6.2Hz,2H),4.45-4.32(m,2H),3.82-3.72(m,2H),3.38-3.33(m,3H),3.30-3.25(m,2H),1.36-1.29(m,3H)。
实施例52 EVO33502
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33502(4.1mg,收率:12%),LCMS(ESI)m/z=562.1[M+H]+,纯度:99.43%。1H NMR(400MHz,DMSO-d6)δ9.39(q,J=2.8Hz,2H),8.71-8.55(m,2H),7.97-7.86(m,2H),7.82-7.74(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.7Hz,2H),3.79-3.74(m,4H),3.60(t,J=4.8Hz,4H),3.38(q,J=7.2Hz,2H),1.18(t,J=7.2Hz,3H)。
实施例53 EVO33503
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33503(2.1mg,收率:4.5%),LCMS(ESI)m/z=576.3[M+H]+,纯度:99.35%。1H NMR(400MHz,DMSO-d6)δ9.44-9.34(m,2H),8.64(q,J=8.8Hz,2H),7.94-7.87(m,2H),7.83-7.72(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.33-4.18(m,2H),4.01-3.93(m,1H),3.67-3.56(m,2H),3.43-3.37(m,2H),2.97-2.85(m,1H),2.63-2.55(m,1H),1.23-1.16(m,6H)。
实施例54 EVO33506
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33506(21.6mg,收率:22.5%),LCMS(ESI)m/z=576.2[M+H]+,纯度:98.69%。1H NMR(400MHz,DMSO-d6)δ9.44-9.33(m,2H),8.65(d,J=8.6Hz,1H),8.59(d,J=8.6Hz,1H),7.90(d,J=1.7Hz,1H),7.85-7.77(m,3H),7.73-7.66(m,1H),6.88(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.8Hz,2H),3.93-3.87(m,2H),3.86-3.77(m,4H),3.63(t,J=5.5Hz,2H),3.38(q,J=7.3Hz,2H),1.99-1.91(m,2H),1.19(t,J=7.3Hz,3H).
实施例55 EVO33179
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33179(10mg,收率:26%),LCMS(ESI)m/z=574.1[M+H]+,纯度:99.73%。1H NMR(400MHz,DMSO-d6)δ9.35(t,J=6.0Hz,1H),9.09(s,1H),8.29(d,J=9.2Hz,1H),8.19(d,J=8.2Hz,1H),7.88(d,J=1.6Hz,1H),7.79(d,J=1.6Hz,1H),7.47(s,1H),7.21(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.35(s,2H),4.69(d,J=6.0Hz,2H),4.31-4.27(m,4H),3.37(q,J=7.2Hz,2H),2.04-1.97(m,1H),1.17(t,J=7.2Hz,3H),0.88-0.76(m,4H)。
实施例56 EVO33361
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33361(16mg,收率:47.5%),LCMS(ESI)m/z=577.9[M+H]+,纯度:99.3%。1H NMR(400MHz,DMSO-d6)δ9.36(t,J=5.9Hz,1H),9.10(s,1H),8.32(s,2H),7.88(d,J=1.6Hz,1H),7.79(d,J=1.7Hz,1H),7.48(s,1H),7.32(d,J=8.6Hz,1H),6.46(d,J=8.5Hz,1H),6.35(s,2H),4.70(d,J=5.8Hz,2H),4.28(s,4H),4.17(q,J=7.0Hz,2H),3.37(q,J=7.4Hz,2H),1.28(t,J=7.0Hz,3H),1.18(t,J=7.4Hz,3H)。
实施例57 EVO33240
第1步:
室温下,间溴苄胺(1.0g,5.37mmol)、Na2CO3(1.14g,10.75mmol)、Boc2O(1.29g,5.91mmol)和THF(20mL)室温搅拌2小时,LC-MS监测反应结束,加入水(30mL),EA(30mL*3)萃取,有机相用无水Na2SO4干燥,过滤,滤液浓缩后得到白色固体EVO33240-A1(1.15g,粗品),LCMS(ESI)m/z=286.1[M+H]+。
第2步:
N2保护下,加入EVO33240-A1(130mg,454.28μmol),(2S,6R)-2,6-二甲基-4-(6-乙烯基-2-吡啶基)吗啉(99.17mg,454.28μmol),Pd(OAc)2(10.20mg,45.43μmol),三邻甲苯膦(27.65mg,90.86μmol),三乙胺(137.91mg,1.36mmol)和DMF(2mL),升温至120℃,5小时后检测反应有少量原料剩余,冷至室温后用硅藻土过滤,滤液中加入水(30mL),EA(30mL*3)萃取,有机相用饱和氯化钠溶液(30mL*3)洗涤,无水Na2SO4干燥,过滤,滤液浓缩后,中压正相柱层析纯化(PE/EA=0-50%)得淡黄色固体EVO33240-A2(50mg,收率:26%),LCMS(ESI)m/z=424.3[M+H]+。
第3步:
室温下,EVO33240-A2(50mg,118.05μmol),DCM(5mL)和TFA(40.38mg,354.15μmol),搅拌2小时,LC-MS监测反应结束,减压浓缩,除去大部分TFA,冻干处理得黄色油状物EVO33240-A3(50mg,粗品)直接进入下一步。LCMS(ESI)m/z=324.1[M+H]+。
第4步:
室温下,7-(乙基磺酰基)苯并[d][1,3]二氧戊烯-5-羧酸(22.47mg,92.76μmol)溶于DMF(7.94mL)中,加入DIPEA(59.94mg,463.78μmol)和HATU(52.90mg,139.13μmol)搅拌5分钟后加入EVO33240-A3(30mg,92.76μmol),继续搅拌,3小时候反应结束,向体系中加入水(20mL),乙酸乙酯(30mL*3)萃取,合并有机相盐水洗涤三次,无水Na2SO4干燥,过滤,浓缩,得到粗品,随后制备液相进行制备,浓缩,冻干得白色产物EVO33240(5mg,收率:9.6%),LCMS(ESI)m/z=564.1[M+H]+;纯度:96.14%。1H NMR(400MHz,DMSO-d6)δ9.17(t,J=6.0Hz,1H),7.82(d,J=1.6Hz,1H),7.73(d,J=1.6Hz,1H),7.60-7.50(m,4H),7.35(t,J=7.6Hz,1H),7.25(d,J=7.6Hz,1H),7.17-7.09(m,1H),6.82(d,J=7.2Hz,1H),6.75(d,J=8.4Hz,1H),6.33(s,2H),4.49(d,J=5.6Hz,2H),4.27-4.18(m,2H),3.67-3.61(m,2H),3.36(t,J=7.2Hz,2H),2.45-2.37(m,2H),1.18(d,J=6.4Hz,6H),1.15(t,J=7.2Hz,3H)。
实施例58 EVO33343
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33343(2.6mg,收率:6.2%),LCMS(ESI)m/z=665.6[M+H]+,纯度:97.71%。1H NMR(400MHz,DMSO-d6)δ9.22(t,J=5.8Hz,1H),8.49(d,J=5.0Hz,1H),7.84(d,J=1.6Hz,1H),7.76(d,J=1.6Hz,1H),7.60-7.50(m,
4H),7.42-7.34(m,1H),6.87(d,J=7.3Hz,1H),6.81(d,J=8.6Hz,1H),6.33(s,2H),4.57(d,J=5.8Hz,2H),4.28-4.21(m,2H),3.67-3.56(m,2H),3.40-3.36(m,2H),2.45-2.35(m,2H),1.20-1.15(m,9H)。
实施例59&实施例60 EVO33338&EVO33339
第1步:
室温下,5-溴-1,3-二氟-2-硝基苯(10g,42.02mmol)、K2CO3(29.04g,210.10mmol)、苄胺(4.50g,42.02mmol)和THF(500mL)搅拌3小时。TLC(PE/DCM=5/1)显示原料苄胺消失,双氟化物有少量剩余。过滤,EA洗涤滤饼,滤液中加入粗硅胶旋干,中压正相柱层析纯化(PE/DCM=0-20%)得黄色固体EVO33338-A1(10.3g,收率:75.39%)。LCMS(ESI)m/z=324.8/326.8[M+H]+。
第2步:
氩气下,EVO33338-A1(9.9g,30.45mmol)、乙硫醇钠(3.84g,45.67mmol)和THF(200mL)油浴25℃搅拌过夜。TLC(PE/DCM=4/1)显示少量原料未反应完全。加水(300mL)和饱和氯化钠溶液(100mL),EA萃取3次,合并有机相,依次以水和饱和氯化钠溶液洗涤1次,无水Na2SO4干燥,过滤,滤液旋干,得橙红色固体EVO33338-A2(11.1g,粗品)。LCMS(ESI)m/z=366.8/368.8[M+H]+。
第3步:
反应瓶中加入EVO33338-A2(11.1g,30.22mmol),CH3CN(200mL),水(200mL)和Oxone(55.74g,90.67mmol),油浴35℃搅拌过周末,LC-MS显示约25%为亚砜,75%为产物。补加Oxone(27.87g,45.34mmol),CH3CN(100mL),水(100mL),油浴35℃搅拌过夜。LC-MS显示约11%为亚砜。蒸去溶剂,加入水(200mL),搅拌片刻后抽滤,水洗,收集滤饼,加入DCM溶解,中压正相柱层析纯化(PE/EA=0-40%)得橙色固体EVO33338-A3(10.3g,粗品)。LCMS(ESI)m/z=398.8/400.8[M+H]+。
第4步:
室温下,向EVO33338-A3(3g,7.51mmol)中依次加入Pd(dppf)Cl2-CH2Cl2(613.61mg,751.39μmol),DMF(50mL)和MeOH(50mL),TEA(2.28g,22.54mmol,3.14mL),反应体系用CO置换3次后,油浴80℃搅拌过夜,TLC(PE/EA=3/1)显示原料基本转化完全。蒸去MeOH,加入水,以EA萃取3次,合并有机相依次以水洗3次,饱和氯化钠溶液洗1次,有机相旋干,中压正相柱层析纯化(PE/EA=0-25%)得橙黄色油状物EVO33338-A4(980mg,粗品)。
第5步:
室温下,EVO33338-A4(980mg,2.59mmol)中加入MeOH(30mL)和Pd(OH)2(20%)(200mg,1.42mmol),H2置换后,室温搅拌3小时。LC-MS显示反应结束。经Celite抽滤,MeOH洗涤,滤液旋干,中压正相柱层析纯化(DCM/MeOH=0-5%)得到类白色固体EVO33338-A5(566mg,收率:84.61%)。LCMS(ESI)m/z=258.9[M+H]+。
第6步:
氩气保护下,EVO33338-A5(565mg,2.19mmol),CH3CN(18mL)和亚硝酸异戊酯(384.38mg,3.28mmol,439.29μL)油浴60℃搅拌1小时。LC-MS显示反应完全。旋干,加入MTBE(30mL),超声后搅拌片刻,抽滤,少量MTBE洗涤,收集滤饼。滤液旋干,加入PE/EA=1/2打浆,抽滤,少量PE/EA=1/1洗涤,收集滤饼;两次滤饼合并,得浅灰色固体EVO33338-A6(490mg,收率:83%)。LCMS(ESI)m/z=269.8[M+H]+。
第7步:
Ar保护,冰水浴下,三口瓶中加入EVO33338-A6(400mg,1.49mmol)和无水DMF(16mL),加入NaH(60%)(76mg,1.9mmol),搅拌1小时。滴入CH3I(560mg,3.95mmol,245.6μL),冰水浴下搅拌1小时,TLC(PE/EA=1/1)显示原料反应完全。饱和NH4Cl溶液淬灭,EA萃取3次,合并的有机相以水洗涤2次,饱和氯化钠溶液洗涤1次,有机相蒸干得粗品,中压正相柱层析纯化(PE/EA=
0-50%)出两个峰,依次收集组分,减压浓缩得到:A:白色固体EVO33338-A7(38mg),LCMS(ESI)m/z=283.9[M+H]+。B:类白色固体(109mg),以PE/EA=1/1(6mL)室温打浆10min,抽滤,洗涤,收集得到类白色固体EVO33339-A1(97mg),LCMS(ESI)m/z=283.9[M+H]+。
第8步:
室温下,加入EVO33338-A7(35mg,123.54μmol),THF(2mL),MeOH(1mL)和水(1mL),油浴40℃搅拌溶清,加入NaOH(34.59mg,864.80μmol),继续搅拌2小时。TLC(PE/EA=1/2)显示原料反应完全。蒸去有机溶剂,加入水(6mL),以2N稀HCl溶液调pH~1,析出固体,抽滤,水洗至中性,抽干,收集滤饼得到白色固体EVO33338-A8(26mg,收率:78.16%)。LCMS(ESI)m/z=270.2[M+H]+,268.2[M+H]-。
参照EVO33338-A8,得到白色固体EVO33339-A2(26mg,收率:68.39%)。LCMS(ESI)m/z=270.2[M+H]+,268.2[M+H]-。
第9步:
室温下,加入中间体1-A1(25.95mg,67.26μmol)、EVO33338-A8(20mg,74.27μmol)、DMF(3mL)、DIPEA(95.99mg,742.73μmol,129.37μL)和HATU(33.89mg,89.13μmol),油浴30℃搅拌40分钟。加入EA,依次以水、饱和氯化钠溶液洗涤,有机相旋干。剩余物经中压正相柱层析纯化(DCM/MeOH=0-3%)得到黄色固体粗品(28mg)。加入CH3CN(4mL),室温打浆,抽滤,少量CH3CN洗涤,抽干,收集滤饼得到黄绿色固体EVO33338(25mg,收率:56.03%)。LCMS(ESI)m/z=601.1[M+H]+。HPLC纯度:98.0%。1H NMR(400MHz,DMSO-d6)δ9.75(t,J=6.0Hz,1H),9.41(s,1H),9.16(d,J=1.6Hz,1H),8.70-8.61(m,3H),7.94-7.86(m,2H),7.73(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),4.87(d,J=5.8Hz,2H),4.62(s,3H),4.31(d,J=11.6Hz,2H),3.72-3.58(m,4H),2.54-2.46(m,2H),1.25-1.17(m,9H)。
参照EVO33338,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33339(20mg,收率:44.83%)。LCMS(ESI)m/z=601.1[M+H]+。纯度:97.6%。1H NMR(400MHz,DMSO-d6)δ9.74(t,J=6.0Hz,1H),9.41(s,1H),9.03(s,1H),8.65(q,J=8.4Hz,2H),8.54(s,1H),7.94-7.86(m,2H),7.73(t,J=8.0Hz,1H),7.02(d,J=8.4Hz,1H),4.87(d,J=6.0Hz,2H),4.67(s,3H),4.31(d,J=10.4Hz,2H),3.73-3.55(m,4H),2.54-2.46(m,2H),1.21(d,J=6.2Hz,6H),1.15(t,J=7.2Hz,3H)。
实施例61 EVO33341
第1步:
将化合物EVO3337-A6(790mg,3.06mmol)及TEA(1.55g,15.29mmol)加入到无水DCM(5mL)中,缓慢滴加SOCl2(1.09g,9.18mmol)。在50℃下反应2小时。反应完毕,将反应中加入DCM和水,分层萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得粗品,中压正相柱层析纯化(PE/EA=5/1),得到产物EVO33341-A1(650mg,收率:74%)。1H NMR(400MHz,Chloroform-d)δ9.03(d,J=1.6Hz,1H),8.95(d,J=1.6Hz,1H),4.06(s,3H),3.67(q,J=7.6Hz,2H),1.32(t,J=7.6Hz,3H)。
第2步:
往25ml瓶中加入EVO33341-A1(650mg,2.27mmol)、THF(5mL)、Methanol(5mL),水(2mL)和LiOH(476mg,11.35mmol),25℃搅拌2小时。反应完毕,用稀HCl(1N)调pH=3,用中压反相柱层析纯化(H2O/CH3CN=0-50%),冻干得白色固体EVO3341-A2(540mg,收率:87%),LCMS(ESI)m/z=271.2[M-H]-。
第3步:
室温下,将EVO33341-A2(30mg,0.109mmol)和中间体1-A1(38mg,0.109mmol)溶于DMF(3mL)中,依次加入DIPEA(42mg,0.326mmol)和HATU(62mg,0.163mmol),反应体系在室温下搅拌1小时。反应完毕,反应体系加水淬灭,用EA萃取2次,合并有机相,水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,Prep-HPLC制备后,冻干得淡黄色固体EVO33341(18mg,收率:27%),LCMS(ESI)m/z=604.4[M+H]+。纯度:99.16%。1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.91(d,J=1.6Hz,1H),8.85(d,J=1.6Hz,1H),8.70(d,J=8.8Hz,1H),8.42(d,J=8.8Hz,1H),8.11-8.07(m,2H),8.06(d,J=7.6Hz,1H),7.76-7.69(m,1H),6.80(d,J=8.4Hz,1H),5.07(d,J=5.2Hz,2H),4.25-4.17(m,2H),3.84-3.75(m,2H),3.67(q,J=7.6Hz,2H),2.67-2.58(m,2H),1.35-1.30(m,9H)。
实施例62 EVO33349
第1步:
Ar保护下,将化合物8-溴-[1,2,4]***并[1,5-a]吡啶-6-甲酸甲酯(800mg,3.12mmol)、乙基硫代S-甲基酯(1.41g,15.62mmol)、三(二亚苄基丙酮)二钯(286mg,312μmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(361mg,624μmol)和磷酸钾(1.99g,9.37mmol)加入到叔丁醇(0.5mL)及甲苯(5mL)混合溶液中,在110℃下反应24小时。反应完毕,反应液减压浓缩,中压正相快速柱层析得到白色固体EVO33349-A2(350mg,收率:50%),LCMS(ESI)m/z=224.1[M+H]+。
第2步:
室温下,将EVO33349-A2(350mg,1.57mmol)溶于乙腈(5mL)和水(5mL)溶液中,加入固体Oxone(2.89g,4.70mmol),反应搅拌过夜。反应完毕,将反应液浓缩,加入EA和水,分层萃取,合并有机相,无水Na2SO4干燥,过滤,减压浓缩得粗品,中压正相柱层析纯化(PE/EA=3/1),得到白色固体EVO33349-A3(220mg,收率:54%),LCMS(ESI)m/z=256.1[M+H]+。
第3步:
反应瓶中加入EVO33349-A3(220mg,862μmol)、THF(2mL)、Methanol(2mL)、水(1mL)和LiOH(108mg,2.59mmol),25℃搅拌2小时。反应完毕,用稀HCl(1N)调pH=3,中压反相柱层析纯化(H2O/CH3CN=0-50%),冻干得白色固体EVO3349-A4(130mg,收率:62%),LCMS(ESI)m/z=240.2[M-H]-。
第4步:
室温下,将EVO33349-A4(25mg,0.103mmol)和中间体1-A1(36mg,0.103mmol)溶于DMF(3mL)中,依次加入DIPEA(40mg,0.311mmol)和HATU(59mg,0.155mmol),室温搅拌1小时。反应完毕,加水淬灭,用EA萃取2次,合并有机相,水和饱和氯化钠溶液各洗涤1次,无水Na2SO4干燥,过滤,浓缩得粗品,Prep-HPLC制备后,冻干得淡黄色固体EVO33349(6mg,收率:10%),LCMS(ESI)m/z=572.9[M+H]+。纯度:99.90%。1H NMR(400MHz,Chloroform-d)δ9.54(d,J=1.6Hz,1H),9.28(s,1H),8.67(d,J=3.2Hz,1H),8.66(d,J=3.6Hz,1H),8.59(s,1H),8.40(d,J=8.4Hz,1H),8.03(d,J=7.2Hz,1H),8.00(s,1H),7.88-7.84(m,1H),7.74-7.69(m,1H),6.79(d,J=8.4Hz,1H),5.02(d,J=4.9Hz,2H),4.25-4.17(m,2H),3.83-3.76(m,2H),3.53(s,3H),2.68-2.61(m,2H),1.33(d,J=6.4Hz,6H)。
实施例63 EVO33350
参照化合物EVO33349,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33350(28mg,收率:36%),LCMS(ESI)m/z=572.4[M+H]+,纯度:99.97%,1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.58(s,1H),9.41(s,1H),8.69-8.60(m,2H),8.42(s,1H),8.32(s,1H),7.92-7.84(m,3H),7.74(t,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),4.88-4.80(m,2H),4.35-4.26(m,2H),3.72-3.62(m,2H),3.58(s,3H),2.66-2.60(m,2H),1.21(d,J=5.6Hz,6H)。
实施例64 EVO33383
第1步:
室温下,反应瓶中加入7-溴苯并[D][1,3]二氧戊环-5-羧酸(900mg,3.67mmol)、K2CO3(1.02g,7.35mmol)和DMF(10mL),然后滴加CH3I(1.04g,7.35mmol),室温搅拌16小时。向体系缓慢滴加饱和氯化铵溶液,析出白色固体,过滤,滤饼用水淋洗(5mL*3),滤饼烘干得白色固体EVO33383-A1(936mg,收率:98.4%)。
第2步:
室温下,反应瓶中加入EVO33383-A1(400mg,1.54mmol)、苄硫醇(230.14mg,1.85mmol)、DIPEA(598.67mg,4.63mmol,806.84μL)和无水1,4-二氧六环(5mL),Ar置换,加入Xantphos(178.69mg,308.82μmol)和Pd2(dba)3(141.39mg,154.41μmol),再次Ar置换,油浴加热93℃,反应6小时。向体系加入水(30mL),EA萃取(20mL*3),有机相水洗和饱和氯化钠溶液洗,无水Na2SO4干燥,
过滤,浓缩得粗品,中压正相柱层析纯化(PE/EA=0–10%)得黄色油状物EVO33383-A2(570mg,粗品)。
第3步:
室温下,EVO33383-A2(60mg,198.45μmol)溶于混合溶剂(2mL,ACN:H2O:AcOH=80:2:1),加入1,3-二氯-5,5-二甲基咪唑啉-2,4-二酮(58.65mg,297.67μmol,39.10μL),室温搅拌2.5小时。减压浓缩除去溶剂,得EVO33383-A3(60mg,粗品)直接下一步反应。
第4步:
室温下,反应瓶中加入EVO33383-A3(60mg,215.31μmol),TEA(0.2mL)和DCM(2mL),最后加入甲胺溶液(0.2mL,2M in THF),室温搅拌1小时。减压浓缩拌料过柱,中压正相柱层析纯化(PE/EA=0–50%)得淡黄色固体EVO33383-A4(36mg,收率:61.2%),LCMS(ESI)m/z=274.0[M+H]+。
第5步:
室温下,反应瓶中加入EVO33383-A4(36mg,131.74μmol)和MeOH(1.5mL),再加入LiOH.H2O(22.11mg,526.97μmol)和H2O(1.5mL),油浴加热33℃反应1.5小时。减压浓缩除去甲醇,加入水(0.5mL),用1N稀盐酸调pH=3,析出白色固体,过滤,滤饼水洗(1mL*3),滤饼烘干,得到类白色固体EVO33383-A5(21mg,收率:61.5%),LCMS(ESI)m/z=260.0[M+H]+。
第6步:
室温下,反应瓶中加入EVO33383-A5(21mg,81.01μmol)、中间体1-A1(28.31mg,81.01μmol)、DIPEA(52.35mg,405.04μmol,70.55μL)、HATU(46.20mg,121.51μmol)和无水DMF(2mL),25℃反应3小时。加水淬灭,EA萃取,有机相水洗,饱和氯化钠溶液洗,无水Na2SO4干燥,过滤,减压浓缩,高效液相制备柱分离,冷冻干燥得产物EVO33383(26mg,收率:54.3%)。LCMS(ESI)m/z=591.0[M+H]+。纯度:99.7%。1H NMR(400MHz,DMSO-d6)δ9.39-9.35(m,2H),8.68-8.61(m,2H),7.91(d,J=7.2Hz,1H),7.86(d,J=1.6Hz,1H),7.78-7.72(m,3H),7.66(bs,1H),7.03(d,J=8.4Hz,1H),6.32(s,2H),4.77(d,J=6.0Hz,2H),4.33-4.30(m,2H),3.70-3.64(m,2H),2.54(s,3H),2.52-2.47(m,2H),1.21(d,J=6.4Hz,6H)。
实施例65 EVO33381
参照化合物EVO33383,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33381(20mg,收率:69.4%),LCMS(ESI)m/z=604.4[M+H]+,纯度:99.9%。1H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.68-8.61(m,2H),7.92-7.89(m,2H),7.80-7.72(m,3H),7.03(d,J=8.8Hz,1H),6.36(s,
2H),4.78(d,J=5.6Hz,2H),4.31(d,J=11.6Hz,2H),3.71-3.64(m,2H),3.37-3.35(m,2H),2.53-2.47(m,2H),1.70-1.60(m,2H),1.21(d,J=6.0Hz,6H),0.96(t,J=7.4Hz,3H)。
实施例66 EVO33382
参照化合物EVO33383,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33382(37mg,收率:63.9%),LCMS(ESI)m/z=602.4[M+H]+,纯度:99.9%。1H NMR(400MHz,DMSO-d6)δ9.43-9.39(m,2H),8.64(q,J=8.6Hz,2H),7.92-7.90(m,2H),7.80-7.79(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J=8.8Hz,1H),6.36(s,2H),4.78(d,J=5.6Hz,2H),4.31(dd,J=13.2,2.4Hz,2H),3.71-3.64(m,2H),2.97-2.91(m,1H),2.52-2.47(m,2H),1.22-1.19(m,8H),1.13-1.07(m,2H)。
实施例67 EVO33384
参照化合物EVO33383,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33384(24mg,收率:57.6%),LCMS(ESI)m/z=605.0[M+H]+,纯度:98.4%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.68-8.61(m,2H),7.91(d,J=7.6Hz,1H),7.82-7.73(m,4H),7.03(d,J=8.4Hz,1H),6.30(s,2H),4.78(d,J=6.0Hz,2H),4.31(d,J=11.6Hz,2H),3.70-3.65(m,2H),2.75(s,6H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H)。
实施例68 EVO33500
第1步:
室温下,4-氨基-5-溴-2-氯吡啶(1g,4.85mmol)、O-乙基二硫代碳酸钾(3.1g,19.41mmol)混于DMF(10mL),油浴130℃搅拌。LC-MS监测反应结束。加水淬灭,EA(50mL*3)萃取,减压浓缩,中压正相柱层析纯化(PE/EA=0-100%)得到类白色固体EVO33500-A1(850mg,收率:87%),LCMS(ESI)m/z=202.9[M+H]+。
第2步:
室温下,EVO33500-A1(850mg,4.21mmol)和SOCl2(10mL)搅拌。LC-MS监测反应结束。加水(20mL)淬灭,产品析出,抽滤,得到类白色固体EVO33500-A2(800mg,收率:93%),LCMS(ESI)m/z=204.9[M+H]+。
第3步:
N2保护下,EVO33500-A2(700mg,3.46mmol),(2S,6R)-2,6-二甲基-4-(6-(三甲基锡基)吡啶-2-基)吗啉(1.2g,3.46mmol),Pd(dppf)Cl2(253mg,0.34mmol)和无水1,4-二氧六环(10mL)油浴100℃搅拌。LC-MS监测反应结束。加水淬灭,EA(50mL x 3)萃取,减压浓缩。中压正相柱层析纯化(DCM/EA=0-30%)得到类白色固体EVO33500-A3(510mg,收率:41%),LCMS(ESI)m/z=361.1[M+H]+。
第4步:
N2保护下,EVO33500-A3(480mg,1.33mmol),N-叔丁基碳酰基甲基三氟硼酸钾(474mg,2mmol),cataCXium A-Pd-G2(87mg,0.13mmol),K3PO4(564mg,2.66mmol),1,4-二氧六环(10mL)和水(1mL)油浴80℃搅拌。LC-MS监测反应结束,少量原料剩余。加水淬灭,EA(50mL x 3)萃取,
减压浓缩,中压正相柱层析纯化(DCM/EA=0-30%)得白色固体EVO33500-A4(212mg,收率:35%),LCMS(ESI)m/z=456.2[M+H]+。
第5步:
0℃下,氯化氢的1,4-二氧六环溶液(3mL)滴入EVO33500-A4(212mg,0.46mmol)的DCM(5mL)溶液中。LC-MS监测反应结束。直接浓缩得固体粗品EVO33500-A5(151mg,粗品),LCMS(ESI)m/z=356.1[M+H]+。
第6步:
N2保护下,EVO33500-A5(60mg,0.17mmol)、EVO33138-A4(41mg,0.17mmol)、DMF(3mL)、EDCl(65mg,0.34mmol)、HOBt(46mg,0.34mmol)和DIEA(44mg,0.34mmol)室温搅拌过夜。LC-MS监测反应结束,生成产物。加水淬灭,EA(50mL)萃取,无水Na2SO4干燥后减压浓缩,经高效液相制备柱分离,冻干得产物EVO33500(22.6mg,收率:20%),LCMS(ESI)m/z=582.1[M+H]+;纯度:99.36%。1H NMR(400MHz,DMSO-d6)δ9.38-9.27(m,2H),7.90(t,J=1.6Hz,2H),7.82-7.75(m,2H),7.62(d,J=7.2Hz,1H),7.13(d,J=8.8Hz,1H),6.36(s,2H),4.71(d,J=5.6Hz,2H),4.30-4.21(m,2H),3.72-3.60(m,2H),3.30(s,3H),2.60-2.53(m,2H),1.20(d,J=6.0Hz,6H)。
实施例69 EVO33408
参照化合物EVO33168,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33408(7mg,收率:27%),LCMS(ESI)m/z=604.0[M+H]+,纯度:98.1%。1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),9.19(d,J=7.6Hz,1H),8.70-8.62(m,2H),7.96-7.89(m,3H),7.86(d,J=1.6Hz,1H),7.80-7.76(m,1H),7.07(d,J=8.4Hz,1H),6.37(s,2H),5.47-5.36(m,1H),4.39-4.29(m,2H),3.76-3.64(m,2H),3.44-3.38(m,2H),2.57-3.47(m,2H),1.67(d,J=6.8Hz,3H),1.25(d,J=6.0Hz,6H),1.22-1.18(t,J=7.2Hz,3H)。
实施例70 EVO33411
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33411(4.5mg,收率:5.07%),LCMS(ESI)m/z=602.27[M+H]+,纯度:96.99%。1H NMR(400MHz,DMSO-d6)δ9.84(t,J=5.6Hz,1H),9.41(s,1H),8.71-8.59(m,2H),8.57(d,J=8.4,2H),7.90(d,J=7.2Hz,1H),7.86(s,1H),7.75(t,J=8.4,1H),7.03(d,J=8.4Hz,1H),5.58(s,2H),4.85(d,J=6Hz,2H),4.37-4.20(m,2H),
3.73(q,J=7.6Hz,2H),3.69-3.65(m,2H),2.54-2.45(m,2H),1.22(d,J=6.4Hz,6H),1.17(t,J=7.2Hz,3H)。
实施例71 EVO33412
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33412(5.5mg,收率:8.23%),LCMS(ESI)m/z=602.25[M+H]+,纯度:98.62%。1H NMR(400MHz,DMSO-d6)δ9.81(t,J=6Hz,1H),9.41(s,1H),8.80(s,1H),8.71-8.65(m,3H),7.94-7.85(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),5.75(s,2H),4.86(d,J=5.6Hz,2H),4.31(d,J=10.8Hz,2H),3.72-3.62(m,2H),3.48(q,J=7.6Hz,2H),2.55-2.44(m,2H),1.22(d,J=6Hz,6H),1.18(t,J=7.6Hz,3H)。
实施例72 EVO33376
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33376(17.1mg,收率:50.5%),LCMS(ESI)m/z=592.44[M+H]+,1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.36(t,J=5.9Hz,1H),8.70-8.59(m,2H),8.05(d,J=1.7Hz,1H),7.93-7.85(m,2H),7.81-7.70(m,2H),7.03(d,J=8.5Hz,1H),5.58(s,1H),4.79(d,J=5.8Hz,2H),4.35-4.28(m,2H),3.72-3.63(m,2H),2.54-2.44(m,2H),1.53(s,6H),1.21(d,J=6.2Hz,6H)。
实施例73 EVO33398
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33398(24.6mg,收率:50.2%),LCMS(ESI)m/z=576.18[M+H]+,1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.67(d,J=8.6Hz,1H),8.44-8.31(m,1H),8.08-7.98(m,2H),7.82(d,J=1.6Hz,1H),7.76-7.68(m,2H),7.62-7.53(m,1H),6.75(d,J=8.5Hz,1H),6.25(s,2H),4.98(d,J=5.2Hz,2H),4.53-4.39(m,1H),4.15-4.01(m,2H),3.95-3.80(m,2H),3.78-3.64(m,1H),3.40-3.25(m,3H),1.41-1.28(m,6H)。
实施例74 EVO33403
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33403(18.2mg,收率:31%),LCMS(ESI)m/z=582.12[M+H]+,纯度:99.41%。1H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.90(d,J=8.4Hz,1H),8.75(d,J=8.0Hz,1H),8.47(d,J=8.4Hz,1H),8.06-8.01(m,2H),7.93(d,J=8.0Hz,1H),7.80(d,J=1.6Hz,1H),7.77(br,2H),7.69(d,J=1.6Hz,1H),7.40(t,J=4.8Hz,1H),6.25(s,2H),4.98(d,J=5.2Hz,2H),3.31(q,J=7.6Hz,2H),2.73(s,6H),1.35(t,J=7.6Hz,3H)。
实施例75 EVO33416
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33416(32.8mg,收率:45%),LCMS(ESI)m/z=558.26[M+H]+,纯度:86.1%。1H NMR(400MHz,Chloroform-d)δ9.46(s,1H),8.99(t,1H),8.92(d,J=8.7Hz,1H),8.59-8.51(m,2H),8.14(d,J=7.4Hz,1H),7.82-7.73(m,1H),7.64-7.56(m,1H),7.37(d,J=1.7Hz,1H),6.89(d,J=8.5Hz,1H),6.04(s,2H),5.05(d,J=6.1Hz,2H),4.21(d,J=12.6Hz,2H),3.80(d,J=6.6Hz,2H),2.75-2.60(m,2H),1.76(s,3H),1.70(s,3H),1.35(d,J=6.2Hz,6H)。
实施例76 EVO33432
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33432(78.8mg,收率:54%),LCMS(ESI)m/z=542.23[M+H]+,纯度:99.55%。1H NMR(400MHz,Chloroform-d)δ9.19(s,1H),8.62(d,J=8.6Hz,1H),8.35(d,J=8.7Hz,1H),7.98(d,J=8.0Hz,2H),7.73-7.63(m,2H),7.60(s,1H),7.29(d,J=1.5Hz,1H),6.78(d,J=8.4Hz,1H),6.12-6.01(m,2H),5.11-4.78(m,3H),4.21(d,J=12.5Hz,2H),3.80(d,J=4.0Hz,2H),2.70-2.58(m,2H),1.52(d,J=6.5Hz,3H),1.34(d,J=6.2Hz,6H)。
实施例77 EVO33458
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33458(3.88mg,收率:16%),LCMS(ESI)m/z=555.26[M+H]+,纯度:97.2%。1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.63(d,J=8.5Hz,1H),8.37(d,J=8.7Hz,1H),8.08-7.95(m,2H),7.76-7.67(m,1H),7.59-7.50(m,1H),7.30-7.27(m,1H),6.79(d,J=8.4Hz,1H),6.07(s,2H),4.96(d,J=4.8Hz,2H),4.33-4.16(m,2H),3.92-3.73(m,2H),2.73-2.56(m,2H),1.55(s,6H),1.34(d,J=6.2Hz,6H)。
实施例78 EVO33467
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33467(9.28mg,收率:24%),LCMS(ESI)m/z=570.19[M+H]+,纯度:98.4%。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.20(t,J=6.0Hz,1H),8.69-8.59(m,2H),7.90(d,J=7.2Hz,1H),7.77-7.69(m,2H),7.65(d,J=1.6Hz,1H),7.49(d,J=1.6Hz,1H),7.03(d,J=8.4Hz,1H),6.45(s,1H),6.17(s,2H),5.02(d,J=6.8Hz,2H),4.76(d,J=5.6Hz,2H),4.67(d,J=6.8Hz,2H),4.35-4.27(m,2H),3.71-3.62(m,2H),2.55-2.45(m,2H),1.21(d,J=6.0Hz,6H)。
实施例79 EVO33486
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33486(14.81mg,收率:42%),LCMS(ESI)m/z=588.20[M+H]+,纯度:99.06%。1H NMR(400MHz,Chloroform-d)δ9.82(d,J=2.0Hz,1H),9.56(s,1H),8.78(d,J=2.0Hz,1H),8.33(s,1H),8.30-8.25(m,1H),8.14(s,1H),8.08(s,1H),7.75-7.71(m,1H),7.36(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),5.46-5.45(m,2H),5.23(s,2H),5.07(d,J=5.6Hz,2H),4.29-4.26(m,2H),3.85-3.79(m,2H),3.24-3.19(m,2H),2.72-2.66(m,2H),1.38(d,J=6.4Hz,6H)1.37-1.33(m,3H)。
实施例80 EVO33490
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33490(16mg,收率:48%),LCMS(ESI)m/z=580.43[M+H]+,纯度:99.13%。1H NMR(400MHz,DMSO-d6)δ9.61(t,J=6.0Hz,1H),9.47(s,1H),8.90(d,J=8.4Hz,1H),8.78(d,J=8.4Hz,1H),8.65(d,J=7.8Hz,1H),8.33(s,1H),8.29-8.23(m,2H),8.16(t,J=7.8Hz,1H),7.92-7.89(m,3H),5.33(s,2H),5.15(s,2H),4.85(d,J=5.6Hz,2H),3.38(q,J=7.2Hz,2H),2.57(s,6H),1.15(t,J=7.2Hz,3H)。
实施例81 EVO33504
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33504(27.8mg,收率:36%),LCMS(ESI)m/z=576.2[M+H]+,纯度:99.31%。1H NMR(400MHz,DMSO-d6)δ9.44-9.36(m,2H),8.64(q,J=8.4Hz,2H),7.94-7.87(m,2H),7.82-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.32-4.20(m,2H),3.97(d,J=10Hz,1H),3.70-3.52(m,2H),3.40(q,J=7.2Hz,2H),2.95-2.88(m,1H),2.62-2.52(m,1H),1.23-1.16(m,6H)。
实施例82 EVO33507
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33507(14.7mg,收率:19.1%),LCMS(ESI)m/z=576.22[M+H]+,纯度:98.65%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.66(s,2H),7.90(d,J=1.6Hz,1H),7.83-7.79(m,3H),7.69(t,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.15-4.11(m,1H),3.64-3.59(m,3H),3.50(q,J=8.6Hz,1H),3.38(q,J=7.4Hz,2H),3.30(s,3H),2.14-2.09(m,2H),1.18(t,J=7.2Hz,3H)。
实施例83 EVO33508
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33508(17.8mg,收率:12.14%),LCMS(ESI)m/z=548.51[M+H]+,纯度:95.67%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.66(d,J=8.4Hz,1H),8.60(d,J=8.8Hz,1H),7.91-7.85(m,2H),7.82-7.78(m,2H),7.70(t,J=8Hz,1H),6.56(d,J=8.4Hz,1H),6.35(s,2H),5.67(d,J=6.4Hz,1H),4.78(d,J=5.6Hz,2H),4.65-4.61(m,1H),4.32-4.23(m,2H),3.81-3.78(m,2H),3.38(q,J=7.2Hz,2H),1.18(t,J=7.6Hz,3H)。
实施例84 EVO33509
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33509(8.7mg,收率:12.6%),LCMS(ESI)m/z=574.57[M+H]+,纯度:85.2%。1H NMR(400MHz,DMSO)δ9.42-9.36(m,2H),8.67(d,J=8.8Hz,1H),8.60(d,J=8.4Hz,1H),7.92-7.87(m,2H),7.83-7.77(m,2H),7.72(t,J=8.0Hz,1H),6.58(d,J=8.0Hz,1H),6.35(s,2H),4.78-4.75(m,6H),4.24(s,4H),3.39-3.35(m,2H),1.18(t,J=7.2Hz,3H)。
实施例85 EVO33511
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33511(15.7mg,收率:22.3%),LCMS(ESI)m/z=590.2[M+H]+,纯度:96.33%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.64(dd,J=24.4,8.4Hz,2H),7.90(d,J=1.6Hz,1H),7.84-7.79(m,3H),7.71(t,J=8.0Hz,1H),6.88(d,J=8.4Hz,1H),6.35(s,2H),4.79-4.71(m,3H),4.01-3.94(m,2H),3.55(d,J=11.6Hz,2H),3.38(q,J=7.6Hz,2H),2.98(s,3H),1.90-1.79(m,2H),1.65-1.61(m,2H),1.18(t,J=7.2Hz,3H)。
实施例86 EVO33512
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33512(20.7mg,收率:30.2%),LCMS(ESI)m/z=576.24[M+H]+,纯度:97.94%。1H NMR(400MHz,DMSO-d6)δ9.41-9.39(m,2H),8.68-8.63(m,2H),7.90(d,J=1.6Hz,1H),7.85(d,J=7.6Hz,1H),7.81-7.80(m,2H),7.72(t,J=8.4Hz,1H),6.87(d,J=8.4Hz,1H),6.35(s,2H),5.51-5.44(m,1H),4.78(d,J=6.0Hz,2H),4.03-3.97(m,1H),3.87-3.82(m,1H),3.79-3.75(m,1H),3.70(q,J=8.0Hz,1H),3.38(q,J=7.2Hz,
2H),3.00(s,3H),2.33-2.25(m,1H),1.96-1.88(m,1H),1.19(t,J=7.6Hz,3H)。
实施例87 EVO33513
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33513(2.1mg,收率:3.8%),LCMS(ESI)m/z=590.7[M+H]+,纯度:95.27%。1H NMR(400MHz,DMSO-d6)δ9.40-9.38(m,2H),8.68-8.59(m,2H),7.90(d,J=1.6Hz,1H),7.83-7.79(m,3H),7.69(t,J=7.6Hz,1H),6.81(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=6.4Hz,2H),3.81(t,J=6.0Hz,2H),3.70(t,J=5.6Hz,2H),3.41-3.34(m,3H),3.13(s,3H),1.18(t,J=7.2Hz,3H),0.45-0.40(m,4H)。
实施例88 EVO33522
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33522(10.7mg,收率:23.48%),LCMS(ESI)m/z=591.24[M+H]+,纯度:91.3%。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.06(s,1H),8.84(s,1H),8.44(d,J=8.4Hz,1H),8.29(d,J=8.8Hz,1H),7.90(d,J=1.6Hz,1H),7.86-7.80(m,2H),7.73-7.69(m,1H),7.00(d,J=8.4Hz,1H),6.86(s,1H),6.38(s,2H),4.29(dd,J=12.8,2.4Hz,2H),3.71-3.64(m,2H),3.40(d,J=7.2Hz,2H),2.52-2.46(m,2H),1.22-1.18(m,9H)。
实施例89 EVO33525
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33525(13.5mg,收率:29.4%),LCMS(ESI)m/z=588.06[M+H]+,纯度:99.38%。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=5.6Hz,1H),9.40(s,1H),8.64(q,J=8.4Hz,2H),7.99(s,1H),7.91(d,J=7.2Hz,1H),7.80(s,1H),7.75(t,J=8.0Hz,1H),7.69(s,1H),7.03(d,J=8.8Hz,1H),4.80(d,J=5.6Hz,2H),4.62(t,J=8.0Hz,1H),4.41(dd,J=8.4,2.0Hz,1H),4.31(d,J=12.8Hz,2H),3.97-3.90(m,1H),3.72-3.64(m,2H),3.31(s,3H),2.53-2.47(m,2H),1.34(d,J=7.2Hz,3H),1.22(d,J=6.0Hz,6H)。
实施例90 EVO33535
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33535(15.5mg,收率:22.12%),LCMS(ESI)m/z=560.24[M+H]+,纯度:98.57%。1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.75(d,J=8.8Hz,1H),8.40(d,J=8.8Hz,1H),8.06(s,1H),8.00(d,J=7.2Hz,1H),7.82(d,J=1.6Hz,1H),7.87-7.58(m,3H),6.85(d,J=8.4Hz,1H),6.27(s,2H),5.01(d,J=5.2Hz,2H),3.70-3.66(m,4H),3.33(q,J=7.6Hz,2H),1.75-1.68(m,6H),1.37(t,J=7.6Hz,3H)。
实施例91 EVO33536
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33536(23mg,收率:19%),LCMS(ESI)m/z=546.19[M+H]+,纯度:95.02%。1H NMR(400MHz,DMSO-d6)δ9.43-9.35(m,2H),8.65(s,2H),7.90(d,J=1.6Hz,1H),7.82-7.78(m,3H),7.68(dd,J=8.4,7.2Hz,1H),6.62(d,J=8.0Hz,1H),6.35(s,2H),4.78(d,J=6.0Hz,2H),3.57-3.47(m,4H),3.38(q,J=7.6Hz,2H),2.04-1.96(m,4H),1.18(t,J=7.2Hz,3H)。
实施例92 EVO33540
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33540(21.8mg,收率:31.19%),LCMS(ESI)m/z=562.21[M+H]+,纯度:98.33%。1H NMR(400MHz,DMSO-d6)δ9.43-9.36(m,2H),8.65(s,2H),7.90(d,J=1.6Hz,1H),7.81-7.79(m,3H),7.68(t,J=7.6Hz,1H),6.61(d,J=8.4,1H),6.35(s,2H),4.98(d,J=3.6Hz,1H),4.78(d,J=5.8Hz,2H),4.44(s,1H),3.66-3.55(m,3H),3.46(d,J=11.2Hz,1H),3.38(q,J=7.4Hz,2H),2.12-2.03(m,1H),1.99-1.93(m,1H),1.18(t,J=7.4Hz,3H)。
实施例93 EVO33546
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33546(7.1mg,收率:16.5%),LCMS(ESI)m/z=578.2[M+H]+,纯度:98.31%。1H NMR(400MHz,DMSO-d6)δ9.40-9.39(m,2H),8.66(d,J=8.4Hz,1H),8.59(d,J=8.4Hz,1H),7.90-7.86(m,2H),7.81-7.80(m,2H),7.40(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.06-4.03(m,4H),3.38(dd,J=14.8,7.2Hz,2H),2.69-2.67(m,4H),1.18(t,J=7.2Hz,3H)。
实施例94 EVO33600
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33600(8.58mg,收率:20%),LCMS(ESI)m/z=556.2[M+H]+,纯度:98.8%。1H NMR(400MHz,Chloroform-d)δ9.77(d,J=2.0Hz,1H),9.55(s,1H),8.73(d,J=2.0Hz,1H),8.00(s,1H),7.74-7.72(m,1H),7.72-7.70(m,1H),7.67(d,J=2.0Hz,1H),7.36(d,J=2.0Hz,1H),7.35-7.33(m,1H),6.79(d,J=8.8Hz,1H),6.10(d,2H),5.01(d,J=6.0Hz,2H),4.30-4.26(m,2H),3.85-3.80(m,2H),2.72-2.64(m,2H),1.67(s,6H),1.38(d,J=6.4Hz,6H)。
实施例95 EVO33415
参照化合物EVO33174,经高效液相制备柱分离,再冷冻干燥得到棕色固体EVO33415(8.19mg,收率:17.25%,纯度:94%),LCMS(ESI)m/z=580.38[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.57(s,1H),7.97-7.95(m,1H),7.86(s,1H),7.68-7.67(m,1H),7.46-7.44(m,1H),6.34(s,2H),4.84(s,2H),4.57(q,J=6.8Hz,1H),4.11-4.07(m,2H),3.95-3.92(m,2H),3.75-3.67(m,2H),3.28(s,3H),3.11-3.08(m,2H),2.45-2.40(m,2H),1.70(d,J=7.2Hz,3H),1.25(d,J=6.0Hz,6H)。
实施例96 EVO33426
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33426(14.14mg,收率:36.89%,纯度:98.1%,LCMS(ESI)m/z=551.38[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.22(t,J=6.0Hz,1H),8.54-8.45(m,1H),7.88(d,J=1.6Hz,1H),7.75(d,J=1.6Hz,1H),7.59-7.49(m,
4H),7.38(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6.81(d,J=8.8Hz,1H),6.35(s,2H),4.58(d,J=5.6Hz,2H),4.30-4.19(m,2H),3.66-3.59(m,2H),3.29(s,3H),2.44-2.38(m,2H),1.18(d,J=6.0Hz,6H)。
实施例97 EVO33342
参照化合物EVO33341,经高效液相制备柱分离,再冷冻干燥得到产物EVO33342(15.8mg,收率:28%),LCMS(ESI)m/z=588.39[M+H]+,纯度:98.8%。1H NMR(400MHz,Chloroform-d)δ9.65-9.59(m,1H),9.51(s,1H),9.03(d,J=0.8Hz,1H),8.91(d,J=8.8Hz,1H),8.72(d,J=0.8Hz,1H),8.62(d,J=8.8Hz,1H),8.45(s,1H),8.13(d,J=7.2Hz,1H),7.76(d,J=8.0Hz,1H),6.88(d,J=8.4Hz,1H),5.18(d,J=6.0Hz,2H),4.24-4.19(m,2H),3.82-3.74(m,2H),3.50(q J=7.2Hz,2H),2.68-2.63(m,2H),1.35-1.29(m,9H)。
实施例98 EVO33430
参照化合物EVO33341,经高效液相制备柱分离,再冷冻干燥得到产物EVO33430(10.3mg,收率:22%),LCMS(ESI)m/z=590.10[M+H]+,纯度:95.7%。1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.89(s,1H),8.86(s,1H),8.68(d,J=8.4Hz,1H),8.40(d,J=8.8Hz,1H),8.06-8.00(m,3H),7.72(t,J=8.0Hz,1H),6.80(d,J=8.4Hz,1H),5.06(d,J=4.8Hz,2H),4.24-4.19(m,2H),3.83-3.76(m,2H),3.48(s,3H),2.69-2.59(m,2H),1.33(d,J=6.0Hz,6H)。
实施例99 EVO33389
第1步:
室温下,反应瓶中加入7-溴苯并[d][1,3]二氧代-5-羧酸甲酯(500mg,1.93mmol),三丁基锡基甲醇(929.59mg,2.90mmol),XPhosPd G2(151.86mg,193.01μmol)和无水1,4-二氧六环(20mL),Ar置换三次,油浴加热至100℃反应16小时。反应液降至室温,减压浓缩后得粗品,中压正相柱层析纯化(EA/PE=0-100%)得类白色固体EVO33389-A1(364mg,收率:89.7%),LCMS(ESI)m/z=211.0[M+H]+。
第2步:
室温,Ar保护下,反应瓶中加入EVO33389-A1(364mg,1.73mmol)和无水DCM(10mL),冷浴降温至-10℃;控温±5℃加入PBr3(937.57mg,3.46mmol,325.55μL),加完后自然升至室温搅拌2小时。反应液直接减压浓缩得粗品,中压正相柱层析纯化(EA/PE=0-20%)得类白色固体EVO33389-A2(322mg,收率:68.1%),LCMS(ESI)m/z=273.1/275.1[M+H]+。
第3步:
室温下,反应瓶中加入EVO33389-A2(322mg,1.18mmol),无水ACN(10mL)和TMSCN(233.97mg,2.36mmol,295.04μL),冰水浴降至0~5℃,缓慢滴加TBAF溶液(1.0M in THF,2.5mL),自然升至室温反应2小时。减压浓缩得粗品,中压正相柱层析纯化(EA/PE=0-30%)得类白色固体EVO33389-A3(229mg,收率:88.6%),LCMS(ESI)m/z=220.0[M+H]+。
第4步:
室温下,反应瓶中加入EVO33389-A3(50mg,228.11μmol),LiOH.H2O(19.14mg,456.22μmol),MeOH(1mL)和H2O(1mL),室温搅拌16小时。减压浓缩旋除溶剂,1N稀盐酸溶液调pH=3~4,析出白色固体,过滤,滤饼用冰水淋洗,烘干得类白色固体EVO33389-A4(44mg,收率:94.0%),LCMS(ESI)m/z=204.10[M-H]-,含约15%氰基水解的副产物。
第5步:
室温下,反应瓶中依次加入EVO33389-A4(21mg,102.36μmol),EVO33070A7(35.77mg,102.36μmol),无水DMF(2mL)和TEA(51.79mg,511.78μmol,71.33μL),再加入HATU(58.38mg,153.53
μmol),室温搅拌2小时,加水淬灭后处理。经高效液相制备柱分离,冷冻干燥得淡黄色固体EVO33389(36mg,收率:65.6%),LCMS(ESI)m/z=537.4[M+H]+,纯度:99.5%。1H NMR(400MHz,DMSO-d6)δ9.39(d,J=1.2Hz,1H),9.20(t,J=6.0Hz,1H),8.68-8.61(m,2H),7.91(d,J=7.2Hz,1H),7.77-7.72(m,2H),7.61(d,J=1.6Hz,1H),7.54(d,J=1.6Hz,1H),7.03(d,J=8.4Hz,1H),6.21(s,2H),4.77(d,J=6.0Hz,2H),4.31(d,J=12.0Hz,2H),4.04(s,2H),3.70-3.65(m,2H),2.53-2.47(m,2H),1.21(d,J=6.4Hz,6H)。
实施例100 EVO33414
参照化合物EVO33389,经高效液相制备柱分离,再冷冻干燥得黄色固体EVO33414(42mg,收率:43.4%),LCMS(ESI)m/z=565.4[M+H]+,纯度:97.6%。1H NMR(400MHz,DMSO-d6)δ9.39(d,J=0.8Hz,1H),9.24(t,J=5.8Hz,1H),8.67-8.60(m,2H),7.91(d,J=7.6Hz,1H),7.78-7.72(m,2H),7.64(d,J=1.6Hz,1H),7.58(d,J=1.6Hz,1H),7.03(d,J=8.4Hz,1H),6.22(s,2H),4.77(d,J=6.0Hz,2H),4.31(dd,J=12.8,2.4Hz,2H),3.71-3.64(m,2H),2.53-2.47(m,2H),1.76(s,6H),1.21(d,J=6.4Hz,6H)。
实施例101 EVO33392
第1步:
室温下,反应瓶中加入EVO33381-B1(124mg,415.67μmol)和THF(3mL),再加入NaOMe的甲醇溶液(5.4M in methanol,623.51μmol),室温搅拌2小时,原料消失,EVO33381-B2未出对应分子离子峰,母液直接用于下一步反应。
第2步:
室温下,反应液中加入2-溴乙醇(155.83mg,1.25mmol),室温搅拌1小时。反应液直接减压浓缩得粗品,中压正相柱层析纯化(EA/PE=0-60%)得无色油状物EVO33392-A1(50mg,收率:46.9%),LCMS(ESI)m/z=257.0[M+H]+。
第3步:
室温下,反应瓶中加入Oxone(431.79mg,702.37μmol)和H2O(2mL),用饱和碳酸氢钠溶液调pH=7~8,再加入EVO33392-A1(60mg,234.12μmol)和ACN(3.5mL),室温搅拌3小时。反应液减压浓缩得粗品,中压正相柱层析纯化(MeOH/DCM=0-10%)得无色油状物EVO33392-A2(60mg,收率:88.9%),LCMS(ESI)m/z=289.0[M+H]+。
第4步:
室温下,反应瓶中加入EVO33392-A2(60mg,208.14μmol)和MeOH(1mL),氢氧化锂(17.47mg,416.27μmol)用水(1mL)溶解后加入,油浴加热33℃反应1小时。反应液减压浓缩后,DMF(2mL)溶解浓缩产品,过反相柱(乙腈:0.1%甲酸水),再冷冻干燥得类白色固体EVO33392-A3(29mg,收率:50.8%),LCMS(ESI)m/z=273.0[M-H]-。
第5步:
室温下,反应瓶中依次加入EVO33392-A3(29mg,105.74μmol),中间体1-A1(36.95mg,105.74μmol),无水DMF(2mL),DIPEA(68.33mg,528.72μmol,92.09μL),最后加入HATU(60.31mg,158.62μmol)室温搅拌1小时。加水淬灭后处理,经高效液相制备柱分离,冷冻干燥得淡黄色固体EVO33392(36mg,收率:56.2%),LCMS(ESI)m/z=606.4[M+H]+,纯度:99.9%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.68-8.61(m,2H),7.92-7.89(m,2H),7.79-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.90(t,J=5.4Hz,1H),4.78(d,J=5.6Hz,2H),4.32(d,J=12.8Hz,2H),3.76(q,J=5.6Hz,2H),3.70-3.65(m,2H),3.54(t,J=6.2Hz,2H),2.53-2.47(m,2H),1.21(d,J=6.4Hz,6H)。
实施例102 EVO33523
第1步:
室温下,微波管中加入EVO33522-A2(30mg,84.55μmol),DMSO(1.0mL),甲基肼硫酸盐(243mg,1.69mmol),K2CO3(350mg,2.54mmol),水(1.0mL),封管,投料8批次。先搅拌0.5h,然后加热到110℃搅拌48小时。冷至室温后,分别向各个微波管中加入甲基肼硫酸盐(243mg,1.69mmol)和K2CO3(350mg,2.54mmol),封管,先室温搅拌0.5小时,然后加热到110℃搅拌48小时。LC-MS检测反应结果均为60%产物和30%原料。加入EA(10mL)和H2O(10mL)稀释,收集有机相,水相用EA反萃3次。合并有机相,用饱和氯化钠溶液(50mL x 1)洗涤,无水硫酸钠干燥,过滤浓缩至干,剩余物经柱层析纯化(DCM/MeOH:10/1)得到黄色油状物EVO33523-A1(150mg,纯度:70%),经制备板纯化(DCM/MeOH:10/1)得EVO33523-A1(100mg,收率:36.51%,纯度:90%)。LCMS(ESI)m/z=365.46[M+H]+。
第2步:
冰水浴下,EVO33522-A1(56mg,137.40μmol),DMF(1mL)和DIPEA(88mg,687.00μmol)搅拌10分钟,加入7-乙基砜苯并[d][1,3]二氧代-5-羧酸(28mg,109.92μmol),继续搅拌10分钟,然后加入EDCI(53mg,275.00μmol)及HOBt(19mg,140.74μmol),室温搅拌1小时。加入EA(30mL),用水(50mL x 2)洗涤,水相反萃取,合并有机相,用饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤浓缩至干,经高效液相制备柱分离,冷冻干燥得淡黄色固体EVO33523(28mg,收率:32.71%),LCMS(ESI)m/z=605.24[M+H]+,纯度:97.02%。1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.11(s,1H),8.45(d,J=8.4Hz,1H),8.29(d,J=8.8Hz,1H),7.91(d,J=1.6Hz,1H),7.85-7.81(m,2H),7.70(t,J=8.4Hz,1H),7.00(m,2H),6.39(s,2H),4.29(dd,J=12.8,2.4Hz,2H),3.71-3.63(m,2H),3.48(s,3H),3.41(dd,J=14.8,7.2Hz,2H),2.47(d,J=12.0Hz,2H),1.22(d,J=4.8Hz,3H),1.20(t,J=3.6Hz,6H)。
实施例103 EVO33031
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33031(26mg,收率:43%),LCMS(ESI)m/z=556.51[M+H]+,纯度:98.8%。1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.74(d,J=8.6Hz,1H),8.43(d,J=8.6Hz,1H),8.17(s,1H),8.06(d,J=7.2Hz,1H),7.98-7.91(m,1H),7.76-7.68(m,3H),6.82(d,J=8.4Hz,1H),5.29-5.24(m,2H),5.11(s,2H),5.04(d,J=5.6Hz,2H),4.21(d,J=11.2Hz,2H),3.82-3.76(m,2H),2.64(t,J=11.6Hz,2H),1.75(s,3H),1.70(s,3H),1.33(d,J=6.0Hz,6H)。
实施例104 EVO33036
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33036(3mg,收率:3%),LCMS(ESI)m/z=546.21[M+H]+,纯度:98.1%。1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.87(d,J=8.4Hz,1H),8.76(d,J=7.6Hz,1H),8.46(d,J=8.4Hz,1H),8.08-8.01(m,2H),7.94(d,J=7.6Hz,1H),7.83-7.76(m,3H),7.62(s,1H),7.42(t,J=5.4Hz,1H),5.36(s,2H),5.10(s,2H),5.01(d,J=5.4Hz,2H),2.77(s,6H),1.62(s,6H)。
实施例105 EVO33038
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33038(23mg,收率:30%),LCMS(ESI)m/z=548.42[M+H]+,纯度:99.23%。1H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.88(d,J=8.4Hz,1H),8.77(d,J=7.6Hz,1H),8.47(d,J=8.4Hz,1H),8.08-8.03(m,2H),7.95(d,J=7.6Hz,1H),7.82(s,2H),7.68(s,1H),7.65(s,1H),7.46-7.40(m,1H),5.30-5.25(m,2H),5.13(s,2H),5.01(d,J=4.8Hz,2H),2.78(s,6H),1.75(s,3H),1.70(s,3H)。
实施例106 EVO33041
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到棕色固体EVO33041(5.22mg,收率:14.04%),LCMS(ESI)m/z=562.22[M+H]+,纯度:99.47%。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.10(t,J=6.0Hz,1H),8.70-8.57(m,2H),7.91(d,J=7.6Hz,1H),7.82(d,J=1.6Hz,1H),7.78-7.69(m,2H),7.43(d,J=1.6Hz,1H),7.02(d,J=8.4Hz,1H),6.10(s,2H),5.24(s,1H),4.76(d,J=
5.6Hz,2H),4.31(dd,J=13.2,2.4Hz,2H),3.71-3.63(m,2H),2.45-2.39(m,2H),1.21(d,J=6.4Hz,6H)。
实施例107 EVO33140
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33140(24.1mg,收率:36.3%),LCMS(ESI)m/z=573.68[M+H]+,纯度:92.5%。1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.72(d,J=8.7Hz,1H),8.43(d,J=8.7Hz,1H),8.13(s,1H),8.06(d,J=7.4Hz,1H),7.98(s,1H),7.86(s,1H),7.76-7.70(m,2H),6.82(d,J=8.5Hz,1H),5.87(s,1H),5.01(d,J=5.5Hz,2H),4.27-4.16(m,2H),3.88-3.70(m,4H),3.21-3.09(m,2H),3.05(s,3H),2.70-2.54(m,2H),1.34(d,J=6.2Hz,6H)。
实施例108 EVO33412-B
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33412-B(34mg,收率:14.83%),LCMS(ESI)m/z=588.31[M+H]+,纯度:98.83%。1H NMR(400MHz,DMSO-d6)δ9.80(t,J=5.6Hz,1H),9.42(s,1H),8.77(dd,J=13.2,1.2Hz,2H),8.71-8.61(q,J=8.8Hz,2H),7.91(d,J=7.2Hz,2H),7.75(t,J=7.2Hz,1H),7.03(d,J=8.4Hz,1H),5.78(s,2H),4.87(d,J=5.6Hz,2H),4.31(d,J=11.2Hz,2H),3.67(m,2H),3.39(s,3H),2.53-2.47(m,2H),1.22(d,J=6.0Hz,6H)。
实施例109 EVO33435
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33435(23mg,收率:22%),LCMS(ESI)m/z=554.49[M+H]+,纯度:97.5%。1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.74(d,J=8.6Hz,1H),8.42(d,J=8.6Hz,1H),8.17(s,1H),8.06(d,J=7.2Hz,1H),7.99-7.92(m,1H),7.85(s,1H),7.72(t,J=8.0Hz,1H),7.66(s,1H),6.82(d,J=8.4Hz,1H),5.34(s,2H),5.09(s,2H),5.03(d,J=5.6Hz,2H),4.21(d,J=11.2Hz,2H),3.82-3.77(m,2H),2.64(t,J=11.6Hz,2H),1.62(s,6H),1.33(d,J=6.0Hz,6H)。
实施例110 EVO33453
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33453(5mg,收率:8.3%),LCMS(ESI)m/z=575.16[M+H]+,纯度:96.70%。1H NMR(400MHz,Chloroform-d)δ9.24(s,1H),8.63(d,J=8.4Hz,1H),8.35(d,J=8.4Hz,1H),8.01(d,J=7.2Hz,1H),7.97(s,1H),7.86(d,J=1.6Hz,1H),7.70(t,J=8.0Hz,1H),7.64(d,J=1.6Hz,1H),7.54(t,J=4.8Hz,1H),6.77(d,J=8.4Hz,1H),6.24(s,2H),4.95(d,J=5.2Hz,2H),4.21(d,J=11.2Hz,2H),3.85-3.75(m,2H),3.25(s,3H),2.63(t,J=11.6Hz,2H),1.33(d,J=6.0Hz,6H)。
实施例111 EVO33461
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33461(3.32mg,收率:23%),LCMS(ESI)m/z=562.47[M+H]+,纯度:96.7%。1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.77(d,J=8.8Hz,1H),8.47(d,J=8.8Hz,1H),8.18(s,1H),8.11(d,J=7.2Hz,1H),7.89-7.73(m,2H),7.67-7.66(m,1H),7.53-7.52(m,1H),6.86(d,J=8.4Hz,1H),6.16(s,2H),5.05(d,J=5.6Hz,2H),4.27-4.26(m,2H),3.86-3.83(m,2H),2.71-2.65(m,2H),2.05(t,J=18.4Hz,3H),1.38(d,J=6.0Hz,6H)。
实施例112 EVO33485
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33485(20mg,收率:27%),LCMS(ESI)m/z=570.47[M+H]+,纯度:99.64%。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),9.12(t,J=6.0Hz,1H),8.73-8.60(m,2H),7.93(d,J=7.2Hz,1H),7.83(d,J=2.0Hz,1H),7.80-7.73(m,2H),7.46(d,J=2.0Hz,1H),7.05(d,J=8.4Hz,1H),6.10(s,2H),5.09(s,1H),4.78(d,J=6.0Hz,2H),4.39-4.28(m,2H),3.78-3.64(m,2H),2.57-2.55(m,2H),1.94-1.85(m,1H),1.80-1.71(m,1H),1.50(s,3H),1.24(d,J=6.0Hz,6H),0.76(t,J=7.2Hz,3H)。
实施例113 EVO33488
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到淡黄色固体EVO33488(33mg,收率:46.5%),LCMS(ESI)m/z=587.5[M+H]+,纯度:98.4%。1H NMR(400MHz,DMSO-d6)δ9.55(t,J=6.0Hz,1H),9.38(s,1H),8.63(d,J=8.4Hz,1H),8.32-8.26(m,3H),7.85(s,1H),7.79(t,J=2.2Hz,1H),7.69(d,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.13(dd,J=8.4,2.4Hz,1H),5.32(t,J=2.0Hz,2H),5.14(s,2H),4.82(d,J=6.0Hz,2H),3.76-3.70(m,4H),3.37(q,J=7.2Hz,2H),2.33(dd,J=12.2,10.6Hz,2H),1.18(d,J=6.0Hz,6H),1.15(t,J=7.2Hz,3H)。
实施例114 EVO33526
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33526(10.3mg,收率:18.4%),LCMS(ESI)m/z=600.15[M+H]+,纯度:98.6%。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=6.0Hz,1H),9.39(s,1H),8.64(q,J=8.4Hz,2H),7.98(d,J=1.6Hz,1H),7.91(d,J=7.6Hz,1H),7.80-7.71(m,3H),7.03(d,J=8.4Hz,1H),4.80(d,J=5.6Hz,2H),4.50(s,2H),4.31(d,J=13.2Hz,2H),3.71-3.64(m,2H),3.28(s,3H),2.53-2.47(m,2H),1.79(q,J=4.4Hz,2H),1.22(d,J=6.4Hz,6H),1.10(q,J=4.4Hz,2H)。
实施例115 EVO33530
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33530(26mg,收率:22%),LCMS(ESI)m/z=588.5[M+H]+,纯度:98.56%。1H NMR(400MHz,DMSO-d6)δ9.55(t,J=6.0Hz,1H),9.40(s,1H),8.69-8.59(m,2H),8.39(s,1H),8.23(s,1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.75(t,J=8.4Hz,1H),7.03(d,J=8.8Hz,1H),5.80-5.75(m,1H),5.15(d,J=12.4Hz,1H),5.05(d,J=13.6Hz,1H),4.82(d,J=4.8Hz,2H),4.31(dd,J=12.8,2.4Hz,2H),3.70-3.65(m,2H),3.32(s,3H),2.52-2.48(m,2H),1.50(d,J=6.4Hz,3H),1.21(d,J=6.4Hz,6H)。
实施例116 EVO33605
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33605(8mg,收率:33%),LCMS(ESI)m/z=548.15[M+H]+,纯度:99.07%。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.14(t,J=6.0Hz,1H),8.89(d,J=8.4Hz,1H),8.77(d,J=8.4Hz,1H),8.66(d,J=7.6Hz,1H),8.24(d,J=8.0Hz,1H),8.14(t,J=7.6Hz,1H),7.91(s,2H),7.86-7.80(m,2H),7.45(d,J=1.6Hz,1H),6.10(s,2H),5.29(s,1H),4.78(d,J=5.6Hz,2H),2.57(s,6H),1.49(s,6H)。
实施例117 EVO33607
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33607(11mg,收率:36%),LCMS(ESI)m/z=550.14[M+H]+,纯度:97.40%。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.24(t,J=6.0Hz,1H),8.89(d,J=8.4Hz,1H),8.77(d,J=8.4Hz,1H),8.66(d,J=7.6Hz,1H),8.25(d,J=7.6Hz,1H),8.15(t,J=7.6Hz,1H),7.91(s,2H),7.83(s,1H),7.65(d,J=1.6Hz,1H),7.52(d,J=1.6Hz,1H),6.16(s,2H),4.79(d,J=5.6Hz,2H),2.57(s,6H),1.75(s,3H),1.70(s,3H)。
实施例118 EVO33537
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33537(5.4mg,收率:11.8%),LCMS(ESI)m/z=532.2[M+H]+,纯度:99.48%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.66(d,J=8.6Hz,1H),8.59(d,J=8.6Hz,1H),7.90-7.81(m,2H),7.80(d,J=6.0Hz,2H),7.70(t,J=8.0Hz,1H),6.53(d,J=8.0Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.07(t,J=7.2Hz,4H),3.37(q,J=7.2Hz,2H),2.42-2.34(m,2H),1.18(t,J=7.2Hz,3H)。
实施例119 EVO33541
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33541(7.6mg,收率:
17.2%),LCMS(ESI)m/z=589.2[M+H]+,纯度:97.08%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.66(d,J=8.8Hz,1H),8.59(d,J=8.8Hz,1H),7.89(d,J=1.6Hz,1H),7.85(d,J=7.2Hz,1H),7.81-7.79(m,2H),7.70(t,J=8.4Hz,1H),6.99(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.30(dd,J=8.4,2.0Hz,2H),3.38(q,J=7.2Hz,2H),2.82-2.77(m,2H),2.37-2.31(m,2H),1.18(t,J=7.2Hz,3H),1.08(d,J=6.4Hz,6H)。
实施例120 EVO33544
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33544(11.1mg,收率:9.18%),LCMS(ESI)m/z=592.66[M+H]+,纯度:98.31%。1H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.68-8.60(m,2H),7.94-7.90(m,2H),7.81-7.75(m,3H),7.01(d,J=8.4Hz,1H),6.35(s,2H),4.86-4.81(m,1H),4.78(d,J=5.6Hz,2H),4.34(d,J=12.8Hz,1H),4.23(d,J=12.8Hz,1H),4.02-3.99(m,1H),3.65-3.59(m,1H),3.57-3.48(m,3H),3.40-3.35(m,2H),2.98-2.91(m,1H),2.73-2.66(m,1H),1.18(t,J=7.6Hz,3H)。
实施例121 EVO33547
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33547(13.3mg,收率:15.1%),LCMS(ESI)m/z=554.55[M+H]+,纯度:98.26%。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.43(t,J=6.0Hz,1H),8.91(d,J=8.8Hz,1H),8.79-8.77(m,3H),8.69(d,J=8.0Hz,1H),8.32(d,J=8.0Hz,1H),8.27(d,J=6.4Hz,2H),8.20(t,J=8.0Hz,1H),7.91(s,1H),7.87(s,1H),7.82(d,J=1.6Hz,1H),6.36(s,2H),4.81(d,J=5.6Hz,2H),3.39(q,J=7.2Hz,2H),1.19(t,J=7.2Hz,3H)。
实施例122 EVO33561
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33561(7mg,收率:22.22%),LCMS(ESI)m/z=589.55[M+H]+,纯度:96.44%。1H NMR(400MHz,DMSO-d6)δ9.46-9.33(m,2H),8.73-8.62(m,2H),7.95-7.86(m,2H),7.82-7.72(m,3H),6.74(d,J=8.0Hz,1H),6.36(s,2H),4.78(d,J=5.6Hz,2H),4.08-3.96(m,2H),3.83-3.78(m,1H),3.75-3.64(m,1H),3.55-
3.51(m,1H),3.41-3.35(m,2H),2.90(dd,J=10.0,4.4Hz,6H),2.47-2.44(m,1H),2.27(m,1H),1.18(t,J=7.2Hz,3H)。
实施例123 EVO33077
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33077(3.45mg,收率:13.26%),LCMS(ESI)m/z=563.18[M+H]+,纯度:95.8%。1H NMR(400MHz,DMSO-d6)δ9.39(t,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),8.27(d,J=1.6Hz,1H),8.21(d,J=1.6Hz,1H),7.61-7.49(m,4H),7.39(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6.81(d,J=8.8Hz,1H),5.30(d,J=2.0Hz,2H),5.12(s,2H),4.62(d,J=6.0Hz,2H),4.24(dd,J=13.2,2.4Hz,2H),3.66-3.58(m,2H),3.38-3.32(m,2H),2.43-2.37(m,2H),1.18(d,J=6.0Hz,6H),1.13(t,J=7.2Hz,3H)。
实施例124 EVO33466
参照化合物EVO33392,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33466(6mg,收率:11.0%),LCMS(ESI)m/z=618.2[M+H]+,纯度:98.6%。1H NMR(400MHz,DMSO-d6)δ9.78(t,J=6.0Hz,1H),9.41(s,1H),8.75(dd,J=16.8,1.4Hz,2H),8.65(q,J=8.8Hz,2H),7.92-7.89(m,2H),7.75(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),5.75(s,2H),4.90-4.85(m,3H),4.31(d,J=12.4Hz,2H),3.78(q,J=5.6Hz,2H),3.70-3.63(m,4H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H)。
实施例125 EVO33493
参照化合物EVO33392,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33493(85.35mg,收率:69.7%),LCMS(ESI)m/z=620.2[M+H]+,纯度:99.8%。1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.64(q,J=8.8Hz,2H),7.91-7.89(m,2H),7.79-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.71-3.63(m,6H),3.14(s,3H),2.53-2.47(m,2H),1.21(d,J=6.4Hz,6H)。
实施例126 EVO33602
参照化合物EVO33392,经高效液相制备柱分离,再冷冻干燥得到EVO33602(8.54mg,收率:25%),LCMS(ESI)m/z=598.43[M+H]+,纯度:99.78%。1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.44(t,J=5.6Hz,1H),8.93(d,J=8.4Hz,1H),8.80(d,J=8.4Hz,1H),8.70(d,J=7.2Hz,1H),8.28(d,J=7.2Hz,1H),8.19(t,J=7.6Hz,1H),7.95-7.93(m,3H),7.90(s,1H),7.83(d,J=1.6Hz,1H),6.39(s,2H),4.93(t,J=5.6Hz,1H),4.83(d,J=5.6Hz,2H),3.80(q,J=6.0Hz,2H),3.58(t,J=6.0Hz,2H),2.60(s,6H)。
实施例127 EVO33037
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33037(4.72mg,收率:32.7%),LCMS(ESI)m/z=568.49[M+H]+,纯度:90.9%。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.15(t,J=5.9Hz,1H),8.69-8.58(m,2H),7.90(d,J=7.4Hz,1H),7.78-7.70(m,2H),7.66(d,J=1.7Hz,1H),7.44(d,J=1.7Hz,1H),7.03(d,J=8.5Hz,1H),6.13(s,2H),5.56(s,1H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.74-3.61(m,3H),2.71-2.59(m,2H),2.28-2.14(m,2H),2.03-1.89(m,1H),1.71-1.59(m,1H),1.24(d,J=6.2Hz,6H)。
实施例128 EVO33185
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33185(27mg,收率:58%),LCMS(ESI)m/z=587.2[M+H]+,纯度:94.8%。1H NMR(400MHz,DMSO-d6)δ9.79-9.71(m,1H),9.40(s,1H),9.06(s,1H),8.70-8.57(m,4H),7.93-7.87(m,1H),7.86(s,1H),7.74(t,J=7.9Hz,1H),7.02(d,J=8.5Hz,1H),4.85(d,J=5.7Hz,2H),4.79(s,2H),4.38-4.24(m,2H),3.74-3.61(m,2H),3.35(s,3H),2.57-2.42(m,2H),1.21(d,J=6.2Hz,6H)。
实施例129 EVO33438
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到产物EVO33438(60mg,收率:86%),LCMS(ESI)m/z=615.23[M+H]+,纯度:98.1%。1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),9.17-9.03(m,1H),8.88(d,J=8.8Hz,1H),8.61-8.52(m,2H),8.48-8.38(m,2H),8.12(d,J=7.4Hz,1H),7.79-7.71(m,1H),7.30(d,J=3.2Hz,1H),6.90-6.83(m,1H),6.75(d,J=3.2Hz,1H),5.14(d,J=5.8Hz,2H),4.79(t,J=5.1Hz,2H),4.24-4.18(m,2H),3.97(t,J=5.1Hz,2H),3.84-3.75(m,2H),3.44(s,3H),2.70-2.59(m,2H),1.34(d,J=6.2Hz,6H)。
实施例130 EVO33080
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33080(16.86mg,收率:26.15%),LCMS(ESI)m/z=628.30[M+H]+,纯度:98.54%。1H NMR(400MHz,DMSO-d6)δ9.56(t,J=6.0Hz,1H),9.30(s,1H),8.57(d,J=8.8Hz,2H),8.32(s,1H),8.29(d,J=8.6Hz,1H),8.26(s,1H),7.96(s,1H),7.78(s,1H),7.73(s,1H),5.32(s,2H),5.14(s,2H),4.80(d,J=5.8Hz,2H),4.71(d,J=12.9Hz,2H),3.74-3.64(m,2H),3.37(q,J=7.2Hz,2H),3.01-2.86(m,2H),1.22(d,J=6.2Hz,6H),1.15(t,J=7.3Hz,3H)。
实施例131 EVO33081
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33081(23.13mg,收率:37.94%),LCMS(ESI)m/z=630.30[M+H]+,纯度:99.89%。1H NMR(400MHz,DMSO-d6)δ9.38(t,J=5.9Hz,1H),9.29(s,1H),8.59-8.53(m,2H),8.29(d,J=8.6Hz,1H),7.96(s,1H),7.90(d,J=1.7Hz,1H),7.80(d,J=1.6Hz,1H),7.76-7.72(m,2H),6.35(s,2H),4.75(d,J=5.8Hz,2H),4.72(d,J=13.2Hz,2H),3.72-3.67(m,2H),3.38(q,J=7.4Hz,2H),3.01-2.87(m,2H),1.22(d,J=6.2Hz,6H),1.18(t,J=7.4Hz,3H)。
实施例132 EVO33229
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33229(12.97mg,收率:16.3%),LCMS(ESI)m/z=559.26[M+H]+,纯度:99.89%。1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),9.13(t,J=5.9Hz,1H),8.97(d,J=8.6Hz,1H),8.78(d,J=8.6Hz,1H),8.75-8.70(m,2H),8.50(d,J=1.6Hz,1H),8.40(dd,J=7.9,1.0Hz,1H),8.21(t,J=7.9Hz,1H),7.85-7.79(m,2H),7.45(d,J=1.8Hz,1H),6.10(s,2H),5.27(s,1H),4.78(d,J=5.7Hz,2H),2.69(s,3H),1.50(s,6H)。
实施例133 EVO33566
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33566(9.8mg,收率:19.85%),LCMS(ESI)m/z=608.4[M+H]+,纯度:99.66%。1H NMR(400MHz,DMSO-d6)δ9.40(d,J=4.0Hz,2H),8.73-8.65(m,1H),8.55(d,J=8.6Hz,1H),8.09(dd,J=8.2,2.9Hz,1H),7.89(d,J=1.6Hz,1H),7.82-7.78(m,2H),7.71(dd,J=13.1,8.2Hz,1H),6.35(s,2H),4.78(d,J=5.8Hz,2H),4.01(d,J=12.1Hz,2H),3.83-3.71(m,2H),3.37(q,J=7.4Hz,2H),2.67(dd,J=12.8,10.5Hz,2H),1.21-1.16(m,9H)。
实施例134 EVO33571
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到白色固体EVO33571(16.87mg,收率:20.1%),LCMS(ESI)m/z=591.3[M+H]+,纯度:99.65%。1H NMR(400MHz,DMSO-d6)δ9.60(t,J=5.9Hz,1H),9.49(s,1H),8.99(d,J=8.6Hz,1H),8.79(d,J=8.7Hz,1H),8.75-8.70(m,2H),8.51(d,J=1.7Hz,1H),8.41(d,J=7.8Hz,1H),8.33(s,1H),8.28(s,1H),8.24(t,J=7.9Hz,1H),7.91(s,1H),5.32(d,J=2.1Hz,2H),5.15(s,2H),4.85(d,J=5.8Hz,2H),3.38(q,J=7.3Hz,2H),2.69(s,3H),1.16(t,J=7.3Hz,3H)。
实施例135 EVO33012
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33012(23mg,收率:28.8%),LCMS(ESI)m/z=529.53[M+H]+,纯度:97.40%。1H NMR(400MHz,Chloroform-d)δ8.51(d,J=5.2Hz,1H),7.79(s,2H),7.61(s,1H),7.56-7.49(m,3H),7.42(d,J=4.4Hz,1H),7.28-7.24(m,1H),6.76(d,J=7.2Hz,1H),6.62(d,J=8.4Hz,1H),5.34(s,2H),5.09(s,2H),4.80(d,J=5.2Hz,2H),4.17(d,J=11.2Hz,2H),3.80-3.70(m,2H),2.60-2.54(m,2H),1.61(s,6H),1.31(d,J=6.0Hz,6H)。
实施例136 EVO33024
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到黄色固体EVO33012(9.3mg,收率:58.8%),LCMS(ESI)m/z=531.50[M+H]+,纯度:98.50%。1H NMR(400MHz,Chloroform-d)δ8.53(d,J=5.2Hz,1H),7.83-7.78(m,1H),7.68(s,1H),7.65(s,1H),7.57-7.49(m,3H),7.43(d,J=4.8Hz,1H),7.30-7.25(m,1H),6.77(d,J=7.2Hz,1H),6.63(d,J=8.4Hz,1H),5.27(s,2H),5.12(s,2H),4.81(d,J=5.2Hz,2H),4.17(d,J=11.2Hz,2H),3.79-3.74(m,2H),2.61-2.55(m,2H),1.70(s,6H),1.32(d,J=6.0Hz,6H)。
实施例137 EVO33608
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到EVO33608(21.26mg,收率:30.7%),LCMS(ESI)m/z=549.49[M+H]+,纯度:97.2%。1H NMR(400MHz,DMSO-d6)δ9.26(t,J=5.9Hz,1H),8.50(d,J=5.1Hz,1H),7.90(d,J=1.4Hz,1H),7.62(d,J=1.4Hz,1H),7.61-7.48(m,4H),7.38(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6.81(d,J=8.6Hz,1H),4.70(t,J=8.8Hz,2H),4.59(d,J=5.8Hz,2H),4.24(dd,J=13.0,2.4Hz,2H),3.64-3.54(m,4H),3.24(s,3H),2.41(dd,J=12.8,10.5Hz,2H),1.18(d,J=6.2Hz,6H)。
实施例138 EVO33039
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33039(13.26mg,收率:13%),LCMS(ESI)m/z=594.2[M+H]+,纯度:98.67%。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.25(t,J=5.9Hz,1H),8.64(q,J=8.6Hz,2H),7.91(d,J=7.4Hz,1H),7.78(s,1H),7.74(t,J=7.9Hz,1H),7.67(d,J=1.7Hz,1H),7.61(d,J=1.6Hz,1H),7.03(d,J=8.5Hz,1H),6.43(td,J=54.0,8.0Hz,1H),6.18(s,2H),4.77(d,J=5.8Hz,2H),4.31(dd,J=12.9,2.4Hz,2H),3.70-3.65(m,2H),2.53-2.47(m,2H),1.84(d,J=23.8Hz,3H),1.22(d,J=6.2Hz,6H)。
实施例139 EVO33484
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33484(22.93mg,收率:41.8%),LCMS(ESI)m/z=610.4[M+H]+,纯度:98.88%。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.18(t,J=5.9Hz,1H),8.67-8.60(m,2H),7.92-7.90(m,2H),7.76-7.72(m,2H),7.58(d,J=1.8Hz,1H),7.03(d,J=8.5Hz,1H),6.80(s,1H),6.13(s,2H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.70-3.65(m,2H),2.53-2.47(m,2H),1.80(s,3H),1.21(d,J=6.2Hz,6H)。
实施例140 EVO33492
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33492(14.92mg,收率:14.5%),LCMS(ESI)m/z=592.3[M+H]+,纯度:99.97%。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.15(t,J=5.9Hz,1H),8.69-8.59(m,2H),7.91(d,J=7.4Hz,1H),7.83(d,J=1.7Hz,1H),7.78-7.70(m,2H),7.52(d,J=1.7Hz,1H),7.03(d,J=8.5Hz,1H),6.15-6.09(m,3H),6.06(t,J=55.7Hz,1H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.74-3.60(m,2H),2.53-2.47(m,2H),1.60(s,3H),1.22(d,J=6.2Hz,6H)。
实施例141 EVO33604
参照化合物EVO33138,经高效液相制备柱分离,再冷冻干燥得到EVO33604(20.54mg,收率:23.5%),LCMS(ESI)m/z=612.2[M+H]+,纯度:99.95%。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.29(t,J=5.9Hz,1H),8.64(q,J=8.6Hz,2H),7.91(d,J=7.4Hz,1H),7.78-7.71(m,3H),7.67(d,J=1.6Hz,1H),7.03(d,J=8.5Hz,1H),6.20(d,J=4.9Hz,2H),4.77(d,J=5.8Hz,2H),4.31(dd,J=12.9,2.3Hz,2H),3.71-3.64(m,2H),2.53-2.47(m,2H),2.03(d,J=24.4Hz,3H),1.21(d,J=6.2Hz,6H)。
实施例142 EVO33082
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33082(8.71mg,收率:14.24%),LCMS(ESI)m/z=596.37[M+H]+,纯度:99.68%。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.08(t,J=6.0Hz,1H),8.59-8.53(m,2H),8.28(d,J=8.6Hz,1H),7.96(s,1H),7.82(d,J=1.8Hz,1H),7.73(d,J=1.6Hz,1H),7.70(s,1H),7.43(d,J=1.7Hz,1H),6.10(s,2H),5.26(s,1H),4.79-4.66(m,4H),3.74-3.63(m,2H),2.93(t,J=10.2Hz,2H),1.49(s,6H),1.22(d,J=6.1Hz,6H)。
实施例143 EVO33083
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33083(9.16mg,收率:36.52%),LCMS(ESI)m/z=598.36[M+H]+,纯度:95.82%。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.19(t,J=6.0Hz,1H),8.60-8.53(m,2H),8.28(d,J=8.7Hz,1H),7.96(s,1H),7.74(d,J=1.7Hz,1H),7.71(s,1H),7.64(d,J=1.7Hz,1H),7.50(d,J=1.7Hz,1H),6.16(s,2H),4.82-4.64(m,4H),3.76-3.63(m,2H),2.93(t,J=11.0Hz,2H),1.72(d,J=22.3Hz,6H),1.22(d,J=6.1Hz,6H)。
实施例144 EVO33253
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33253(11.27mg,收率:16.67%),LCMS(ESI)m/z=584.24[M+H]+,纯度:99.56%。1H NMR(400MHz,DMSO-d6)δ9.60(t,J=5.9Hz,1H),9.47(s,1H),8.92(d,J=8.6Hz,1H),8.77(d,J=8.6Hz,1H),8.69(d,J=7.8Hz,1H),8.35–8.30(m,2H),8.27(s,1H),8.20(t,J=7.9Hz,1H),8.12(s,1H),7.90(s,1H),7.82(s,1H),5.33(s,2H),5.15(s,2H),4.85(d,J=5.7Hz,2H),3.37(q,J=7.3Hz,2H),2.58(s,3H),1.16(t,J=7.3Hz,3H)。
实施例145 EVO33254
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33254(6.95mg,收率:10.96%),LCMS(ESI)m/z=552.20[M+H]+,纯度:94.91%。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.13(t,J=5.9Hz,1H),8.91(d,J=8.6Hz,1H),8.77(d,J=8.6Hz,1H),8.71(d,J=7.9Hz,1H),8.33(d,J=7.8Hz,1H),8.19(t,J=7.9Hz,1H),8.12(s,1H),7.86-7.79(m,3H),7.45(d,J=1.8Hz,1H),6.10(s,2H),5.27(s,1H),4.78(d,J=5.8Hz,2H),2.58(s,3H),1.50(s,6H)。
实施例146 EVO33573
参照化合物EVO33173,经高效液相制备柱分离,再冷冻干燥得到EVO33573(8.03mg,收率:10.4%),LCMS(ESI)m/z=567.24[M+H]+,纯度:99.15%。1H NMR(400MHz,DMSO-d6)δ9.96(d,J=2.2Hz,1H),9.60(t,J=5.8Hz,1H),9.48(s,1H),8.97(d,J=8.6Hz,1H),8.79(d,J=8.6Hz,1H),8.72(d,J=7.9Hz,1H),8.43-8.39(m,2H),8.34(d,J=1.4Hz,1H),8.28-8.22(m,2H),7.91(s,1H),5.32(d,J=2.1Hz,2H),5.15(s,2H),4.85(d,J=5.7Hz,2H),3.38(q,J=7.3Hz,2H),2.78(s,3H),1.16(t,J=7.3Hz,3H)。
实施例147 EVO33610
参照化合物EVO33240,经高效液相制备柱分离,再冷冻干燥得到EVO33610(25mg,收率:32.7%),LCMS(ESI)m/z=531.53[M+H]+,纯度:99.0%。1H NMR(400MHz,Chloroform-d)δ8.50(d,J=5.4Hz,1H),7.82-7.73(m,1H),7.62(d,J=1.7Hz,1H),7.58-7.48(m,3H),7.44(dd,J=5.4,1.6Hz,1H),7.32-7.27(m,1H),6.76(d,J=7.2Hz,1H),6.62(d,J=8.5Hz,1H),6.04(s,2H),4.80(d,J=5.3Hz,2H),4.16(dd,J
=13.1,2.2Hz,2H),3.80-3.70(m,2H),2.62-2.53(m,2H),1.62(s,6H),1.31(d,J=6.2Hz,6H)。
效果实施例1化合物对BRM和BRG1ATPase的抑制活性检测实验
为了表征化合物对BRM和BRG1的ATPase抑制活性,使用ADP-GloTM Kinase Assay(Promega,#V9101)检测ATPase反应终点体系中的ADP量来评价ATPase活性,分两步进行:首先,ATPase反应后,加入ADP-Glo Reagent终止反应并耗尽剩余的ATP;然后,加入Kinase Detection Reagent,将ADP转化为ATP,并通过荧光素酶/荧光素反应消耗ATP产生化学发光信号,信号与ATP(ATPase反应生成的ADP转化而来)浓度成正比。与无化合物处理的对照孔相比,通过发光信号的减少,来评价化合物的ATPase抑制活性。通过化合物浓度与ATPase活性百分比之间的数据关系,计算IC50值。
具体操作如下:将待测化合物(溶解在DMSO中,浓度10uM-1nM,50nL/孔)添加到384孔板中(Greiner#781280)中。每孔加入2.5μL BRM截断体(表达纯化的BRM ATPase-SnAC Domain,参照文献描述DOI:10.1021/acs.jmedchem.8b01318)或BRG1截断体(表达纯化的BRG1 ATPase-SnAC Domain,参照文献描述DOI:10.1021/acs.jmedchem.8b01318)和DNA(Invitrogen#15632011)的混合溶液(蛋白终浓度30nM,DNA终浓度80nM)。每孔加入2.5μL ATP(Promega#V9101,终浓度400uM)开始酶反应。体系缓冲液为20mM Tris,pH 8.0,50mM NaCl,20mM MgCl2,0.1%Tween-20,1mM DTT,总体积为5μL,在25℃下反应60分钟。之后加入ADP Glo试剂(5μL),25℃下孵育90分钟。然后加入Kinase Detection Reagent(10μL),25℃下孵育60分钟。最后检测化学发光。
酶活的测定结果列于下表中:
其中,A表示IC50≤100nM;B表示100nM<IC50≤500nM;C表示500nM<IC50≤1000nM;D表示1000nM<IC50≤5000nM;E表示5000nM<IC50≤10000nM;F表示IC50>10000nM;N.A.表示未检测。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (10)
- 一种如式I所示的化合物或其药学上可接受的盐,其特征在于,
其中,Y为C或N;R1为羟基、氰基、卤素、氨基、氘、未取代或被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基;所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代或被1个或多个氘取代的C3-C6的环烷基或-NR1-1-2R1-1-3;R1-2为O或NR1-2-1;R1-2-1为氢或未取代或被1个或多个氘取代的C1-C6的烷基;各个R1-1-1独立地为OR1-1-1-1、未取代或被1个或多个氘取代的C1-C6的烷基或氘;R1-1-1-1为氢或未取代或被1个或多个氘取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代或被1个或多个氘取代的C1-C6的烷基;各个R1-3独立地为羟基、氰基、卤素、氨基、未取代或被1个或多个氘取代的C1-C6的烷基或氘;各个R1-4和R1-5独立地为羟基、氘或未取代或被1个或多个氘取代的C1-C6的烷基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢、氘、卤素或未取代或被1个或多个氘取代的C1-C6的烷基;R1-8为氢或未取代或被1个或多个氘取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代或被1个或多个R2-4取代的C6-C10的芳基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R2-1独立地为氘、卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-1和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;各个R2-2独立地为氘、卤素、未取代或被1个或多个R2-2-1取代的C1-C6的烷基、氧代基(=O), 或者,两个R2-2和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;各个R2-3独立地为氘、卤素、未取代或被1个或多个R2-3-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-3和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;各个R2-4独立地为氘、卤素、未取代或被1个或多个R2-4-1取代的C1-C6的烷基、氧代基(=O),或者,两个R2-4和与之相连的碳原子形成未取代或被1个或多个氘取代的C3-C6的环烷基;R2-1-1、R2-2-1、R2-3-1和R2-4-1独立地为氘或羟基;A为未取代或被1个或多个氘取代的C6-C10的亚芳基、未取代或被1个或多个氘取代的5-12元的亚杂芳基或未取代或被1个或多个氘取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;L为连接健、未取代或被1个或多个氘取代的C2-C6的亚烯基或未取代或被1个或多个氘取代的C1-C6的亚烷基;Q为未取代或被1个或多个R3-1取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代或被一个或多个R3-1取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素或氘;R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代或被一个或多个R4-2取代的C2-C6的烯基、未取代或被一个或多个R4-3取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代或被一个或多个R4-7取代的C1-C6的烷氧基或-NR4-9R4-8;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R4-1独立地为氘、卤素、羟基、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;各个R4-2独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;各个R4-3独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;各个R4-4独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C1-C6的烷基;各个R4-5独立地为氘、卤素、羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5- 2R4-5-3或未取代或被1个或多个氘取代的C1-C6的烷氧基;各个R4-5-1独立地为氘、羟基或卤素;R4-5-2和R4-5-3独立地为氢或未取代或被1个或多个氘取代的C1-C6的烷基;各个R4-6独立地为氘、卤素、氰基、羟基、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;各个R4-7独立地为氘、卤素、未取代或被1个或多个氘取代的C1-C6的烷基或未取代或被1个或多个氘取代的C1-C6的烷氧基;R4-9和R4-8独立地为氢、未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代或被1个或多个氘取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R4-8-1独立地为氘、羟基、未取代或被一个或多个R4-8-1-1取代的C1-C6的烷氧基或OR4-8-1-2;各个R4-8-1-1独立地为氘或未取代或被1个或多个氘取代的C3-C6的环烷基;各个R4-8-1-2独立地为未取代或被1个或多个氘取代的C3-C6的环烷基。 - 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,所述的如式I所示的化合物满足如下条件中的一种或多种:(1)R1中,所述多个为2个、3个、4个、5个、6个或7个;(2)R1中,所述C1-C6的烷基为甲基、乙基、丙基、异丙基或异丁基;(3)R1中,所述“未取代或被1个或多个R1-4取代的C3-C6的环烷基”中,所述C3-C6的环烷基为环丁基,例如,(4)R1中,所述3-6元的杂环烷基中的杂原子为N、O或S,优选为O,所述3-6元的杂环烷基中的杂原子数优选为1个;(5)R1中,所述“未取代或被1个或多个R1-5取代的3-6元的杂环烷基”中;所述3-6元的杂环烷基为4元杂环烷基,例如,(6)R1-1中,所述“未取代或被1个或多个R1-1-1取代的C1-C6的烷基”中;所述多个为2个;(7)R1-1中,所述C1-C6的烷基为甲基、乙基或丙基;(8)R1-1中,所述C3-C6的环烷基为环丙基;(9)R1-1-1中,所述C1-C6的烷基为甲基;(10)R1-1-1-1中,所述C1-C6的烷基为甲基;(11)R1-1-2和R1-1-3中,所述C1-C6的烷基为甲基;(12)R1-3中,所述卤素为F、Cl或Br,优选为F;(13)R1-3中,所述“未取代或被1个或多个氘取代的C1-C6的烷基”中;所述多个为2个或3个;(14)R1-3中,所述C1-C6的烷基为甲基或乙基;(15)R1-6和R1-7中,所述C1-C6的烷基为甲基;(16)R1-8中,所述C1-C6的烷基为甲基;(17)R2和R3中,所述5-6元的杂芳基中的杂原子独立地选自N、O和S的一种或两种,杂原子数为1个、2个或3个;(18)R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基”中;所述5-6元的杂芳基为5元的杂芳基,例如,(19)R2和R3中,所述4-6元的杂环烷基中的杂原子独立地选自N或O中的一种或两种,杂原子数优选为1个或2个;(20)R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-2取代的4-6元的杂环烷基”中;所述4-6元的杂环烷基为5-6元的杂环烷基,例如,(21)R2和R3中,所述“R2和R3与其相连的原子形成未取代或被1个或多个R2-3取代的C4-C6的环烷基”中;所述C4-C6的环烷基为环戊烷;(22)R2和R3中,所述C6-C10的芳基为苯基;(23)R2-1中,所述卤素为F、Cl或Br,优选为F;(24)R2-1中,所述C1-C6的烷基为甲基或乙基;(25)R2-2中,所述卤素为F、Cl或Br,优选为F;(26)R2-2中,所述C3-C6的环烷基为环丙基;(27)A中,所述亚芳基为亚苯基;(28)A中,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种;杂原子数为1个、2个或3个;(29)A中,所述5-12元的亚杂芳基为6元亚杂芳基、6元亚杂芳基并5元亚杂芳基或6元亚杂芳基并6元亚杂芳基,例如,(30)A中,所述5-12元的亚杂环烷基中的杂原子独立地为N;杂原子数优选为1个;(31)A中,所述5-12元的亚杂环烷基为6元亚杂芳基并6元亚杂环烷基,例如,(32)L中,所述C2-C6的亚烯基为乙烯基,例如,(33)Q中,所述C6-C10的亚芳基为亚苯基;(34)Q中,所述5-12元的亚杂芳基中的杂原子独立地选自N和O中的一种或两种,杂原子数 为1个、2个或3个;(35)Q中,所述“未取代或被一个或多个R3-1取代的5-12元的亚杂芳基”中;所述5-12元的亚杂芳基为6元亚杂芳基、5元亚杂芳基并6元亚芳基或6元亚杂芳基并5元亚杂芳基,例如,(36)Q中,所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;(37)Q中,所述5-12元的亚杂环烷基为、6元亚杂芳基并6元亚杂环烷基,例如,(38)R3-1中,所述卤素为F、Cl或Br,优选为F;(39)R4中,所述“未取代或被一个或多个R4-1取代的C1-C6的烷基”中;所述C1-C6的烷基为乙基,例如,(40)R4中,所述C2-C6的炔基为乙炔基;(41)R4中,所述“未取代或被一个或多个R4-4取代的C3-C6的环烷基”中;所述多个为两个;(42)R4中,所述“未取代或被一个或多个R4-4取代的C3-C6的环烷基”中;所述C3-C6的环烷基为环丙基或环丁基,例如,(43)R4中,所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或两种,杂原子数优选为1个或2个;(44)R4中,所述未取代或被一个或多个R4-5取代的4-12元的杂环烷基中;所述多个为两个;(45)R4中,所述“未取代或被一个或多个R4-5取代的4-12元的杂环烷基”中;所述4-12元的杂环烷基为4-7元的杂环烷基或7-9元双桥环,例如,(46)R4中,所述5-12元的杂芳基中的杂原子为N,杂原子数优选为1个或2个;(47)R4中,所述“未取代或被一个或多个R4-6取代的5-12元的杂芳基”中;所述多个为两个;(48)R4中,所述“未取代或被一个或多个R4-6取代的5-12元的杂芳基”中;所述5-12元的杂芳基为5元或6元杂芳基,例如,(49)R4中,所述C1-C6的烷氧基为乙氧基,例如,(50)R4-1中,所述C1-C6的烷氧基为甲氧基;(51)R4-4中,所述卤素为F、Cl或Br,优选为F;(52)R4-5中,所述C1-C6的烷基为甲基;(53)R4-5中,所述C1-C6的烷氧基为甲氧基;(54)R4-5-2和R4-5-3中,所述C1-C6的烷基为甲基;(55)R4-6中,所述卤素为F、Cl或Br,优选为F;(56)R4-6中,所述C1-C6的烷基为甲基;(57)R4-9和R4-8中所述C1-C6的烷基为甲基或乙基;(58)R4-9和R4-8中,所述4-6元的杂环烷基中的杂原子为O,杂原子数优选为1个;(59)R4-9和R4-8中,所述4-6元的杂环烷基为5元或6元杂环烷基;(60)R4-8-1-2中,所述C3-C6的环烷基为环丙基。
- 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,所述的如式I所示的化合物满足如下条件中的一种或多种:(1)Y为C或N;较佳地为C;(2)R1为被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基;所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;进一步较佳地为或被1个或多个R1-3取代的C1-C6的烷基;更进一步较佳地为(3)R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代的C3-C6的环烷基或-NR1- 1-2R1-1-3;较佳地为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;进一步较佳地为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;更进一步较佳地为未取代的C1-C6的烷基;(4)R1-2为O或NR1-2-1;较佳地为O;(5)R1-2-1为氢;(6)各个R1-1-1独立地为OR1-1-1-1、未取代的C1-C6的烷基或未取代的C1-C6的烷氧基;较佳地为OR1-1-1-1或未取代的C1-C6的烷基;进一步较佳地为未取代的C1-C6的烷基;(7)R1-1-1-1为氢或未取代的C1-C6的烷基;较佳地为未取代的C1-C6的烷基;(8)R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;(9)各个R1-3独立地为羟基、氰基、卤素、氨基、未取代的C1-C6的烷基或氘;较佳地为羟基、氰基、卤素、未取代的C1-C6的烷基或氘;进一步较佳地为羟基、氰基、卤素或未取代的C1-C6的烷基;更进一步较佳地为羟基或卤素;(10)各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;较佳地为羟基、卤素或未取代的C1-C6的烷基;(11)各个R1-4和R1-5独立地为羟基;(12)X为-CR1-6R1-7-或-NR1-8-;较佳地为-CR1-6R1-7-;(13)R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;较佳地为氢;(14)R1-8为未取代的C1-C6的烷基;(15)R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代的C6-C10的芳基;较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1 个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;进一步较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;更进一步较佳地为未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;还可更进一步较佳地为未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;(16)各个R2-1独立地为卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基或氧代基(=O);较佳地为卤素或未取代的C1-C6的烷基;进一步较佳地为未取代的C1-C6的烷基;(17)各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;较佳地为氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;进一步较佳地为氧代基(=O);(18)各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);较佳地为卤素;(19)各个R2-3独立地为氧代基(=O);(20)R2-1-1为羟基;(21)A为未取代的C6-C10的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基;较佳地为未取代的5-12元的亚杂芳基;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;(22)L为连接健或未取代的C2-C6的亚烯基;较佳地为连接健;(23)Q为未取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;较佳地为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;进一步较佳地为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;(24)各个R3-1独立地为卤素;(25)R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代的C1-C6的烷氧基或-NR4-9R4-8;较佳地为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;进一步较佳地为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1- C6的烷氧基;更进一步较佳地为未取代的C2-C6的炔基、未取代的C3-C6的环烷基或被一个或多个R4- 6取代的5-12元的杂芳基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;(26)各个R4-1独立地为未取代的C1-C6的烷氧基;(27)各个R4-4独立地为卤素;(28)各个R4-5独立地为羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5-2R4-5-3或未取代的C1-C6的烷氧基;较佳地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;进一步较佳地为未取代的C1-C6的烷氧基;(29)各个R4-5-1独立地为羟基;(30)R4-5-2和R4-5-3独立地为未取代的C1-C6的烷基;(31)各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;较佳地为氰基或未取代的C1-C6的烷基;(32)R4-9和R4-8独立地为未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;(33)各个R4-8-1独立地为OR4-8-1-2;和(34)各个R4-8-1-2独立地为未取代的C3-C6的环烷基。
- 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,所述的如式I所示的化合物满足如下任一方案,方案1:Y为C或N;R1为被1个或多个R1-3取代的C1-C6的烷基、未取代或被1个或多个R1-4取代的C3-C6的环烷基或未取代或被1个或多个R1-5取代的3-6元的杂环烷基;所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基、未取代的C3-C6的环烷基或-NR1-1-2R1-1- 3;R1-2为O或NR1-2-1;R1-2-1为氢;各个R1-1-1独立地为OR1-1-1-1、未取代的C1-C6的烷基或未取代的C1-C6的烷氧基;R1-1-1-1为氢或未取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、氰基、卤素、氨基、未取代的C1-C6的烷基或氘;各个R1-4和R1-5独立地为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基、未取代或被1个或多个R2-3取代的C4-C6的环烷基或未取代的C6-C10的芳基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R2-1独立地为卤素、未取代或被1个或多个R2-1-1取代的C1-C6的烷基或氧代基(=O);各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;各个R2-3独立地为氧代基(=O);R2-1-1为羟基;A为未取代的C6-C10的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的C6-C10的亚芳基、未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为未取代或被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代或被一个或多个R4-4取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基、未取代的C1-C6的烷氧基或-NR4-9R4-8;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R4-1独立地为未取代的C1-C6的烷氧基;各个R4-4独立地为卤素;各个R4-5独立地为羟基、未取代或被一个或多个R4-5-1取代的C1-C6的烷基、-NR4-5-2R4-5-3或未取代的C1-C6的烷氧基;各个R4-5-1独立地为羟基;R4-5-2和R4-5-3独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;较佳地为氰基或未取代的C1-C6的烷基;R4-9和R4-8独立地为未取代或被一个或多个R4-8-1取代的C1-C6的烷基或未取代的4-6元的杂环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;各个R4-8-1独立地为OR4-8-1-2;各个R4-8-1-2独立地为未取代的C3-C6的环烷基;方案2:Y为C或N;R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;R1-2为O或NR1-2-1;R1-2-1为氢;各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;R1-1-1-1为氢或未取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、氰基、卤素、未取代的C1-C6的烷基或氘;各个R1-4为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原为N或O,杂原子数为1个或2个;各个R2-1独立地为卤素或未取代的C1-C6的烷基;各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;各个R2-3独立地为氧代基(=O);A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选 自N和S中的一种或两种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;R4-1独立地为未取代的C1-C6的烷氧基;各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;各个R4-5-1独立地为羟基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;方案3:Y为C或N;R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;R1-2为O或NR1-2-1;R1-2-1为氢;各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;R1-1-1-1为未取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、氰基、卤素或未取代的C1-C6的烷基;各个R1-4为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;各个R2-3独立地为氧代基(=O);A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;R4-1独立地为未取代的C1-C6的烷氧基;各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;各个R4-5-1独立地为羟基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;方案4:Y为C或N;R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;R1-2为O或NR1-2-1;R1-2-1为氢;各个R1-1-1独立地为OR1-1-1-1或未取代的C1-C6的烷基;R1-1-1-1为未取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、氰基、卤素或未取代的C1-C6的烷基;各个R1-4为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代或被1个或多个R2-3取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;各个R2-2独立地为卤素、未取代的C1-C6的烷基、氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;各个R2-3独立地为氧代基(=O);A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代或被一个或多个R3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个、2个或3个;所述 5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-12元的杂环烷基、未取代或被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为被一个或多个R4-1取代的C1-C6的烷基、未取代的C2-C6的炔基、未取代的C3-C6的环烷基、未取代或被一个或多个R4-5取代的4-6元的杂环烷基、未取代或被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个或2个;R4-1独立地为未取代的C1-C6的烷氧基;各个R4-5独立地为未取代或被一个或多个R4-5-1取代的C1-C6的烷基或未取代的C1-C6的烷氧基;各个R4-5-1独立地为羟基;各个R4-6独立地为氰基或未取代的C1-C6的烷基;方案5:Y为C;R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基或-NR1-1-2R1-1-3;R1-2为O或NR1-2-1;R1-2-1为氢;各个R1-1-1独立地为未取代的C1-C6的烷基;R1-1-2和R1-1-3独立地为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基或卤素;各个R1-4为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢或未取代的C1-C6的烷基;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元 的杂芳基中的杂原子独立地选自N和S中的一种或两种;杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为N或O;杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;各个R2-2独立地为氧代基(=O),或者,两个R2-2和与之相连的碳原子形成C3-C6的环烷基;A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种;杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基或未取代的C1-C6的烷基;方案6:Y为C;R1为被1个或多个R1-3取代的C1-C6的烷基或未取代或被1个或多个R1-4取代的C3-C6的环烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;R1-2为O;各个R1-1-1独立地为未取代的C1-C6的烷基;各个R1-3独立地为卤素;各个R1-4为羟基;X为-CR1-6R1-7-或-NR1-8-;R1-6和R1-7独立地为氢;R1-8为未取代的C1-C6的烷基;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元的杂芳基中的杂原子为N;杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为N或O,杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;各个R2-2独立地为氧代基(=O);A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种,杂原子数为1个、2个或3个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基或未取代的C1-C6的烷基;方案7:Y为C;R1为或未取代或被1个或多个R1-3取代的C1-C6的烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;R1-2为O;各个R1-1-1独立地为OR1-1-1-1;R1-1-1-1为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;X为-CR1-6R1-7-;R1-6和R1-7独立地为氢;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个或2个;各个R2-1独立地为卤素或未取代的C1-C6的烷基;各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);A为未取代的5-12元的亚杂芳基,所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂 原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;方案8:Y为C;R1为或被1个或多个R1-3取代的C1-C6的烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;R1-2为O;各个R1-1-1独立地为OR1-1-1-1;R1-1-1-1为氢或未取代的C1-C6的烷基;各个R1-3独立地为羟基、卤素、未取代的C1-C6的烷基或氘;X为-CR1-6R1-7-;R1-6和R1-7独立地为氢;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种;杂原子数为1个、2个或3个,所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个或2个;各个R2-1独立地为卤素火或未取代的C1-C6的烷基;各个R2-2独立地为卤素、未取代的C1-C6的烷基或氧代基(=O);A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;方案9:Y为C;R1为或被1个或多个R1-3取代的C1-C6的烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;R1-2为O;各个R1-1-1独立地为OR1-1-1-1;R1-1-1-1为未取代的C1-C6的烷基;各个R1-3独立地为羟基、卤素或未取代的C1-C6的烷基;X为-CR1-6R1-7-;R1-6和R1-7独立地为氢;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代或被1个或多个R2-2取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;各个R2-2独立地为卤素;A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;各个R3-1独立地为卤素;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基、卤素或未取代的C1-C6的烷基;方案10:Y为C;R1为或被1个或多个R1-3取代的C1-C6的烷基;R1-1为未取代或被1个或多个R1-1-1取代的C1-C6的烷基;R1-2为O;各个R1-1-1独立地为OR1-1-1-1;R1-1-1-1为未取代的C1-C6的烷基;各个R1-3独立地为羟基、卤素或未取代的C1-C6的烷基;X为-CR1-6R1-7-;R1-6和R1-7独立地为氢;R2和R3与其相连的原子形成未取代或被1个或多个R2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-6元的杂芳基中的杂原子为N或O,杂原子数为1个或2个;所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个或2个;各个R2-1独立地为未取代的C1-C6的烷基;A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;L为连接健或未取代的C2-C6的亚烯基;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-12元的杂环烷基、被一个或多个R4-6取代的5-12元的杂芳基或未取代的C1-C6的烷氧基;所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、被一个或多个R4-5取代的4-6元的杂环烷基、被一个或多个R4-6取代的5-6元的杂芳基或未取代的C1-C6的烷氧基;所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个或2个;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-5独立地为未取代的C1-C6的烷基;各个R4-6独立地为氰基或未取代的C1-C6的烷基;方案11:Y为C;R1为R1-1为未取代的C1-C6的烷基;R1-2为O;X为-CR1-6R1-7-;R1-6和R1-7独立地为氢;R2和R3与其相连的原子形成未取代的4-6元的杂环烷基或未取代的C4-C6的环烷基;所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述4-6元的杂环烷基中的杂原子为O,杂原子数为1个;A为未取代的5-12元的亚杂芳基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,所述5-12元的亚杂芳基中的杂原子为N,杂原子数为1个或2个;L为连接健;Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基;所述5-6元的亚杂芳基中的杂原子为N,杂原子数为1个;所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种,杂原子数为1个、2个或3个;R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、或被一个或多个R4-6取代的5-12元的杂芳基;所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种,杂原子数为1个、2个或3个;较佳地,R4为未取代的C2-C6的炔基、未取代的C3-C6的环烷基、或被一个或多个R4-6取代的5-6元的杂芳基;所述5-6元的杂芳基中的杂原子为N,杂原子数为1个;各个R4-6独立地为氰基或未取代的C1-C6的烷基。
- 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,所述的如式I所示的化合物满足如下条件中的一种或多种:(1)R1为(2)X为亚甲基、(3)为(4)A为(5)L为(6)Q为(7)R4为
- 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,所述的如式I所示的化合物为以下任一结构,
- 一种如权利要求1-6中任一项所述如式I所示的化合物或其药学上可接受的盐在制备BRM ATPase抑制剂中的用途。
- 一种药物组合物,其特征在于,其包含如权利要求1-6中任一项所述如式I所示的化合物或其药学上可接受的盐、以及药学上可接受的载体。
- 一种如权利要求1-6中任一项所述如式I所示的化合物或其药学上可接受的盐在制备药物中的用途,其特征在于,所述药物用于治疗BRM ATPase相关的疾病或所述药物用于治疗黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌或结直肠癌。
- 如权利要求9所述的用途,其特征在于,所述BRM ATPase相关的疾病为黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌或结直肠癌。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106573915A (zh) * | 2014-08-01 | 2017-04-19 | 纽韦卢森公司 | 针对布罗莫结构域有活性的化合物 |
WO2019152437A1 (en) * | 2018-01-30 | 2019-08-08 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN110267953A (zh) * | 2016-12-22 | 2019-09-20 | 因赛特公司 | 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂 |
WO2020160100A1 (en) * | 2019-01-29 | 2020-08-06 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
WO2021155264A1 (en) * | 2020-01-29 | 2021-08-05 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
WO2021155316A1 (en) * | 2020-01-29 | 2021-08-05 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN113645971A (zh) * | 2019-01-29 | 2021-11-12 | 福宏治疗公司 | 化合物及其用途 |
WO2022103899A1 (en) * | 2020-11-10 | 2022-05-19 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN115297861A (zh) * | 2020-01-29 | 2022-11-04 | 福宏治疗公司 | 化合物及其用途 |
-
2023
- 2023-11-10 WO PCT/CN2023/131053 patent/WO2024099440A1/zh unknown
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106573915A (zh) * | 2014-08-01 | 2017-04-19 | 纽韦卢森公司 | 针对布罗莫结构域有活性的化合物 |
CN110267953A (zh) * | 2016-12-22 | 2019-09-20 | 因赛特公司 | 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂 |
WO2019152437A1 (en) * | 2018-01-30 | 2019-08-08 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
WO2020160100A1 (en) * | 2019-01-29 | 2020-08-06 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN113645971A (zh) * | 2019-01-29 | 2021-11-12 | 福宏治疗公司 | 化合物及其用途 |
WO2021155264A1 (en) * | 2020-01-29 | 2021-08-05 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
WO2021155316A1 (en) * | 2020-01-29 | 2021-08-05 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN115297861A (zh) * | 2020-01-29 | 2022-11-04 | 福宏治疗公司 | 化合物及其用途 |
WO2022103899A1 (en) * | 2020-11-10 | 2022-05-19 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
Non-Patent Citations (1)
Title |
---|
DATABASE REGISTRY 15 July 2022 (2022-07-15), ANONYMOUS: "- 1,4-Benzodioxin-6-carboxamide, 8-chloro-2,3-dihydro-N-[1-[4-(4-methyl-1- piperazinyl)phenyl]ethyl]- (CA INDEX NAME)", XP093170032, Database accession no. 2791631-80-4 * |
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