WO2024012570A1 - Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical use thereof - Google Patents

Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical use thereof Download PDF

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Publication number
WO2024012570A1
WO2024012570A1 PCT/CN2023/107465 CN2023107465W WO2024012570A1 WO 2024012570 A1 WO2024012570 A1 WO 2024012570A1 CN 2023107465 W CN2023107465 W CN 2023107465W WO 2024012570 A1 WO2024012570 A1 WO 2024012570A1
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alkyl
group
substituted
membered
alkoxy
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PCT/CN2023/107465
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French (fr)
Chinese (zh)
Inventor
张晨
廖雨亭
王健民
高秋
石荣华
邹思佳
陈泉龙
唐平明
余彦
李瑶
严庞科
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西藏海思科制药有限公司
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Publication of WO2024012570A1 publication Critical patent/WO2024012570A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in AR-related diseases such as cancer diseases.
  • Androgen receptor is a hormone nuclear receptor that can be structurally divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD), which can regulate the induction of Gene expression in prostate cancer, therefore, inhibition of the androgen receptor is an effective approach to treating prostate cancer.
  • the androgen receptor inhibitors currently on the market such as enzalutamide and bicalutamide, mainly exert inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor, but some patients may experience symptoms during treatment.
  • Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve the problem of resistance has become a focus of clinical medicine.
  • Small molecule degraders are drugs that use the body's ubiquitin-proteasome system (UPS) to perform targeted degradation of target proteins. With its unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development such as tumors and autoimmune diseases.
  • UPS ubiquitin-proteasome system
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells.
  • Molecular glue is a type of small molecule that brings the target protein into contact with E3 ubiquitin ligase, inducing interaction between the two, thereby leading to the degradation of the target protein. From a functional perspective, molecular glue mainly works by filling the gap between the target protein and E3 ubiquitin ligase, enhancing the binding interface between the two and promoting a strong interaction between the two (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glues have the advantages of catalytically driving target protein degradation and not requiring a binding pocket on the target protein, and have the potential to act on undruggable targets.
  • the purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, safer, and capable of inhibiting and degrading AR or/and AR-Vs (especially AR-V7) for the treatment of AR and AR.
  • Related diseases such as prostate cancer.
  • the present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
  • L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-20 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • L is selected from a bond or -C 1-10 hydrocarbyl-, 1 to 10 of the hydrocarbyl groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 )
  • the methylene unit is optionally replaced by -Ak-, -Cy-;
  • each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, or Ak5;
  • each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
  • each -Cy- is independently selected from a bond or optionally substituted one of the following groups: 4-8 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 Heterospirocyclyl group, 7-10-membered hetero-bridged cyclyl group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group , benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 ,
  • the heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N
  • L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-C
  • L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-C
  • L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy2 -Cy3-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Cy1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Ak3-, -Ak
  • L is selected from the group consisting of bonds, groups shown in Table L-1, Table L-2, and Table L-3, and the left side of the group is connected to B;
  • L is selected from a bond or a group shown in Table L-2, and the left side of the group is connected to B;
  • L is selected from the groups shown in Table L-3, and the left side of the group is connected to B;
  • L is selected from
  • Cy1 is selected from 4-6 membered nitrogen-containing heterocycles optionally substituted by 1 to 4 RL2 ;
  • L is selected from
  • R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl,
  • the heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • each R L is independently selected from H or C 1-6 alkyl
  • each R L is independently selected from H or C 1-4 alkyl
  • each R L is independently H, methyl, or ethyl
  • each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the optionally substituted groups: 4-7 membered heteromonocyclyl, 4-10 membered heterocyclyl , 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic alkyl group, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 5-10 membered Bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 10 membered heteroaryl or 6 to 10 membered aryl, when substituted, by 1 to 4 RL2 substitution, the heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from the group consisting of bonds, 4-7 membered nitrogen-containing heteromonocyclyl groups, 4-10 membered nitrogen-containing heterocyclic groups, 5-12 membered nitrogen-containing heterocyclic groups.
  • each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from bonded or substituted or unsubstituted One of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutyl cyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclohexyl, cyclopentylcyclohexyl, cyclohexyl, cyclo
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from triazolyl, and the triazolyl is optionally selected from F, Cl, Br, I, OH, NH 2.
  • Substituted by COOH, CN, O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
  • each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from bonded or substituted or unsubstituted One of the following groups: When substituted, by 1 to 4 R L2 ;
  • B is selected from
  • B 1 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b 1 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B2 is selected from C3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 1 is selected from C 3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b 1 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from C 3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B3 is selected from C3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 , and the heterocycle
  • the ring group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from bonds
  • L is selected from a bond or
  • L is selected from a bond or
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from bond, O, S, NR b5a ;
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from -CH 2 -;
  • v 1 , v 2 , v 3 , v 4 are each independently selected from 0, 1, 2, 3, or 4;
  • L 1 , L 2 are each independently selected from the group consisting of bonds, -CH 2 -, -OCH 2 -, -SCH 2 -, -NHCH 2 -, -O-, -S-, -NH- ;
  • B is selected from V is selected from a bond or L 1 , and L 1 and L 2 are not bonds;
  • B is selected from
  • B is selected from
  • B is selected from
  • B is selected from
  • V is selected from bond, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , O-(Q 2 ) v2 -, -( Q 2 ) v2 -O, -(Q 2 ) v2 -;
  • V is selected from bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene -NR b5a , OC 1-4 alkylene, C 1-4 alkylene-O, C 1-4 alkylene, the alkylene is optionally substituted by 1 to 4 R b4 or R b5 ;
  • V is selected from the group consisting of bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C( CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O,S;
  • v 2 , v 4 are each independently selected from 1, 2, 3 or 4;
  • Y 1 , Y 3 are each independently selected from bond, O, S, NR b5a ;
  • Y 2 and Y 4 are each independently selected from O, S, NR b5a ;
  • Y 1 , Y 3 are each independently selected from bond, O, S, NH;
  • Y 2 and Y 4 are each independently selected from O, S, NH;
  • R b5a is selected from H, CF 3 , CHF 2 , CH 2 F, CH 2 OH, CH 2 CN, CH 2 NH 2 , methyl, ethyl, cyclopropyl;
  • B is selected from
  • B is selected from
  • B is selected from
  • B is selected from
  • b1, b2, and b3 are each independently selected from 0, 1, 2, 3, and 4;
  • b1, b2, and b3 are each independently selected from 0, 1, and 2;
  • B 1 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 4- 7 monocyclic alkyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, the above B 1 is optionally substituted by 1 to 4 R b2 , and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterocyclyl Bridged ring group, C 4-7 monocyclic alkyl group, C 6-14 cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, 5-10 membered heteroaryl group or 6- 14-membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 4- 7 monocyclic alkyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, the above B 2 is optionally substituted by 1 to 4 R b2 , and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 1 is selected from 6-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 6- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 1 is optionally substituted by 1 to 4 R b2 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 3- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 3- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 2 is optionally substituted by 1 to 4 R b2 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B is selected from one of the following groups, substituted or unsubstituted: cyclohexyl, phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine , pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzene Thiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentyl Cyclopentyl, cyclopentylpyrrolidinyl, carbazole, when substituted
  • B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b1 ;
  • B 1 is selected from B 1A ;
  • B1 is selected from substituted or unsubstituted phenyl or pyridine, and when substituted, is optionally substituted by 1 to 4 Rb1 ;
  • B is selected from one of the following groups, substituted or unsubstituted: phenyl, cyclohexyl, piperidine, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene , benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquin Phenoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 ;
  • B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole , thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolopyrrole, 3-pyridazinone, 2-pyridone, 1,2,3 ,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentyl pyrrolidinyl, when substituted, is substituted by 1 to 4 R b2 ;
  • B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b2 ;
  • B 2 is selected from B 2A ;
  • B2 is selected from pyrazole
  • B2 is selected from The B 2 is optionally replaced by 1 or 2 R b2 ;
  • each of B 1A and B 2A is independently selected from one of the optionally substituted following structures: When substituted, B 1A is replaced by 1 to 4 R b1 and B 2A is replaced by 1 to 4 R b2 ;
  • B is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl , pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azepanyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole , 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3 ,4-tetrahydroquinoline, 1,2,3,4-tetrahydro
  • B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b3 ;
  • B 3 and B 2 are connected through a carbon-nitrogen bond
  • R b21 is each independently selected from H, methyl, ethyl, isopropyl;
  • R b22 is each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
  • R b22 is each independently selected from H, NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
  • CN COOH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C Substituted with 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N of heteroatoms;
  • any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclyl group or a 5- to 7-membered heterocyclic ring.
  • the carbocyclyl group or heterocyclic ring is optionally C 1-4 alkyl or C 1-4 alkyl substituted by 1 to 4 selected from halogen, OH, -NH 2 , CN, C 1-4 alkyl, halogen, cyano Substituted with an oxygen substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclyl group or a 5- to 7-membered heterocyclic ring.
  • the carbocyclyl group or heterocyclic ring is optionally Substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy , the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a phenyl ring group, pyrrolidine, piperidine, piperazine, morpholine ring group, azepine, cyclohexane Alkene, cyclopentene, cyclopentane, cyclohexane, the pyrrolidine, piperidine, piperazine, morpholine ring, azepine, cyclohexene, cyclopentene, cyclopentane, cyclohexane Hexane is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy Substituted by substituents;
  • R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered Heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 selected from F, Cl , Br, I,
  • R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, NHC 1-4 alkyl, N(C 1 -4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl base, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, the alkyl, alkenyl
  • the base, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl,
  • R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , COOH, or any Choose one of the following substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl , oxanyl, oxanyl, O-cyclopropyl, NH-cyclopropyl, morpholine, when
  • any R b4 , R b5 and the carbon atom connected thereto together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring, and the cycloalkyl group or heteromonocyclic ring optionally Substituted by 1 to 4 C 1-4 alkyl or cyano groups selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl , the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • each X is independently selected from NH, O, or S;
  • each m1 is independently selected from 0, 1, 2, or 3;
  • each m2 is independently selected from 0, 1, 2, or 3;
  • n is each independently selected from 0, 1, 2, 3, or 4;
  • B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, and its right side is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2:
  • each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • each q is independently selected from 0, 1, 2, 3, or 4;
  • each q is independently selected from 0, 1, 2, or 3;
  • each q is independently selected from 0, 1, or 2;
  • K is selected from K1, K2, K3, K4;
  • K1 is selected from
  • K1 is selected from
  • K2 is selected from
  • K2 is selected from
  • K3 is selected from In certain embodiments, K3 is selected from
  • K4 is selected from In certain embodiments, K4 is selected from
  • each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl, or 5-12 membered heteroaryl, said heterocyclyl or
  • the heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • E is each independently selected from C 3-10 carbocyclyl, phenylcyclyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, said heterocyclyl or heteroaryl Contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • each E is independently selected from phenylcyclyl, 5-6 membered heteroaryl, and the heterocyclyl or heteroaryl contains 1 to 3 (eg, 1, 2, 3) selected from Heteroatoms of O, S, and N;
  • each E is independently selected from phenyl, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole base, furan ring group, thiophene ring group, oxazole ring group, indoline ring group, isoindoline ring group, 1,2,3,4-tetrahydroquinoline ring group or 1,2,3,4 -Tetrahydroisoquinoline ring;
  • each E is independently selected from phenyl, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole base, furan ring group, thiophene ring group or oxazole ring;
  • E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring;
  • each E is independently selected from phenyl ring or pyridine ring;
  • A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said heterocyclyl or heteroaryl Containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • A is selected from C 3-8 carbocyclyl, phenylcyclyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • A is selected from benzene, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, furan Ring group, thiophene ring group or oxazole ring;
  • A is selected from phenyl or pyridine rings
  • each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, said heterocyclyl or
  • the heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • each F is independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 pentacyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl Cyclic group, 4-7-membered heteromonocyclic group, 4-10-membered heterocyclic group, 8-15-membered heterotricyclic group, 5-12-membered heterospirocyclic group, 5-10-membered heterocyclic group, C 6-14 aryl, 5-10 membered heteroaryl, the heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • each F is independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 pentacyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl Cyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group base, C 6-14 aryl group, 5-10 membered heteroaryl group,
  • the heteromonocyclic group, heteroacyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
  • each F is independently selected from phenyl, pyridyl, pyrimidine, pyrazine, pyridazine,
  • each F is independently selected from phenyl, pyridyl, pyrimidine, pyrazine, pyridazine,
  • each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl , 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridine Imidazolyl, benzimidazolyl, benzopyridine Imidazo
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, N;
  • R q is selected from H or C 1-6 alkyl
  • R q is selected from H or C 1-4 alkyl
  • R q is selected from H, methyl, ethyl
  • Rk1 is selected from Rk7a ;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected Heteroatoms from O, S, N;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected Heteroatoms from O, S, N;
  • each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so
  • each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
  • each R k5 is independently selected from C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 , SO 2 ,
  • each R k5 is independently selected from CO, CH 2 , SO 2 or
  • each R k6 is independently selected from CO, CH, SO, SO 2 , CH 2 or N;
  • each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
  • each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
  • each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ), or NH;
  • each Rk7 is independently selected from CH2 , O, N( CH3 ), or NH;
  • R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1 Substituted by -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituents;
  • R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1 Substituted by -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
  • Rk7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, heterocycloalkyl or cycloalkyl
  • the base is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl 1 to 4 are selected from F, Cl, Br
  • R k7a is selected from H, CF 3 , methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH (CH 3 )CF 3 , -CH(CH 3 )-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;
  • R k7a is selected from H, CF 3 , methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
  • R k7a is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl
  • each Rk8 is independently selected from C, N, or CH;
  • each R k9 is independently selected from bond, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
  • each R k9 is independently selected from CO, SO 2 or CH 2 ;
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
  • M 3 is selected from -NH- or -O-;
  • 1 to 4 e.g., 1, 2, 3, 4
  • R k14 is selected from a 5-6 membered heteroaryl group
  • the heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from N, O, S;
  • Rk14 is selected from
  • K is selected from one of the structural fragments shown in Table K-1;
  • K is selected from one of the structural fragments shown in Table K-2;
  • n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • the compound represented by general formula (I) is selected from one of the structures represented by (Ia) or (Ib);
  • the compound represented by general formula (I) is selected from general formula (Id),
  • R b4 and R b5 are each independently selected from H, methyl, ethyl, and isopropyl;
  • R b4 and R b5 and the carbon atoms to which they are connected together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and the said cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group are optional Substituted by 1 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • B 2 is selected from 5-6 membered heteroaryl or 6-membered aryl, preferably from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and the B 2 is optionally replaced by 1 to 3 R b2 Substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl group, C 4-7 monocyclic alkyl group, C 6-14 paracycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-6-membered heteroaryl or 6-membered aryl, preferably phenyl, pyrrolyl, pyrazolyl , imidazolyl, triazolyl, the B 3 is optionally substituted by 1 to 3 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • R d is selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
  • L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
  • q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
  • Each -Cy- is independently selected from one of the bonded or optionally substituted groups: 4-8 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4- 6- carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl , heteroaryl, heteromonocyclyl, heterocyclyl, heterospirocyclyl or heterobridged cyclyl containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from
  • B 1 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle.
  • the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b1 .
  • the heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
  • B 2 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle.
  • the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 .
  • the heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from bonds, O, S, NR b5a ;
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from
  • v 1 , v 2 , v 3 and v 4 are each independently selected from 0, 1, 2, 3 or 4;
  • n is independently selected from 0, 1, 2, 3 or 4;
  • any one of R b1 and R b3 , R b2 and R b3 are directly connected to form a C 5-7 carbocyclic group or a 5 to 7-membered heterocyclic ring, and the carbocyclic group or heterocyclic ring is optionally selected from 1 to 4 Substituted from halogen, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy substituents , the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 F, Cl, Br, I, OH,
  • any R b4 , R b5 and the carbon atoms connected to them together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring
  • the cycloalkyl group or heteromonocyclic ring is optionally selected from 1 to 4 From F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono
  • the cyclyl group, heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
  • X is each independently selected from NH, O or S;
  • n1 is each independently selected from 0, 1, 2 or 3;
  • n2 is independently selected from 0, 1, 2 or 3;
  • R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, the carbocyclyl, alkenyl, alkynyl,
  • the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
  • K is selected from K1, K2, K3, K4;
  • R q is selected from H or C 1-6 alkyl
  • A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, and the heterocyclyl or heteroaryl contains 1 to 4 selected from Heteroatom of O, S or N;
  • Each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, the heterocyclyl or heteroaryl containing 1 to 4 A heteroatom selected from O, S or N;
  • Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
  • R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl
  • M 3 is selected from -NH- or -O-;
  • the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
  • n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  • V is selected from key or L 1 ;
  • L 1 and L 2 are not keys
  • B 1 is selected from 6-7-membered heteromonocyclic group, 5-14-membered heterocyclic group, 5-12-membered heterospirocyclic group, 7-10-membered heterobridged cyclic group, C 6-8 monocarbocyclic group Base, C 6-14 paracycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzo C 3-10 carbocyclyl group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic ring group, 12 to 18 membered heterotricyclyl group, 5-10 membered heteroaryl group or 6-14 membered aryl group, the B 1 is optionally substituted by 1 to 4 R b2 , the Heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14 paracycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered heterocyclyl, C 12-18 Tricyclic ring group, 12 to 18 membered heterotricyclyl group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl group Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14 cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 membered bridged cycloalkyl group, benzo C 3-10 carbocyclyl group, benzo 3 to 10 membered heterocyclyl group, C 12- 18- membered tricyclic group, 12- to 18-membered heterotricyclic group, 5-10-membered heteroaryl group or 6-14-membered aryl group, the B 2 is optionally substituted by 1 to 4 R b2 , the heteroaryl
  • the base or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, C 6-10 aryl base, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy
  • the base, alkylthio group, cycloalkyl group, aryl group, heteroaryl group or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N (C 1-4 al
  • L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-,
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the optionally substituted following groups: 4-7 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospiro Cyclic group, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the Heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S
  • q is independently selected from 0, 1, 2, 3 or 4;
  • R L are each independently selected from H or C 1-6 alkyl
  • A is selected from C 3-8 carbocyclyl, phenyl ring, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 selected from O, S or heteroatoms of N;
  • F is each independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 paracyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered Heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 aromatic base, 5-10 membered heteroaryl group,
  • the heteromonocyclic group, heteroacyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
  • the ring is selected from aromatic ring groups or non-aromatic rings
  • Each E is independently selected from C 3-10 carbocyclyl, phenyl ring, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 selected from Heteroatom of O, S or N;
  • R q is selected from H or C 1-4 alkyl
  • R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
  • Rk8 is each independently selected from C, N or CH;
  • R ka is selected from O, S or NH
  • Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl alkyl
  • the base and heterocycloalkyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2 Substituted with -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
  • R k14 selected from
  • V is selected from bonds, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , O-(Q 2 ) v2 -, -(Q 2 ) v2 -O, -(Q 2 ) v2 -;
  • v 2 and v 4 are each independently selected from 1, 2, 3 or 4;
  • Y 1 and Y 3 are each independently selected from bond, O, S, NR b5a ;
  • Y 2 and Y 4 are each independently selected from O, S, NR b5a ;
  • q is independently selected from 0, 1, 2 or 3;
  • R L are each independently selected from H or C 1-4 alkyl
  • E and A are each independently selected from benzene ring group, pyridine ring group, pyridazine ring group, pyrazine ring group, pyrimidine ring group, pyrrole ring group, pyrazole ring group, imidazole ring group, thiazole ring group, furan ring group , thiophene ring or oxazole ring;
  • F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridimidazolyl, benzimidazole base, benzopyrazolyl, benzothi
  • R ka is selected from O, S or NH
  • R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
  • Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I,
  • p1 or p2 are each independently selected from 0, 1, 2 or 3;
  • R L is selected from H, methyl or ethyl
  • q is independently selected from 0, 1 or 2;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropyl cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl and cyclopentyl and cyclopentyl , cyclopentyls
  • NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, Substituted with C 1-4 alkoxy or halogen-substituted C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
  • B 1 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, Isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzox Azole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidine Base, carbazole, when substituted, is substituted by 1 to 4 R b1 ;
  • Or B 1 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b1 ;
  • B 1 is selected from B 1A ;
  • B 2 is selected from one of the following substituted or unsubstituted groups: phenyl ring, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole , indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquin Phenoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 ;
  • Or B 2 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b2 ;
  • B 2 is selected from B 2A ;
  • B 1A and B 2A are each independently selected from one of the optionally substituted following structures: When substituted, B 1A is replaced by 1 to 4 R b1 and B 2A is replaced by 1 to 4 R b2 ;
  • B 3 is selected from one of the following substituted or unsubstituted groups: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyridyl Azole, pyrrole, pyrrolidinyl, piperidine, piperazine, azepine, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzene Pyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline , 1,2,3,4-tetrahydro
  • Or B 3 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b3 ;
  • V is selected from bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene-NR b5a , OC 1-4 alkylene, C 1-4 alkylene- O.
  • C 1-4 alkylene group, the alkylene group is optionally substituted by 1 to 4 R b4 or R b5 ;
  • any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic ring, and the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, OH, -NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy, said The heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • K is selected from one of the structural fragments shown in Table K-1;
  • Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
  • B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, its right side is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2;
  • K is selected from one of the structural fragments shown in Table K-2;
  • L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -C
  • V is selected from bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C(CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O, S;
  • L is selected from a bond or one of the structural fragments shown in Table L-1, Table L-2 or Table L-3, in which the left side of the group is connected to B and the remaining groups are defined as in the second, third, fourth and fifth of the present invention. Or the same in any of the six embodiments.
  • the present invention relates to a following compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
  • the present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate the disease or condition being treated to some extent (e.g., inhibit or degrade AR or AR cleavage). One or more symptoms of mutant-related diseases such as prostate cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25- 600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75- 500mg, 80-500mg, 90-500mg, 100-500mg, 125-500m
  • the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
  • a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable
  • the salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
  • a method for treating diseases in mammals includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
  • the present invention relates to a kit, which may include a composition in a single dose or multiple dose form.
  • the kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical
  • the amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the above-mentioned pharmaceutical composition for the preparation of treatment and AR Or application in drugs for diseases related to the activity or expression of AR splicing mutants.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs and metabolites.
  • the present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions, wherein:
  • the disease is selected from prostate cancer.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • Halogen refers to F, Cl, Br or I.
  • Halo-substituted means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted” is simply referred to as "halogenated.”
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition.
  • Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Hydrocarbyl refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms.
  • the hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or
  • the heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring group or a spiro ring.
  • Non-limiting examples include Epoxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl , piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6, or 2 to 4 carbon atoms
  • alkenyl examples include but Not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3 -Pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl base, 2-heptenyl, 3-heptenyl, 4-hepten
  • alkynyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • Carbocyclic group or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring group or non-aromatic ring.
  • the aromatic ring group or non-aromatic ring can be a 3 to 8-membered monocyclic group, 4
  • the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring group or non-aromatic ring is optionally a monocyclic group, a bridged ring group or a spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, phenyl ring group, naphthyl ring group, "Carbocyclyl” or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring group or non-aromatic ring.
  • the aromatic ring group or non-aromatic ring can be a 3 to 8-membered monocyclic group, 4 to a 12-membered bicyclic group or a 10- to 15-membered tricyclic system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, heterocyclic group
  • the selectively substituted C, N, and S in the ring can be oxidized into various oxidation states.
  • the heterocyclyl group can be connected to a heteroatom or a carbon atom.
  • the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl group can be connected to a bridged ring group or a spiro ring.
  • Non-limiting examples include ethylene oxide. base, aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, Azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thio Morpholinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuryl, tetrahydropyrrolyl
  • Spirocyclic or “spirocyclyl” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Spiro or “spiryl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "And ring” or "and ring group” can be monovalent, divalent, trivalent or tetravalent.
  • the "bridging ring” or “bridging ring base” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
  • Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system.
  • Heterocyclyl refers to a "paracyclyl” containing heteroatoms.
  • Heterospirocycle refers to a “spirocycle” containing heteroatoms.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • Aryl or "aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic group or a fused ring.
  • the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms.
  • the aryl ring can be fused to a saturated or unsaturated carbocyclyl or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include phenyl ring, naphthyl ring, "Aryl” or “aryl ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, pyridone, pyrazinone, wait.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclyl or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups appearing herein have the same definition as this definition.
  • Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
  • 5-membered 5-membered heteroaryl refers to a 5-membered fused heteroaryl. At least one of the two cyclic rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole ring group, pyrazolopyrrole ring group, pyrazolopyrazole ring group, pyrrolofuran ring group, pyrazofuran ring group , pyrrolothiophene ring, pyrazolothiophene ring.
  • 5- and 6-membered heteroaryl refers to a 5- and 6-membered fused heteroaryl group. At least one of the two cyclic rings contains more than one heteroatom (including but not limited to O, S or N ), the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
  • Constant 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
  • Substituted by 1 to X substituents selected from means substituted by 1, 2, 3...
  • “1 to 4 R k substituted” means substituted with 1, 2, 3 or 4 R k .
  • substituted by 1 to 5 substituents selected from means substituted by 1, 2, 3, 4 or 5 substituents selected from...
  • the hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from H or F means that the hetero-bridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
  • “4-7 membered heteromonocyclic ring” refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings
  • “5-10-membered heterocyclic ring” refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • C xy carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclyl, spirocyclic carbocyclyl, paracyclic carbocyclyl or bridged carbocyclic ring) includes C x , C x+1 , C x+2 , C x+3 , C x+4 ....C y -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), such as C 3-6 cycloalkyl ” refers to C 3 , C 4 , C 5 or C 6 cycloalkyl.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned, and there are hydrogen atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the linking direction includes the reading order direction from left to right and right to left, for example, A-L-B.
  • L is selected from -M-W-, it includes A-M-W-B. and A-W-M-B.
  • Alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
  • IC 50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) by half.
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from formal commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -–0.5mm;
  • THP Boc: tert-butoxycarbonyl
  • Ms TBS: Bn: DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane ;Cbz: NMP: N-methylpyrrolidone; TEA: triethylamine; MsCl: methanesulfonyl chloride.
  • Dissolve 2c (5.0g, 49.93mmol) in 50mL acetic acid, add iodine (12.67g, 49.92mmol) at room temperature, and react at room temperature for 12 hours.
  • Add the reaction solution to 200 mL of water, adjust the pH to 8 with solid potassium carbonate, extract with ethyl acetate (100 mL ⁇ 3), combine the organic phases, wash the organic phase with 50 mL of saturated sodium thiosulfate aqueous solution, and dry over anhydrous sodium sulfate.
  • Preparation method Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% TFA).
  • Gradient elution method Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 2 (0.05g).
  • Dissolve 3b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min.
  • Step 1 Preparation of 5b Dissolve 5a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add cesium carbonate (9.68g, 29.70mmol), 80 °C reaction for 3h.
  • the reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated.
  • the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Compound 9 was obtained by referring to the synthesis method of Example 8 using compounds 9a and 9b as raw materials.
  • 1,4-dioxane (15 mL) was added to cyclopent-2-en-1-one (0.50 g, 6.09 mmol), 14a (2.05 g, 9.14 mmol) and (1,5-cyclooctadiene ) to rhodium (I) chloride dimer (CAS: 12092-47-6) (0.09g, 0.18mmol), add sodium carbonate (1.03g, 9.72mmol) in water (5mL) with stirring at room temperature, and replace nitrogen three times. , react at 90°C for 4 hours.
  • crude product 1 (0.40g).
  • dichloromethane (10 mL) to crude product 1 (0.25 g), cool to 0°C, add methylsulfonyl chloride (0.22g, 1.92mmol) and triethylamine (0.29g, 2.87mmol), and react at 25°C for 2 hours. .
  • Step 4 Preparation of p-toluenesulfonate of 15f
  • Compound 17 was obtained by referring to the synthesis method of Example 10 using compounds 17a and 10d as raw materials.
  • Compound 18 was obtained by referring to the synthesis method of Example 10 using compound 18a as a raw material.
  • Compound 21 was obtained by referring to the synthesis method of Example 20 using compounds 21a and 21A as raw materials.
  • microwave reaction In the microwave tube, add 25b (0.20g, 0.64mmol), 1c (0.16g, 0.64mmol), CuI (0.024g, 0.13mmol), trans-(1R,2R)-N,N'dimethyl 1 , 2-cyclohexanediamine (0.036g, 0.25mmol), potassium phosphate (0.41g, 1.93mmol) and DMF (4mL), after adding, microwave reaction at 140°C for 5h.
  • Compound 26 was obtained by referring to the synthesis method of Example 19 using compounds 26a and 26A as raw materials.
  • Dissolve 29b (2.30g, 7.18mmol) in THF (20mL), add 4mL of water and lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min.
  • Compound 30 was obtained by referring to the synthesis method of Example 23 using compounds 30a and 30A as raw materials.
  • the trifluoroacetate salt of compound 32 was prepared by acidic preparation (acetonitrile/water (containing 0.1% TFA)) by freeze-drying using compounds 32a and 32A as raw materials, referring to the synthesis method of Example 23.
  • Dissolve 34a (0.2g, 0.904mmol) (see WO2018066545 for synthesis method) in 2mL DMF, add 60% sodium hydride (5.3mg) at room temperature, react at room temperature for 15min, then add 4-iodobenzyl bromide (0.32g, 1.08 mmol), react at room temperature for 2 h.
  • the reaction system was added to 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • 36b and 36b′ are respectively one of the isomers of structure 36b-A or 36b-B.
  • Dissolve 36b (0.46g, 1.5mmol) in a mixed solvent of tetrahydrofuran (12mL) and water (3mL), add lithium hydroxide monohydrate (315mg, 7.51mmol), and react at room temperature for 16h.
  • 36c is one of the isomers of structure 36c-A or 36c-B.
  • 36d is one of the isomers of structure 36d-A or 36d-B.
  • Compound 36 is one of the isomers of structure 36-A or 36-B.
  • Dissolve 36b' (0.33g, 1.08mmol) in a mixed solvent of tetrahydrofuran (12mL) and water (3mL), add lithium hydroxide monohydrate (226.8mg, 5.41mmol), and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid solution, extract with ethyl acetate (40 mL ⁇ 3), wash the organic phase with saturated aqueous sodium chloride solution (30 mL ⁇ 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Triethylamine (228 mg, 2.25 mmol) and 2-chloro-4-(trifluoromethyl)aniline (147 mg, 0.75 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 h.
  • 37a is one of the isomers of structure 36c-A or 36c-B.
  • 37b is one of the isomers of structure 36d-A or 36d-B.
  • Compound 37 is one of the isomers of structure 36-A or 36-B.
  • Dissolve 38b (0.7g, 2.19mmol) in a mixed solvent of tetrahydrofuran (16mL) and water (4mL), add lithium hydroxide monohydrate (460mg, 10.96mmol), and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid solution, extract with ethyl acetate (60 mL ⁇ 3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL ⁇ 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure.
  • Compound 39 was obtained by referring to the synthesis method of Example 33 using compound 33a and 3-(Boc-amino)phenylboronic acid pinacol ester as raw materials.
  • Dissolve 40a (1g, 8.61mmol) in dimethyl sulfoxide (20mL), cool to 0°C, add 60% sodium hydride (62mg), and react at room temperature for 1 hour. Cool the reaction system to 0°C, add 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (1.7g, 8.56mmol), and keep at room temperature.
  • 40d is one of the isomers of structure 40d-A or 40d-B.
  • the crude product is prepared by Prep-HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: SunFire@ PrepC18 (19 ⁇ 250nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5mmol/L ammonia); gradient elution: mobile phase A content from 40-90%; flow rate: 12mL/min; column temperature: room temperature ; Detection wavelength: 210nm; Dissolve the sample with DMF and filter it with a 0.45um filter to make a sample solution; elution time: 15min), freeze-dry to obtain compound 40 (30mg, yield: 16%).
  • Prep-HPLC instrument: waters 2767 preparation liquid phase; chromatographic column: SunFire@ PrepC18 (19 ⁇ 250nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5mmol/L ammonia); gradient elution: mobile phase A content from 40-90%; flow rate: 12mL/min; column temperature: room temperature ; Detect
  • 41a (1.17g, 3.4mmol) (see WO2016058544 for the synthesis method), 1A (0.92g, 5.08mmol), TEA (2.06g, 20.4mmol), CuI (130mg, 0.68mmol) and PdCl 2 (PPh 3 ) 2 ( 240 mg, 0.34 mmol), add 5 mL DMF under nitrogen protection, and react at 50°C for 0.5 h.
  • 41c (0.4g, 1.35mmol), 33a (0.5g, 1.34mmol), CuI (13mg, 0.068mmol), (1S,2S)-(+)-N,N'dimethyl-1,2-cyclo Hexamethylenediamine (0.095g, 0.67mmol) and potassium carbonate (0.28g, 2.03mmol) were added with 10mL DMF under nitrogen protection and reacted at 100°C for 2 hours.
  • Dissolve 43b (0.45g, 1.07mmol) and the above crude intermediate 1 (0.46g) in 10 mL DMF, add TEA (0.32g, 3.16mmol), and add CuI (0.03g, 0.16mmol) and PdCl 2 under nitrogen protection.
  • (PPh 3 ) 2 (0.11g, 0.16mmol), reacted at 50°C for 2h.
  • Dissolve 44a (1.0g, 4.1mmol), di-tert-butyl dicarbonate (1.79g, 8.20mmol), TEA (0.82g, 8.10mmol), and DMAP (0.1g, 0.82mmol) in 20 mL dichloromethane, room temperature Reaction 12h.
  • the reaction system was added to 50 mL of methylene chloride, the organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the above crude product 1 (1.17g), 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (0.92g, 5.08mmol), TEA (2.06g, 20.36mmol), CuI (130mg, 0.68mmol) and PdCl 2 (PPh 3 ) 2 (240 mg, 0.34 mmol) was added to the reaction bottle, 5 mL DMF was added under nitrogen protection, and the reaction was carried out at 50°C for 0.5 h.
  • Cool the reaction solution to room temperature add it to 100 mL of ethyl acetate, wash with saturated sodium chloride aqueous solution (50 mL ⁇ 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure.
  • 47A (1.0g, 4.81mmol), di-tert-butyl dicarbonate (1.16g, 5.32mmol) and TEA (0.73g, 7.21mmol) Dissolve in 50mL tetrahydrofuran and react at room temperature for 12h. Add the reaction system to 100 mL of water, extract with ethyl acetate (50 mL :0-9:1) to obtain 47B (1.3g, yield: 88%).
  • Compound 50 was obtained by referring to the synthesis method of Example 49 using compounds 49e and 49b-2 as raw materials.

Abstract

A compound as represented by general formula (I), or a stereoisomer, a deuterated form, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof; and intermediates thereof, and the use thereof in AR-related diseases such as cancers. B-L-K (I)

Description

一种含氮杂环衍生物及其组合物和药学上的应用A nitrogen-containing heterocyclic derivative, its composition and pharmaceutical application 技术领域Technical field
本发明涉及一种通式(I)的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在AR相关疾病如癌症疾病中的用途。The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in AR-related diseases such as cancer diseases.
背景技术Background technique
雄激素受体(Androgen receptor,AR)是一种激素核受体，结构上可划分为N-端活化区域(NTD)、DNA结合区域(DBD)和配体结合区域(LTD)，能够调节诱发前列腺癌的基因表达，因此，抑制雄激素受体是治疗前列腺癌的有效方法。目前上市的雄激素受体抑制剂如恩杂鲁胺、比卡鲁胺等主要是通过与雄激素受体的配体结合区域(LTD)作用发挥抑制效果，但部分患者在治疗过程中会出现由于LTD片段缺失的雄激素受体剪切突变体(Androgen receptor splice variants,AR-Vs)导致的耐药现象。临床前研究表明，雄激素受体剪切突变体能加快恩杂鲁胺耐药的前列腺癌进展，如何解决其耐药问题成为临床医学的关注点。Androgen receptor (AR) is a hormone nuclear receptor that can be structurally divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD), which can regulate the induction of Gene expression in prostate cancer, therefore, inhibition of the androgen receptor is an effective approach to treating prostate cancer. The androgen receptor inhibitors currently on the market, such as enzalutamide and bicalutamide, mainly exert inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor, but some patients may experience symptoms during treatment. Resistance caused by Androgen receptor splice variants (AR-Vs) lacking the LTD fragment. Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve the problem of resistance has become a focus of clinical medicine.
小分子降解剂是一种利用机体泛素-蛋白酶体系统(UPS)对靶蛋白进行定向降解的药物。小分子降解剂凭借独特的催化机制，可以靶向难以成药的靶点，解决药物耐药问题，目前在肿瘤、自身免疫性疾病等药物研发领域是一大热点。Small molecule degraders are drugs that use the body's ubiquitin-proteasome system (UPS) to perform targeted degradation of target proteins. With its unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development such as tumors and autoimmune diseases.
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years.
分子胶(molecular glue)是一类促使靶蛋白和和E3泛素连接酶接触，诱导两者之间产生相互作用，从而导致靶蛋白降解的小分子。从功能性的角度说，分子胶主要是通过填补靶蛋白和E3泛素连接酶的空隙，增强二者的结合界面促进两者之间发生强相互作用(Nat.Commun.,2022,13,815)。与传统的小分子抑制剂相比，分子胶具有催化形式驱动靶蛋白降解和无需在靶蛋白上有结合口袋的优点，具有作用于不可成药靶点的潜力。Molecular glue is a type of small molecule that brings the target protein into contact with E3 ubiquitin ligase, inducing interaction between the two, thereby leading to the degradation of the target protein. From a functional perspective, molecular glue mainly works by filling the gap between the target protein and E3 ubiquitin ligase, enhancing the binding interface between the two and promoting a strong interaction between the two (Nat. Commun., 2022, 13, 815). Compared with traditional small molecule inhibitors, molecular glues have the advantages of catalytically driving target protein degradation and not requiring a binding pocket on the target protein, and have the potential to act on undruggable targets.
因此，有必要开发新型的雄激素受体剪切突变体(Androgen receptor splice variants,AR-Vs，特别是AR-V7突变体)抑制剂和E3泛素连接酶的PROTAC或其它小分子降解剂药物，用于治疗与雄激素受体剪切突变体相关的肿瘤疾病。Therefore, it is necessary to develop new androgen receptor splice mutants (AR-Vs, especially AR-V7 mutants) inhibitors and PROTACs of E3 ubiquitin ligase or other small molecule degrader drugs. , for the treatment of neoplastic diseases associated with androgen receptor splice mutants.
发明内容Contents of the invention
本发明的目的在于提供一种结构新颖的、药效好、生物利用度高、更安全、能抑制并降解AR或/和AR-Vs(特别是AR-V7)的化合物，用于治疗与AR相关疾病如前列腺癌。The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, safer, and capable of inhibiting and degrading AR or/and AR-Vs (especially AR-V7) for the treatment of AR and AR. Related diseases such as prostate cancer.
本发明提供一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物， The present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
B-L-K  (I)；B-L-K (I);
在某些实施方案中，L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-20烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-20 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
在某些实施方案中，L选自键或-C1-10烃基-，所述烃基中有1至10个(例如1、2、3、4、5、6、7、8、9或10)亚甲基单元任选被-Ak-、-Cy-替换；In certain embodiments, L is selected from a bond or -C 1-10 hydrocarbyl-, 1 to 10 of the hydrocarbyl groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ) The methylene unit is optionally replaced by -Ak-, -Cy-;
在某些实施方案中，每个-Ak-各自独立地选自Ak1、Ak2、Ak3、Ak4或Ak5；In certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4, or Ak5;
在某些实施方案中，每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；In certain embodiments, each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O )-, -NR L (CH 2 ) q C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-( CH 2 ) q -NR L -, -(C≡C) q -, -CH＝CH-, -Si(R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O) 2 -or bond, so The -CH 2 -, -CH=CH- is optionally substituted by 1 to 2 C 1 selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, and halogen. Substituted by -6 alkyl, hydroxy-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl;
在某些实施方案中，每个-Cy-各自独立地选自Cy1、Cy2、Cy3、Cy4或Cy5；In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;
在某些实施方案中，每个-Cy-各自独立地选自键或者任选取代的如下基团之一：4-8元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, each -Cy- is independently selected from a bond or optionally substituted one of the following groups: 4-8 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 Heterospirocyclyl group, 7-10-membered hetero-bridged cyclyl group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group , benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , The heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N. When the heteroatom is selected When from S, optionally replaced by 1 or 2 =O;
在某些实施方案中，L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、 -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3 -Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1 -Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5 -, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2 -Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3 -Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4 -, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
在某些实施方案中，L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；In certain embodiments, L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1 -Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2 -Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3 -Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1 -Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1 -Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2 -Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
在某些实施方案中，L选自键、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy2-Cy3-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-NHCO-(CH2)s1-，s1选自0、1、2、3、4、5、6或7；In certain embodiments, L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy2 -Cy3-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Cy1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -NHCO-(CH 2 ) s1 -, s1 is selected from 0, 1, 2, 3, 4, 5, 6 or 7 ;
在某些实施方案中，L选自键、表L-1、表L-2、表L-3所示的基团，基团左侧与B连接；In certain embodiments, L is selected from the group consisting of bonds, groups shown in Table L-1, Table L-2, and Table L-3, and the left side of the group is connected to B;
在某些实施方案中，L选自键或表L-2所示的基团，基团左侧与B连接；In certain embodiments, L is selected from a bond or a group shown in Table L-2, and the left side of the group is connected to B;
在某些实施方案中，L选自表L-3所示的基团，基团左侧与B连接；In certain embodiments, L is selected from the groups shown in Table L-3, and the left side of the group is connected to B;
在某些实施方案中，L选自 In certain embodiments, L is selected from
在某些实施方案中，Cy1选自任选被1至4个RL2取代的如下基团之一：4-12元含氮杂环基，优选4-7元含氮杂单环基、4-10元含氮杂并环基、5-12元含氮杂螺环基、7-10元含氮杂桥环基，所述的含氮杂环基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, Cy1 is selected from one of the following groups optionally substituted by 1 to 4 R L2 : 4-12 membered nitrogen-containing heterocyclyl, preferably 4-7 membered nitrogen-containing heteromonocyclyl, 4 -10-membered nitrogen-containing heterocyclic group, 5-12-membered nitrogen-containing heterospirocyclic group, 7-10-membered nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group contains 1 to 4 (for example, 1, 2 , 3 or 4) heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally substituted by 1 or 2 =O;
在某些实施方案中，Cy1选自任选被1至4个RL2取代的4-6元含氮杂环；In certain embodiments, Cy1 is selected from 4-6 membered nitrogen-containing heterocycles optionally substituted by 1 to 4 RL2 ;
在某些实施方案中，L选自 In certain embodiments, L is selected from
表L-1 L基团












Table L-1 L group












表L-2


Table L-2


表L-3

Table L-3

在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个(例如1或2个)选自卤素、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, - (CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -CH =CH-, -(C≡C) q - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 (for example, 1 or 2) selected from halogen, OH, CN, Substitution of NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by base;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, - (CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -CH =CH-, -C≡C- or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , CF 3. Substituted by hydroxymethyl, methyl, ethyl, methoxy or ethoxy substituents;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-SCH2-、-CH2S-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O- , -SCH 2 -, -CH 2 S-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F) =CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH -, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;
在某些实施方案中，Ak1、Ak2、Ak3、Ak4各自独立的选自-C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-；In certain embodiments, Ak1, Ak2, Ak3, Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH =C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NHCO-;
在某些实施方案中，RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；In certain embodiments, R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, The heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，RL各自独立的选自H或C1-6烷基；In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;
在某些实施方案中，RL各自独立的选自H或C1-4烷基；In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;
在某些实施方案中，RL各自独立的自H、甲基或乙基；In certain embodiments, each R L is independently H, methyl, or ethyl;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或任选取代的如下基团之一：4-7元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the optionally substituted groups: 4-7 membered heteromonocyclyl, 4-10 membered heterocyclyl , 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic alkyl group, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 5-10 membered Bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 10 membered heteroaryl or 6 to 10 membered aryl, when substituted, by 1 to 4 RL2 substitution, the heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键、4-7元含氮杂单环基、4-10元含氮杂并环基、5-12元含氮杂螺环基、7-10元含氮杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、5-10元杂芳基或6-10元芳基，所述杂单环基、杂并环基、杂桥环基、杂螺环基、环烷基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂单环基、杂并环基、杂桥环基、杂螺环基或杂芳基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from the group consisting of bonds, 4-7 membered nitrogen-containing heteromonocyclyl groups, 4-10 membered nitrogen-containing heterocyclic groups, 5-12 membered nitrogen-containing heterocyclic groups. Azaspirocyclyl, 7-10-membered nitrogen-containing heterocyclic bridged group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged ring Alkyl, 5-10 membered heteroaryl or 6-10 membered aryl, the heteromonocyclic group, heterocyclic group, heterobridged cyclic group, heterospirocyclic group, cycloalkyl, aryl or heteroaryl group C 1-4 alkyl optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen , hydroxyl substituted C Substituted with 1-4 alkyl or C 1-4 alkoxy substituents, the heteromonocyclic group, heterocyclic group, heterobridged cyclic group, heterospirocyclic group or heteroaryl group contains 1 to 4 A hetero atom selected from O, S, N. When the hetero atom is selected from S, it is optionally substituted by 1 or 2 =O;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的 如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、吡啶基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；In certain embodiments, each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from bonded or substituted or unsubstituted One of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutyl cyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclohexyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspiro Cyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidyl, cyclobutylazetidine Butyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidine cyclobutyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, Pyrrolidinyl azetidinyl, pyrrolidinopyrrolidyl, pyrrolidinyl piperidinyl, piperidyl azetidinyl, piperidyl pyrrolidinyl, piperidyl piperidinyl base, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiro Piperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyridinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, nitrogen Heterocyclidylspiroazetidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl alkyl, When substituted, by 1 to 4 R L2 ;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自三氮唑基，所述三氮唑基任选被1个选自F、Cl、Br、I、OH、NH2、COOH、CN、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from triazolyl, and the triazolyl is optionally selected from F, Cl, Br, I, OH, NH 2. Substituted by COOH, CN, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自取代的或者未取代的如下基团之一：当被取代时，被1个选自F、CF3、甲基、甲氧基、＝O、羟甲基、COOH、CN、OH或NH2的取代基所取代；In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups, substituted or unsubstituted: When substituted, it is substituted by 1 substituent selected from F, CF 3 , methyl, methoxy, =O, hydroxymethyl, COOH, CN, OH or NH 2 ;
在某些实施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的 如下基团之一： 当被取代时，被1至4个RL2取代；In certain embodiments, each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from bonded or substituted or unsubstituted One of the following groups: When substituted, by 1 to 4 R L2 ;
在某些实施方案中，RL2各自独立地选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的 杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R L2 is independently selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , = O, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, -OC 1 -4 alkylene-OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene -OC 1- 4 alkylene-OC 3-10 carbocyclyl, -OC 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0 -4 alkylene-4 to 10-membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally selected from 1 to 4 F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen substituted C 1 -4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy substituents, the The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，RL2各自独立地选自F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R L2 is independently selected from F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene- OC 1-2 alkyl, -OC 1-2 alkylene - OC 3 -6 carbocyclyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3- 6 carbocyclyl, -OC 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene -4 to 6-membered heterocyclic group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclic group or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted Substituted with C 1-4 alkyl, C 1-4 alkoxy, or halogen-substituted C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;
在某些实施方案中，RL2各自独立地选自F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、OCHF2、OCF3、甲基、甲氧基、＝O、CH2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代；In certain embodiments, each R L2 is independently selected from F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or optionally substituted. 1: Methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 - O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , methyl, methoxy Substituted with substituents such as =O, CH 2 OH, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, and NH 2 ;
在某些实施方案中，Cy1、Cy2、Cy3各自独立的选自取代的或者未取代的如下基团之一： 当被取代时，被1至4个选自F、CF3、OH、甲基、甲氧基、＝O、羟甲基、COOH、CN或NH2的取代基所取代；In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following groups, substituted or unsubstituted: When substituted, substituted with 1 to 4 substituents selected from F, CF 3 , OH, methyl, methoxy, =O, hydroxymethyl, COOH, CN or NH 2 ;
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B1选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b 1 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb2所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B2 is selected from C3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb3所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； In certain embodiments, B 3 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B1选自C3-14碳环基或4-14元杂环，所述碳环基或杂环任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 is selected from C 3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b 1 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自C3-14碳环基或4-14元杂环，所述碳环基或杂环任选被1至4个Rb2所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 2 is selected from C 3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自C3-14碳环基或4-14元杂环，所述碳环基或杂环任选被1至4个Rb3所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B3 is selected from C3-14 carbocyclyl or 4-14 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 , and the heterocycle The ring group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自键；In certain embodiments, B 3 is selected from bonds;
在某些实施方案中，L1选自键或 In certain embodiments, L is selected from a bond or
在某些实施方案中，L2选自键或 In certain embodiments, L is selected from a bond or
在某些实施方案中，Y1、Y2、Y3、Y4各自独立地选自键、O、S、NRb5a；In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from bond, O, S, NR b5a ;
在某些实施方案中，Q1、Q2、Q3、Q4各自独立地选自 In certain embodiments, Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from
在某些实施方案中，Q1、Q2、Q3、Q4各自独立地选自-CH2-；In certain embodiments, Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from -CH 2 -;
在某些实施方案中，v1、v2、v3、v4各自独立地选自0、1、2、3或4；In certain embodiments, v 1 , v 2 , v 3 , v 4 are each independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，L1、L2各自独立地选自键、-CH2-、-OCH2-、-SCH2-、-NHCH2-、-O-、-S-、-NH-；In certain embodiments, L 1 , L 2 are each independently selected from the group consisting of bonds, -CH 2 -, -OCH 2 -, -SCH 2 -, -NHCH 2 -, -O-, -S-, -NH- ;
在某些实施方案中，B选自 V选自键或L1，L1、L2不为键；In certain embodiments, B is selected from V is selected from a bond or L 1 , and L 1 and L 2 are not bonds;
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，V选自键、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、O-(Q2)v2-、-(Q2)v2-O、-(Q2)v2-； In certain embodiments, V is selected from bond, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , O-(Q 2 ) v2 -, -( Q 2 ) v2 -O, -(Q 2 ) v2 -;
在某些实施方案中，V选自键、O、S、NRb5a、NRb5a-C1-4亚烷基、C1-4亚烷基-NRb5a、O-C1-4亚烷基、C1-4亚烷基-O、C1-4亚烷基，所述的亚烷基任选被1至4个Rb4或Rb5所取代；In certain embodiments, V is selected from bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene -NR b5a , OC 1-4 alkylene, C 1-4 alkylene-O, C 1-4 alkylene, the alkylene is optionally substituted by 1 to 4 R b4 or R b5 ;
在某些实施方案中，V选自键、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S；In certain embodiments, V is selected from the group consisting of bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C( CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O,S;
在某些实施方案中，v2、v4各自独立地选自1、2、3或4；In certain embodiments, v 2 , v 4 are each independently selected from 1, 2, 3 or 4;
在某些实施方案中，Y1、Y3各自独立地选自键、O、S、NRb5a；In certain embodiments, Y 1 , Y 3 are each independently selected from bond, O, S, NR b5a ;
在某些实施方案中，Y2、Y4各自独立地选自O、S、NRb5a；In certain embodiments, Y 2 and Y 4 are each independently selected from O, S, NR b5a ;
在某些实施方案中，Y1、Y3各自独立地选自键、O、S、NH；In certain embodiments, Y 1 , Y 3 are each independently selected from bond, O, S, NH;
在某些实施方案中，Y2、Y4各自独立地选自O、S、NH；In certain embodiments, Y 2 and Y 4 are each independently selected from O, S, NH;
在某些实施方案中，Rb5a选自H、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocycle The base, aryl or heteroaryl group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycle Substituted with a substituent of a base, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb5a选自H、C1-4烷基、-(CH2)n-Rb22，所述的-CH2-、烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , and the -CH 2 -, alkyl group is optionally substituted by 1 to 4 selected from F , Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb5a选自H、甲基、乙基、环丙基，所述的甲基、乙基、环丙基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、N(CH3)、CN、CF3、COOH、C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, R b5a is selected from H, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally replaced by 1 to 4 selected from F, Cl, Br, Substituted with substituents of I, OH, =O, NH 2 , N(CH 3 ), CN, CF 3 , COOH, C 1-4 alkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb5a选自H、CF3、CHF2、CH2F、CH2OH、CH2CN、CH2NH2、甲基、乙基、环丙基；In certain embodiments, R b5a is selected from H, CF 3 , CHF 2 , CH 2 F, CH 2 OH, CH 2 CN, CH 2 NH 2 , methyl, ethyl, cyclopropyl;
在某些实施方案中，B选自 In certain embodiments, B is selected from
某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，B选自 In certain embodiments, B is selected from
在某些实施方案中，b1、b2、b3各自独立地选自0、1、2、3、4；In certain embodiments, b1, b2, and b3 are each independently selected from 0, 1, 2, 3, and 4;
在某些实施方案中，b1、b2、b3各自独立地选自0、1、2；In certain embodiments, b1, b2, and b3 are each independently selected from 0, 1, and 2;
在某些实施方案中，B1选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C4-7单环烷基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、5-10元杂芳基或6-14元芳基，所述B1任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 4- 7 monocyclic alkyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, the above B 1 is optionally substituted by 1 to 4 R b2 , and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂 桥环基、C4-7单环烷基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、5-10元杂芳基或6-14元芳基，所述B3任选被1至4个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 3 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterocyclyl Bridged ring group, C 4-7 monocyclic alkyl group, C 6-14 cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, 5-10 membered heteroaryl group or 6- 14-membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C4-7单环烷基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、5-10元杂芳基或6-14元芳基，所述B2任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 2 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 4- 7 monocyclic alkyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl, the above B 2 is optionally substituted by 1 to 4 R b2 , and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B1选自6-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C6-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B1任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 1 is selected from 6-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 6- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 1 is optionally substituted by 1 to 4 R b2 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B3任选被1至4个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 3 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 3- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B2选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B2任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, B 2 is selected from 4-7 membered heteromonocyclyl, 5-14 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered heterobridged cyclyl, C 3- 8 monocarbocyclyl, C 6-14 cycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered hetero Ring group, C 12-18 tricyclic group, 12 to 18 membered heterotricyclic group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 2 is optionally substituted by 1 to 4 R b2 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，B1选自取代或未取代的如下基团之一：环己基、苯基、萘基、噻吩、呋喃、吡咯、吡唑、咪唑、吡啶、2-吡啶酮、嘧啶、吡嗪、哒嗪、喹啉、异喹啉、喹唑啉、3,4-二氢-1H-苯并吡喃、1,2,3,4-四氢喹啉、苯并呋喃、苯并噻吩、苯并吡咯、苯并噁唑、苯并噻唑、苯并咪唑、苯并吡唑、吗啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、咔唑，当被取代时，被1至4个Rb1取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: cyclohexyl, phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine , pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzene Thiophene, benzopyrrole, benzoxazole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentyl Cyclopentyl, cyclopentylpyrrolidinyl, carbazole, when substituted, are substituted by 1 to 4 R b1 ;
在某些实施方案中，B1选自任选取代的如下结构之一： 当被取代时，被1至4个Rb1取代； In certain embodiments, B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b1 ;
在某些实施方案中，B1选自B1A；In certain embodiments, B 1 is selected from B 1A ;
在某些实施方案中，B1选自取代或未取代的苯基或吡啶，当被取代时，任选被1至4个Rb1所取代；In certain embodiments, B1 is selected from substituted or unsubstituted phenyl or pyridine, and when substituted, is optionally substituted by 1 to 4 Rb1 ;
在某些实施方案中，B2选自取代或未取代的如下基团之一：苯基、环己基、哌啶、吡唑、咪唑、三氮唑、噻唑、噁唑、异噁唑、噻吩、苯并吡咯、吲哚、苯并咪唑、苯并吡唑、苯并噻唑、吡唑并四氢吡咯、3-哒嗪酮、2-吡啶酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、 当被取代时，被1至4个Rb2取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, cyclohexyl, piperidine, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene , benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquin Phenoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 ;
在某些实施方案中，B2选自取代或未取代的如下基团之一：苯基、萘基、喹啉、吡唑、吡啶、咪唑、三氮唑、噻唑、噁唑、异噁唑、噻吩、苯并吡咯、吲哚、苯并咪唑、苯并吡唑、苯并噻吩、苯并噻唑、吡唑并四氢吡咯、3-哒嗪酮、2-吡啶酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基，当被取代时，被1至4个Rb2取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole , thiophene, benzopyrrole, indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolopyrrole, 3-pyridazinone, 2-pyridone, 1,2,3 ,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentyl pyrrolidinyl, when substituted, is substituted by 1 to 4 R b2 ;
在某些实施方案中，B2选自任选取代的如下结构之一： 当被取代时，被1至4个Rb2取代；In certain embodiments, B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b2 ;
在某些实施方案中，B2选自B2A；In certain embodiments, B 2 is selected from B 2A ;
在某些实施方案中，B2选自吡唑；In certain embodiments, B2 is selected from pyrazole;
在某些实施方案中，B2选自所述B2任选被1或2个Rb2取代； In certain embodiments, B2 is selected from The B 2 is optionally replaced by 1 or 2 R b2 ;
在某些实施方案中，B1A、B2A各自独立地选自任选取代的如下结构之一： 当被取代时，B1A被1至4个Rb1取代，B2A被1至4个Rb2取代；In certain embodiments, each of B 1A and B 2A is independently selected from one of the optionally substituted following structures: When substituted, B 1A is replaced by 1 to 4 R b1 and B 2A is replaced by 1 to 4 R b2 ;
在某些实施方案中，B3选自取代或未取代的如下基团之一：氧杂环丁基、环丁基、环戊基、环己基、氮杂环丁基、四氢呋喃基、苯基、吡啶、萘基、吡唑、吡咯、吡咯烷基、哌啶、哌嗪、氮杂环己烯基、四氢吡喃基、咪唑、噻吩、噻唑、噁唑、异噁唑、三氮唑、2-吡啶酮、苯并吡咯、苯并吡咯烷、苯并噻吩、苯并噻唑、苯并吡唑、苯并咪唑、吡唑并四氢吡咯、3-哒嗪酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、环丁基螺哌啶基、 当被取代时，被1至4个Rb3取代；In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl , pyridine, naphthyl, pyrazole, pyrrole, pyrrolidinyl, piperidine, piperazine, azepanyl, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole , 2-pyridone, benzopyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3 ,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentyl pyrrolidinyl, cyclobutylspiropiperidinyl, When substituted, by 1 to 4 R b3 ;
在某些实施方案中，B3选自任选取代的如下结构之一： 当被取代时，被1至4个Rb3取代；In certain embodiments, B is selected from one of the optionally substituted structures: When substituted, by 1 to 4 R b3 ;
在某些实施方案中，B3与B2之间通过碳氮键连接； In certain embodiments, B 3 and B 2 are connected through a carbon-nitrogen bond;
在某些实施方案中，选自 In certain embodiments, Selected from
在某些实施方案中，选自 In certain embodiments, Selected from
在某些实施方案中，Rb1、Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、NH2、NHC1-4烷基、N(C1-4烷基)2、-C(＝O)NH2、-C(＝O)NHC1-4烷基、-C(＝O)N(C1-4烷基)2、-C(＝O)OC1-4烷基、-S(＝O)2NH2、-S(＝O)2N(C1-4烷基)2、-S(＝O)2NHC1-4烷基、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4烷基)C(＝O)Rb22、-NHS(＝O)2Rb22、-N(C1-4烷基)S(＝O)2Rb22、-O-C3-12碳环基、-NH-C3-12碳环基、-S-C3-12碳环基、C3-12碳环基、C6-10芳基、5至12元杂芳基、4至12元杂环基、-C1-4亚烷基-Rb22、-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-ORb22，所述的亚烷基、烷基、烯基、炔基、烷氧基、烷硫基、碳环基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、-O-C3-10碳环基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b1 and R b2 are each independently selected from H, F, Cl, Br, I, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2 , NHC 1-4 alkyl, N( C 1-4 alkyl ) 2 , -C(=O)NH 2 , -C(=O)NHC 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -C(=O)OC 1-4 alkyl group, -S(=O) 2 NH 2 , -S(=O) 2 N(C 1-4 alkyl) 2 , -S(=O) 2 NHC 1-4 alkyl, -OR b22 , -C (＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -NHC(＝O)R b22 , -N(C 1-4 alkyl)C( =O)R b22 , -NHS(=O) 2 R b22 , -N(C 1-4 alkyl)S(=O) 2 R b22 , -OC 3-12 carbocyclyl, -NH-C 3- 12 carbocyclyl, -SC 3-12 carbocyclyl, C 3-12 carbocyclyl, C 6-10 aryl, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, -C 1-4 Alkylene-R b22 , -OC 1-4 alkylene- R b22 , -C 1-4 alkylene-OC 1-4 alkylene-R b22 , -C 1-4 alkylene-OC 1 -4 alkylene-OR b22 , the alkylene, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl or heteroaryl groups are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, C 1-4 alkyl , Halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2- 4 alkynyl, -OC 3-10 carbocyclyl, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 options Heteroatoms from O, S, N;
在某些实施方案中，Rb1各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-NH-环丙基、-NH-环丁基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-6元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b1 is independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C( =O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, - CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy base, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxanyl, oxanyl, Morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy , C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl Substituted with a substituent of a base or a 4-6 membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-NH-环丙基、-NH-环丁基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊 基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；In certain embodiments, each R b1 is independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C( =O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, - CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy base, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxanyl, oxanyl, Morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyrrolidinyl base, azetidinyl spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
在某些实施方案中，Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；In certain embodiments, R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, CF 3. Substituted with substituents of COOH, C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NH-C1-4烷基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；In certain embodiments, each R b22 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1 -4 alkyl, C 3-6 cycloalkyl, the alkyl, alkoxy, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 Substituted with substituents of , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb21各自独立的选自H、甲基、乙基、异丙基；In certain embodiments, R b21 is each independently selected from H, methyl, ethyl, isopropyl;
在某些实施方案中，Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NH-C1-4烷基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；In certain embodiments, each R b22 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1 -4 alkyl group, C 3-6 cycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group, alkenyl group, and alkynyl group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH , substituted by substituents of , =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb22各自独立的选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基；In certain embodiments, R b22 is each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
在某些实施方案中，Rb22各自独立的选自H、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、环丙基、环丁基；In certain embodiments, R b22 is each independently selected from H, NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
在某些实施方案中，Rb3各自独立的选自卤素、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自卤素、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b3 is independently selected from halogen, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne group, C 1-4 alkoxy group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -SR b22 , -NH-R b22 , -(CH 2 ) m1 -X -(CH 2 ) m2 -R b24 , -N(R b21 ) 2 , -C(＝O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , - S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N(R b21 ) 2 , -NR b21 C(＝O)R b22 , -NR b21 S (=O) 2 R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, Alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally selected from 1 to 4 halogen, OH, =O, -N (R b21 ) 2. CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C Substituted with 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N of heteroatoms;
在某些实施方案中，Rb3各自独立的选自卤素、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-CH2-Rb22、-CH2CH2-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-O-CH2CH2-Rb24、-S-CH2CH2-Rb24、-NH-CH2CH2-Rb24、-O-CH2-Rb24、-S-CH2-Rb24、-NH-CH2-Rb24、-CH2-O-CH2-Rb24、-CH2-S-CH2-Rb24、-CH2-NH-CH2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自卤素、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b3 is independently selected from halogen, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne group, C 1-4 alkoxy group, C 1-4 alkylthio group, -CH 2 -R b22 , -CH 2 CH 2 -R b22 , -OR b22 , -SR b22 , -NH-R b22 , -O -CH 2 CH 2 -R b24 , -S-CH 2 CH 2 -R b24 , -NH-CH 2 CH 2 -R b24 , -O-CH 2 -R b24 , -S-CH 2 -R b24 , - NH-CH 2 -R b24 , -CH 2 -O-CH 2 -R b24 , -CH 2 -S-CH 2 -R b24 , -CH 2 -NH-CH 2 -R b24 , -N(R b21 ) 2 , -C(＝O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)( R b22 ) 2 , -S(＝O) 2 N(R b21 ) 2 , -NR b21 C(＝O)R b22 , -NR b21 S(＝O) 2 R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl The base, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 4 selected from halogen, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1- 4 alkoxy, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4 -Substituted with a substituent of an 8-membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb3各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁 基、-O-CH2-环丙基、-O-CH2-环丁基、-O-CH2CH2-甲氧基、-O-CH2CH2-O-环丙基、-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-甲氧基、-CH2-O-CH2CH2-O-环丙基、-CH2-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-NH-甲基、-CH2-甲氧基、-CH2-乙氧基、N(CH3)2、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；In certain embodiments, each R b3 is independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C( =O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl, -S -Cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl base, -O-CH 2 -cyclopropyl, -O- CH 2 -cyclobutyl, -O-CH 2 CH 2 -methoxy, -O-CH 2 CH 2 -O-cyclopropyl, -O -CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -methoxy, -CH 2 -O-CH 2 CH 2 -O-cyclopropyl, -CH 2 -O- CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -NH-methyl, -CH 2 -methoxy, -CH 2 -ethoxy, N(CH 3 ) 2 , Methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole, pyrazole, azepine Cyclobutyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
在某些实施方案中，Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、-CH2-环丙基、-CH2-环丁基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基、-CH2OCH2CH2-NH-甲基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、CH2OH、甲基、乙基、异丙基、甲氧基、乙氧基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、吡咯烷基、哌啶基、吡唑基、吗啉基的取代基所取代；In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, =S, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2. -P(=O)(CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, Ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl , triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyrrolidinylcyclopentyl, aza Cyclobutylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, -CH 2 -ring Propyl, -CH 2 -cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O - cyclopropyl, -O-cyclobutyl, -NH- Cyclopropyl, -NH-cyclobutyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -NH-methyl, When substituted, from 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CH 2 F, CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 OH , methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, ? Substituted by a substituent of the linyl group;
在某些实施方案中，Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环，所述的碳环基或者杂环任选被1至4个选自卤素、OH、-NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；In certain embodiments, any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclyl group or a 5- to 7-membered heterocyclic ring. The carbocyclyl group or heterocyclic ring is optionally C 1-4 alkyl or C 1-4 alkyl substituted by 1 to 4 selected from halogen, OH, -NH 2 , CN, C 1-4 alkyl, halogen, cyano Substituted with an oxygen substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环，所述的碳环基或者杂环任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CH2F、CHF2、CF3、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；In certain embodiments, any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclyl group or a 5- to 7-membered heterocyclic ring. The carbocyclyl group or heterocyclic ring is optionally Substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy , the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb1与Rb3、Rb2与Rb3任其一直接连接形成苯环基、吡咯烷、哌啶、哌嗪、吗啉环基、氮杂环己烯、环己烯、环戊烯、环戊烷、环己烷，所述的吡咯烷、哌啶、哌嗪、吗啉环基、氮杂环己烯、环己烯、环戊烯、环戊烷、环己烷任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CH2F、CHF2、CF3、甲基、乙基、甲氧基或乙氧基的取代基所取代；In certain embodiments, any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a phenyl ring group, pyrrolidine, piperidine, piperazine, morpholine ring group, azepine, cyclohexane Alkene, cyclopentene, cyclopentane, cyclohexane, the pyrrolidine, piperidine, piperazine, morpholine ring, azepine, cyclohexene, cyclopentene, cyclopentane, cyclohexane Hexane is optionally substituted by 1 to 4 groups selected from F, Cl, Br, I, OH, NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy Substituted by substituents;
在某些实施方案中，Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、 C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered Heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 selected from F, Cl , Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted Substituted with substituents of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, the heteroaryl or The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、CN、NO2、COOH、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C3-8环烷基、O-C3-8环烷基、NH-C3-8环烷基、C6-10芳基、5-6元杂芳基或3-8元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, NHC 1-4 alkyl, N(C 1 -4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl base, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, the alkyl, alkenyl The base, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1- 4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
在某些实施方案中，Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、CN、NO2、COOH或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、O-环丙基、NH-环丙基、吗啉，当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基的取代基所取代；In certain embodiments, R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , COOH, or any Choose one of the following substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl , oxanyl, oxanyl, O-cyclopropyl, NH-cyclopropyl, morpholine, when substituted, 1 to 4 selected from F, Cl, Br, I, OH, NH 2. The substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 2-4 alkynyl replace;
在某些实施方案中，任意Rb4、Rb5和与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环基、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, any R b4 , R b5 and the carbon atom connected thereto together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring, and the cycloalkyl group or heteromonocyclic ring optionally Substituted by 1 to 4 C 1-4 alkyl or cyano groups selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl , the heteromonocyclic group, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
在某些实施方案中，任意Rb4、Rb5和与其相连接的碳原子共同形成任选取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基，当被取代时，被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, any R b4 , R b5 and the carbon atom to which they are attached together form one of the optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclyl Butyl, azetanyl, azepanyl, oxetanyl, oxetanyl, oxetanyl, when substituted, are 1 to 4 selected from F, Cl, Br, I , OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with substituents of base, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the heteroaryl or heterocyclyl contains 1 to 8 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-10碳环基或4-10元杂环基，所述的碳环基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, said carbocyclyl , alkenyl, alkynyl, heterocyclyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;
在某些实施方案中，Rb23各自独立的选自乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基，所述的乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、 C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, R b23 is each independently selected from vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, azetyl Butyl, oxetanyl, pyrrolidinyl, piperidinyl, the vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopropyl Pentyl, azetidinyl, oxetanyl, pyrrolidinyl and piperidinyl are optionally selected from 1 to 4 from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3. COOH, Substituted with substituents of C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, and C 1-4 alkoxy;
在某些实施方案中，Rb24各自独立的选自C1-4烷氧基、NH-C1-4烷基、NH-C3-6环烷基、C3-6环烷基氧基、C3-10碳环基或4-10元杂环基，所述的烷氧基、碳环基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；In certain embodiments, each R b24 is independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy , C 3-10 carbocyclic group or 4-10 membered heterocyclic group, the alkoxy group, carbocyclic group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl , substituted by a C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
在某些实施方案中，Rb24各自独立的选自甲氧基、乙氧基、丙氧基、异丙氧基、-O-环丙基、-O-环丁基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基，所述的甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代；In certain embodiments, each R b24 is independently selected from methoxy, ethoxy, propoxy, isopropoxy, -O-cyclopropyl, -O-cyclobutyl, cyclopropyl, cyclopropyl Butyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidyl, the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl , cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN Substituted with substituents of , CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, and C 1-4 alkoxy;
在某些实施方案中，X各自独立的选自NH、O或S；In certain embodiments, each X is independently selected from NH, O, or S;
在某些实施方案中，m1各自独立的选自0、1、2或3；In certain embodiments, each m1 is independently selected from 0, 1, 2, or 3;
在某些实施方案中，m2各自独立的选自0、1、2或3；In certain embodiments, each m2 is independently selected from 0, 1, 2, or 3;
在某些实施方案中，n各自独立的选自0、1、2、3或4；In certain embodiments, n is each independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，B选自表B-1、表B-2或表B-3所示的结构片段之一，其右侧与L连接，b1、b2各自独立地选自0、1或2：In some embodiments, B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, and its right side is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2:
表B-1


Table B-1


表B-2









Table B-2









表B-3


Table B-3


在某些实施方案中，q各自独立的选自0、1、2、3、4、5或6；In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;
在某些实施方案中，q各自独立的选自0、1、2、3或4；In certain embodiments, each q is independently selected from 0, 1, 2, 3, or 4;
在某些实施方案中，q各自独立的选自0、1、2或3；In certain embodiments, each q is independently selected from 0, 1, 2, or 3;
在某些实施方案中，q各自独立的选自0、1或2；In certain embodiments, each q is independently selected from 0, 1, or 2;
在某些实施方案中，K选自K1、K2、K3、K4；In certain embodiments, K is selected from K1, K2, K3, K4;
在某些实施方案中，K1选自 In certain embodiments, K1 is selected from
在某些实施方案中，K1选自 In certain embodiments, K1 is selected from
在某些实施方案中，K2选自 In certain embodiments, K2 is selected from
在某些实施方案中，K2选自 In certain embodiments, K2 is selected from
在某些实施方案中，K3选自 在某些实施方案中，K3选自 In certain embodiments, K3 is selected from In certain embodiments, K3 is selected from
在某些实施方案中，K4选自 在某些实施方案中，K4选自 In certain embodiments, K4 is selected from In certain embodiments, K4 is selected from
在某些实施方案中，E各自独立地选自C3-10碳环基、C6-10芳基、3-12元杂环基或5-12元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl, or 5-12 membered heteroaryl, said heterocyclyl or The heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，E各自独立地选自C3-10碳环基、苯环基、4-12元杂环基、5-12元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子； In certain embodiments, E is each independently selected from C 3-10 carbocyclyl, phenylcyclyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, said heterocyclyl or heteroaryl Contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，E各自独立地选自苯环基、5-6元杂芳基，所述杂环基或杂芳基含有1至3个(例如1、2、3个)选自O、S、N的杂原子；In certain embodiments, each E is independently selected from phenylcyclyl, 5-6 membered heteroaryl, and the heterocyclyl or heteroaryl contains 1 to 3 (eg, 1, 2, 3) selected from Heteroatoms of O, S, and N;
在某些实施方案中，E各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基、噁唑环基、吲哚啉环基、异吲哚啉环基、1,2,3,4-四氢喹啉环基或1,2,3,4-四氢异喹啉环；In certain embodiments, each E is independently selected from phenyl, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole base, furan ring group, thiophene ring group, oxazole ring group, indoline ring group, isoindoline ring group, 1,2,3,4-tetrahydroquinoline ring group or 1,2,3,4 -Tetrahydroisoquinoline ring;
在某些实施方案中，E各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基或噁唑环；In certain embodiments, each E is independently selected from phenyl, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole base, furan ring group, thiophene ring group or oxazole ring;
在某些实施方案中，E各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环；In certain embodiments, E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring;
在某些实施方案中，E各自独立的选自苯环基或吡啶环；In certain embodiments, each E is independently selected from phenyl ring or pyridine ring;
在某些实施方案中，A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said heterocyclyl or heteroaryl Containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A选自C3-8碳环基、苯环基、4-7元杂环基或5-6元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；In certain embodiments, A is selected from C 3-8 carbocyclyl, phenylcyclyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N;
在某些实施方案中，A选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基或噁唑环；In certain embodiments, A is selected from benzene, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, furan Ring group, thiophene ring group or oxazole ring;
在某些实施方案中，A选自苯环基或吡啶环；In certain embodiments, A is selected from phenyl or pyridine rings;
在某些实施方案中，F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl, said heterocyclyl or The heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，F各自独立地选自C3-7单环碳环基、C4-10并环碳环基、C5-12螺环碳环基、C5-10桥环碳环基、4-7元杂单环基、4-10元杂并环基、8-15元杂三并环基、5-12元杂螺环基、5-10元杂桥环基、C6-14芳基、5-10元杂芳基，所述杂单环基、杂并环基、杂螺环基、杂桥环基或杂芳基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each F is independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 pentacyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl Cyclic group, 4-7-membered heteromonocyclic group, 4-10-membered heterocyclic group, 8-15-membered heterotricyclic group, 5-12-membered heterospirocyclic group, 5-10-membered heterocyclic group, C 6-14 aryl, 5-10 membered heteroaryl, the heteromonocyclic group, heterocyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，F各自独立地选自C3-7单环碳环基、C4-10并环碳环基、C5-12螺环碳环基、C5-10桥环碳环基、4-7元杂单环基、4-10元杂并环基、8-15元三环杂并环基、12-17元四环杂并环基、5-17元杂螺环基、C6-14芳基、5-10元杂芳基、 所述杂单环基、杂并环基、杂螺环基、杂桥环基或杂芳基含有1至4个选自O、S或N的杂原子；In certain embodiments, each F is independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 pentacyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl Cyclic group, 4-7 membered heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group base, C 6-14 aryl group, 5-10 membered heteroaryl group, The heteromonocyclic group, heteroacyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
在某些实施方案中，F各自独立地选自苯环基、吡啶环基、嘧啶环基、吡嗪环基、哒嗪环基、 In certain embodiments, each F is independently selected from phenyl, pyridyl, pyrimidine, pyrazine, pyridazine,
在某些实施方案中，F各自独立地选自苯环基、吡啶环基、嘧啶环基、吡嗪环基、哒嗪环基、 In certain embodiments, each F is independently selected from phenyl, pyridyl, pyrimidine, pyrazine, pyridazine,
在某些实施方案中，F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡唑基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、吲哚并吡啶、吲哚并噻吩、吲哚并呋喃、 其左侧与L直接连接；In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl , 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridine Imidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl , benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridazinyl, imidazopyrimidinyl, imidazopyridinyl, Imidazopyridazinyl, imidazopyridazinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidine Pyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazolyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridopyrazinyl, pyrazino Pyrazinyl, indolopyridine, indolothiophene, indolofuran, Its left side is directly connected to L;
在某些实施方案中，Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或3-12元杂环，所述的杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、 OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, Q is each independently selected from bond, -O-, -S-, -CH2- , -NRq- , -C(=O)-, -NRqC (=O)- , -C(=O)NR q - or 3-12 membered heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I , Substituted with OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2 , 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Q各自独立地选自-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或4-7元杂环，所述的杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, Q is each independently selected from -O-, -S-, -CH2- , -NRq- , -C(=O)-, -NRqC (=O)-, - C(=O)NR q - or 4-7 membered heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH , =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents substituted, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, N;
在某些实施方案中，Q各自独立地选自键、C(＝O)、Qa或Qb；In certain embodiments, each Q is independently selected from bond, C(=O), Qa, or Qb;
在某些实施方案中，Qa选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 In certain embodiments, Qa is selected from bond, CH2 , NH, N( CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( CH3 )C(=O), C(=O)N(CH 3 ),
在某些实施方案中，Qb选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；In certain embodiments, Qb is selected from bond, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);
在某些实施方案中，Rq选自H或C1-6烷基；In certain embodiments, R q is selected from H or C 1-6 alkyl;
在某些实施方案中，Rq选自H或C1-4烷基；In certain embodiments, R q is selected from H or C 1-4 alkyl;
在某些实施方案中，Rq选自H、甲基、乙基；In certain embodiments, R q is selected from H, methyl, ethyl;
在某些实施方案中，Rk2各自独立地选自键、-C(＝O)-、-S(＝O)2-、-S(＝O)-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from the group consisting of bond, -C(=O)-, -S(=O) 2 -, -S(=O)-, or -C(R k3 ) 2 -;
在某些实施方案中，Rk2各自独立地选自-C(＝O)-、-S(＝O)2-或-C(Rk3)2-；In certain embodiments, each R k2 is independently selected from -C(=O)-, -S(=O) 2 -, or -C(R k3 ) 2 -;
在某些实施方案中，Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基、环烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In certain embodiments, each R k1 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy group, C 3-6 cycloalkyl group, R k7a , the alkyl group, alkoxy group, and cycloalkyl group are optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Substituted with substituents of Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
在某些实施方案中，Rk1选自Rk7a；In certain embodiments, Rk1 is selected from Rk7a ;
在某些实施方案中，Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each R k3 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 (such as 1, 2, 3, 4) substituted by a substituent selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个(例如1、2、3或4个)选自F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkane group or C 1-4 alkoxy group, the alkyl group or alkoxy group is optionally composed of 1 to 4 (for example, 1, 2, 3 or 4) selected from F, Cl, Br, I, OH, NH 2 Substituted by substituents;
在某些实施方案中，Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基，所述甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基任选被1至4个(例如1、2、3或4个)选自F、Cl、Br、I、OH、NH2的取代基所取代；In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl , isopropyl, methoxy, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally replaced by 1 to 4 ( For example, 1, 2, 3 or 4) substituted with substituents selected from F, Cl, Br, I, OH, NH 2 ;
在某些实施方案中，两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-8碳环基或3-8元杂环，所述碳环基或杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子； In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring backbone directly connected to the two together form a C 3-8 carbocyclic group or 3-8 membered heterocycle, the carbocyclyl or heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected Heteroatoms from O, S, N;
在某些实施方案中，两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环基或3-7元杂环，所述碳环基或杂环任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring backbone directly connected to the two together form a C 3-6 carbocyclic group or 3-7 membered heterocycle, the carbocyclyl or heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected Heteroatoms from O, S, N;
在某些实施方案中，Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so The alkyl group, cycloalkyl group or heterocyclyl group is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Cl, Br, I, OH, =O, NH 2 , CN, Substituted with COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected from O, Heteroatoms of S and N;
在某些实施方案中，Rk4各自独立的选自H、OH、NH2、CF3、CN、C1-4烷基；In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;
在某些实施方案中，Rk5各自独立地选自C(CH3)2、CO、CH2、CH2CH2、SO2、 In certain embodiments, each R k5 is independently selected from C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 , SO 2 ,
在某些实施方案中，Rk5各自独立地选自CO、CH2、SO2或 In certain embodiments, each R k5 is independently selected from CO, CH 2 , SO 2 or
在某些实施方案中，Rk6各自独立地选自CO、CH、SO、SO2、CH2或N；In certain embodiments, each R k6 is independently selected from CO, CH, SO, SO 2 , CH 2 or N;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ;
在某些实施方案中，Rk7各自独立地选自C(CH3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3)、N(环丙基)或NH；In certain embodiments, each R k7 is independently selected from C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
在某些实施方案中，Rk7各自独立地选自CO、CH、N、CH2、O、S、N(CH3)或NH；In certain embodiments, each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ), or NH;
在某些实施方案中，Rk7各自独立地选自CH2、O、N(CH3)或NH；In certain embodiments, each Rk7 is independently selected from CH2 , O, N( CH3 ), or NH;
在某些实施方案中，Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代；In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1 Substituted by -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituents;
在某些实施方案中，Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代；In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1 Substituted by -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
在某些实施方案中，Rk7a选自H、C1-4烷基、C3-6环烷基、3-6元杂环烷基，所述的烷基、杂环烷基或环烷基任选被1至4个选自卤素、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In certain embodiments, Rk7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, heterocycloalkyl or cycloalkyl The base is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
在某些实施方案中，Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代； In certain embodiments, Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl 1 to 4 are selected from F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl , substituted by substituents of propynyl, propargyl, C 3-6 cycloalkyl;
在某些实施方案中，Rk7a选自H、CF3、甲基、乙基、异丙基、环丙基、氧杂环丁基、四氢吡喃基、-CH2CF3、-CH(CH3)CF3、-CH(CH3)-环丙基、-CH2-环丙基、-CH2-乙烯基、-CH2-乙炔基、-CH2CH2-甲氧基；In certain embodiments, R k7a is selected from H, CF 3 , methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH (CH 3 )CF 3 , -CH(CH 3 )-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;
在某些实施方案中，Rk7a选自H、CF3、甲基、乙基、环丙基、-CH2-环丙基；In certain embodiments, R k7a is selected from H, CF 3 , methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
在某些实施方案中，Rk7a选自H、CH3、CH2CH3、环丙基；In certain embodiments, R k7a is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl;
在某些实施方案中，Rk8各自独立地选自C、N或CH；In certain embodiments, each Rk8 is independently selected from C, N, or CH;
在某些实施方案中，Rk9各自独立地选自键、C(CH3)2、CO、CH2、CH2CH2或SO2；In certain embodiments, each R k9 is independently selected from bond, C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;
在某些实施方案中，Rk9各自独立地选自CO、SO2或CH2；In certain embodiments, each R k9 is independently selected from CO, SO 2 or CH 2 ;
在某些实施方案中，M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；In certain embodiments, M 1 is selected from the group consisting of bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
在某些实施方案中，M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个(例如1、2、3、4个)选自O、S、N的杂原子；In certain embodiments, M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, The alkyl, cycloalkyl or heterocyclyl group is optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, =O, OH, NH 2 , C 1- Substituted with a 4- alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;
在某些实施方案中，M3选自-NH-或-O-；In certain embodiments, M 3 is selected from -NH- or -O-;
在某些实施方案中，Rk10选自C1-6烷基，所述的烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；In certain embodiments, R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally composed of 1 to 4 (eg, 1, 2, 3, 4) selected from F, Cl, Br, I , substituted by a substituent of =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl;
在某些实施方案中，G选自C6-10芳基或5-10元杂芳基，所述的芳基或者杂芳基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；In certain embodiments, G is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4 ) selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C Substituted with 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heteroaryl contains 1 to 4 (for example, 1, 2, 3, 4) heteroaryls selected from N, O, S atom;
在某些实施方案中，Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio group or -OC(=O)-C 1-6 alkyl group, the alkyl group, alkoxy group or alkylthio group is optionally selected from 1 to 4 (such as 1, 2, 3, 4) Substituted from a substituent of F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In certain embodiments, R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 (For example, 1, 2, 3, 4) substituted with substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
在某些实施方案中，Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个(例如1、2、3、4个)选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个(例如1、2、3、4个)选自N、O、S的杂原子；In certain embodiments, R k14 is selected from a 5-6 membered heteroaryl group, and the heteroaryl group is optionally composed of 1 to 4 (eg, 1, 2, 3, 4) selected from F, Cl, Br , I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3 -6 substituted by a cycloalkyl substituent, the heteroaryl group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from N, O, S;
在某些实施方案中，Rk14选自 In certain embodiments, Rk14 is selected from
在某些实施方案中，K选自表K-1所示的结构片段之一；In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;
在某些实施方案中，K选自表K-2所示的结构片段之一；In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
表K-1



Table K-1



表K-2





Table K-2





在某些实施方案中，n1、n2、n3各自独立的选自0、1、2或3；In certain embodiments, n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;
在某些实施方案中，p1或p2各自独立的选自0、1、2或3；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, or 3;
在某些实施方案中，p1或p2各自独立的选自0、1、2、3、4或5；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
在某些实施方案中，通式(I)所示化合物选自(Ia)或(Ib)所示的结构之一；

In certain embodiments, the compound represented by general formula (I) is selected from one of the structures represented by (Ia) or (Ib);

各个基团的定义与上述实施方案相同；The definition of each group is the same as in the above embodiment;
在某些实施方案中，通式(I)所示化合物选自通式(Id),
In certain embodiments, the compound represented by general formula (I) is selected from general formula (Id),
Rb4、Rb5各自独立的选自H、甲基、乙基、异丙基；R b4 and R b5 are each independently selected from H, methyl, ethyl, and isopropyl;
作为选择，Rb4、Rb5与其相连接的碳原子共同形成环丙基、环丁基、环戊基、环己基，所述的环丙基、环丁基、环戊基、环己基任选被1至4个选自H、F、Cl、Br、I、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；Alternatively, R b4 and R b5 and the carbon atoms to which they are connected together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and the said cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group are optional Substituted by 1 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
B2选自5-6元杂芳基或6元芳基，优选自苯基、吡咯基、吡唑基、咪唑基、三氮唑基，所述B2任选被1至3个Rb2取代，所述的杂芳基含有1至4个选自O、S、N的杂原子； B 2 is selected from 5-6 membered heteroaryl or 6-membered aryl, preferably from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and the B 2 is optionally replaced by 1 to 3 R b2 Substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C4-7单环烷基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、5-6元杂芳基或6元芳基，优选自苯基、吡咯基、吡唑基、咪唑基、三氮唑基，所述B3任选被1至3个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterobridged cyclyl group, C 4-7 monocyclic alkyl group, C 6-14 paracycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-6-membered heteroaryl or 6-membered aryl, preferably phenyl, pyrrolyl, pyrazolyl , imidazolyl, triazolyl, the B 3 is optionally substituted by 1 to 3 R b3 , the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rd选自H、F、Cl、Br、I、OH、COOH、CN、NH2、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基或C1-4烷氧基；R d is selected from H, F, Cl, Br, I, OH, COOH, CN, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;
其余基团与上述任意一种实施方案相同。The remaining groups are the same as in any of the above embodiments.
作为本发明的第一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B-L-K(I)；B-L-K(I);
L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S -(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -NR L ( CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH＝CH-, -Si(R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(＝O )(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- optionally substituted by 1 to 2 selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl Substituted with substituents of C 1-6 alkyl and cyano-substituted C 1-6 alkyl;
q各自独立的选自0、1、2、3、4、5或6；q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
每个-Cy-各自独立地选自键或者或者任选取代的如下基团之一：4-8元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Each -Cy- is independently selected from one of the bonded or optionally substituted groups: 4-8 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4- 6- carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl , heteroaryl, heteromonocyclyl, heterocyclyl, heterospirocyclyl or heterobridged cyclyl containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optional Replaced by 1 or 2 =O;
RL2各自独立地选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基的取代基、卤素取代的C1-4烷氧基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl Base, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene-OC 1-4 alkyl, -OC 1-4 alkylene -OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3 -10 carbocyclyl, -OC 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to a 10-membered heterocyclyl group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclyl group or heterocyclyl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I , OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl substituted Substituted with C 1-4 alkyl, C 1-4 alkoxy substituents, or halogen-substituted C 1-4 alkoxy, the heterocyclic group contains 1 to 4 selected from O, S, N of heteroatoms;
B选自 B is selected from
B1选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle. The carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
B2选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb2所取代，所述的 杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle, the carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 , and the The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
B3选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb3所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle. The carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 . The heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
或者B3选自键；Or B 3 select from key;
L1选自键或 L 1 selected from key or
L2选自键或 L 2 selected from key or
Y1、Y2、Y3、Y4各自独立地选自键、O、S、NRb5a；Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from bonds, O, S, NR b5a ;
Q1、Q2、Q3、Q4各自独立地选自 Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from
v1、v2、v3、v4各自独立地选自0、1、2、3或4；v 1 , v 2 , v 3 and v 4 are each independently selected from 0, 1, 2, 3 or 4;
Rb1、Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、NH2、NHC1-4烷基、N(C1-4烷基)2、-C(＝O)NH2、-C(＝O)NHC1-4烷基、-C(＝O)N(C1-4烷基)2、-C(＝O)OC1-4烷基、-S(＝O)2NH2、-S(＝O)2N(C1-4烷基)2、-S(＝O)2NHC1-4烷基、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4烷基)C(＝O)Rb22、-NHS(＝O)2Rb22、-N(C1-4烷基)S(＝O)2Rb22、-O-C3-12碳环基、-NH-C3-12碳环基、-S-C3-12碳环基、C3-12碳环基、C6-10芳基、5至12元杂芳基、4至12元杂环基、-C1-4亚烷基-Rb22、-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-ORb22，所述的亚烷基、烷基、烯基、炔基、烷氧基、烷硫基、碳环基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、-O-C3-10碳环基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b1 and R b2 are each independently selected from H, F, Cl, Br, I, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -C(=O) NH 2 , -C(=O)NHC 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -C(=O)OC 1-4 alkyl, -S(=O ) 2 NH 2 , -S(=O) 2 N(C 1-4 alkyl) 2 , -S(=O) 2 NHC 1-4 alkyl, -OR b22 , -C(=O)R b22 , -S(=O) 2 R b22 , -P(=O)(R b22 ) 2 , -NHC(=O)R b22 , -N(C 1-4 alkyl)C(=O)R b22 , - NHS(=O) 2 R b22 , -N(C 1-4 alkyl)S(=O) 2 R b22 , -OC 3-12 carbocyclyl, -NH-C 3-12 carbocyclyl, -SC 3-12 carbocyclyl, C 3-12 carbocyclyl, C 6-10 aryl, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, -C 1-4 alkylene -R b22 , -OC 1-4 alkylene- R b22 , -C 1-4 alkylene-OC 1-4 alkylene-R b22 , -C 1-4 alkylene-OC 1-4 alkylene-OR b22 , the alkylene group, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, carbocyclyl group, heterocyclyl group, aryl group or heteroaryl group is optionally selected from 1 to 4 F , Cl, Br, I, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, C 1-4 alkyl, halogen substituted C 1- 4 alkyl, cyano-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -OC 3 -10 carbocyclyl, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;
Rb3各自独立的选自卤素、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自卤素、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 is each independently selected from halogen, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -SR b22 , -NH-R b22 , -(CH 2 ) m1 -X-(CH 2 ) m2 - R b24 , -N(R b21 ) 2 , -C(＝O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N(R b21 ) 2 , -NR b21 C(＝O)R b22 , -NR b21 S(＝O) 2 R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl Oxygen, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted by 1 to 4 selected from halogen, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, Substituted with a substituent of a 5-10-membered heteroaryl group or a 4-10-membered heterocyclyl group, the heteroaryl group or heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;
n各自独立的选自0、1、2、3或4；n is independently selected from 0, 1, 2, 3 or 4;
Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH, C 1- Substituted with substituents of 4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NH-C1-4烷基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代； R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3 -6 cycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group, alkenyl group, and alkynyl group are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents;
或Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环，所述的碳环基或者杂环任选被1至4个选自卤素、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；Or any one of R b1 and R b3 , R b2 and R b3 are directly connected to form a C 5-7 carbocyclic group or a 5 to 7-membered heterocyclic ring, and the carbocyclic group or heterocyclic ring is optionally selected from 1 to 4 Substituted from halogen, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy substituents , the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2. NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, Substituted with C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
或任意Rb4、Rb5和与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环，所述的环烷基或杂单环任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环基、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or any R b4 , R b5 and the carbon atoms connected to them together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring, and the cycloalkyl group or heteromonocyclic ring is optionally selected from 1 to 4 From F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituted by a substituent of a base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclyl group, the heteromono The cyclyl group, heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb5a选自H、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3-6 ring Alkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl The group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
m1各自独立的选自0、1、2或3；m1 is each independently selected from 0, 1, 2 or 3;
m2各自独立的选自0、1、2或3；m2 is independently selected from 0, 1, 2 or 3;
Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-10碳环基或4-10元杂环基，所述的碳环基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, the carbocyclyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
Rb24各自独立的选自C1-4烷氧基、NH-C1-4烷基、NH-C3-6环烷基、C3-6环烷基氧基、C3-10碳环基或4-10元杂环基，所述的烷氧基、碳环基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 is each independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-10 carbocycle group or 4-10 membered heterocyclic group, the alkoxy group, carbocyclyl group, cycloalkyl group, cycloalkyloxy group, heterocyclic group is optionally substituted by 1 to 4 selected from F, Cl, Br, I , OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
K选自K1、K2、K3、K4；K is selected from K1, K2, K3, K4;
K1选自 K1 is selected from
K2选自 K2 is selected from
K3选自 K3 is selected from
K4选自 K4 is selected from
Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或3-12元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O) NR q - or 3-12 membered heterocycle, the heterocycle is optionally composed of 1 to 4 members selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
Rq选自H或C1-6烷基；R q is selected from H or C 1-6 alkyl;
A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, and the heterocyclyl or heteroaryl contains 1 to 4 selected from Heteroatom of O, S or N;
F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；Each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, the heterocyclyl or heteroaryl containing 1 to 4 A heteroatom selected from O, S or N;
Rk2各自独立地选自键、-C(＝O)-、-S(＝O)2-、-S(＝O)-或-C(Rk3)2-；R k2 is each independently selected from the group consisting of bonds, -C(=O)-, -S(=O) 2 -, -S(=O)-, or -C(R k3 ) 2 -;
Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, Rk7a , the alkyl, alkoxy or cycloalkyl is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted by CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4 个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 -cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic ring The group contains 1 to 4 heteroatoms selected from O, S or N;
或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-8碳环基或3-8元杂环，所述碳环基或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring skeleton directly connected to the two together form a C 3-8 carbocyclyl or 3-8 membered heterocycle. , the carbocyclyl or heterocycle is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1 -4 Alkoxy substituents substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl The base or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from the group consisting of bonds, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl Or the heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, so The heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
Rk10选自C1-6烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 ring Substituted by alkyl substituents;
Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents substituted;
Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；R k14 is selected from 5-6 membered heteroaryl groups, and the heteroaryl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkane Substituted by a substituent of a halogen-substituted C 1-4 alkyl group, a hydroxyl-substituted C 1-4 alkyl group, a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
G选自C6-10芳基或5-10元杂芳基，所述的芳基或者杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；G is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3. Substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
n1、n2、n3各自独立的选自0、1、2或3；n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
作为本发明的第二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B选自 B is selected from
或者B选自V选自键或L1；Or B is selected from V is selected from key or L 1 ;
L1、L2不为键；L 1 and L 2 are not keys;
B1选自6-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C6-8单碳环 基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B1任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from 6-7-membered heteromonocyclic group, 5-14-membered heterocyclic group, 5-12-membered heterospirocyclic group, 7-10-membered heterobridged cyclic group, C 6-8 monocarbocyclic group Base, C 6-14 paracycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, benzo C 3-10 carbocyclyl group, benzo 3 to 10 membered heterocyclic group, C 12-18 tricyclic ring group, 12 to 18 membered heterotricyclyl group, 5-10 membered heteroaryl group or 6-14 membered aryl group, the B 1 is optionally substituted by 1 to 4 R b2 , the Heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;
B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B3任选被1至4个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14 paracycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered heterocyclyl, C 12-18 Tricyclic ring group, 12 to 18 membered heterotricyclyl group, 5 to 10 membered heteroaryl group or 6 to 14 membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the heteroaryl group Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
B2选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12元桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B2任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14 cycloalkyl group, C 6-12 spirocycloalkyl group, C 5-12 membered bridged cycloalkyl group, benzo C 3-10 carbocyclyl group, benzo 3 to 10 membered heterocyclyl group, C 12- 18- membered tricyclic group, 12- to 18-membered heterotricyclic group, 5-10-membered heteroaryl group or 6-14-membered aryl group, the B 2 is optionally substituted by 1 to 4 R b2 , the heteroaryl The base or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C3-8环烷基、C6-10芳基、O-C3-8环烷基、NH-C3-8环烷基、5-6元杂芳基或3-8元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, C 6-10 aryl base, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy The base, alkylthio group, cycloalkyl group, aryl group, heteroaryl group or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N (C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2 -4 alkynyl, C 3-6 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N ;
Rb5a选自H、C1-4烷基、-(CH2)n-Rb22，所述的-CH2-、烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , and the -CH 2 -, alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 Alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;
其余基团定义与本发明第一种实施方案相同。The definitions of the remaining groups are the same as in the first embodiment of the present invention.
作为本发明的第三种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、 -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3 -Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4 -Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Cy2-Cy3-Ak5-Cy4-;
Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S -, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -(C ≡C) q - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkane Substituted with substituents such as C 1-4 alkoxy group, halogen-substituted C 1-4 alkyl group, hydroxyl-substituted C 1-4 alkyl group, and cyano-substituted C 1-4 alkyl group;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或任选取代的如下基团之一：4-7元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the optionally substituted following groups: 4-7 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospiro Cyclic group, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the Heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S , optionally replaced by 1 or 2 =O;
q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
RL各自独立的选自H或C1-6烷基；R L are each independently selected from H or C 1-6 alkyl;
其余基团定义与本发明第一或二种实施方案相同。The definitions of the remaining groups are the same as those in the first or second embodiment of the present invention.
作为本发明的第四种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶；As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal;
K2选自 K2 is selected from
K3选自 K3 is selected from
A选自C3-8碳环基、苯环基、4-7元杂环基或5-6元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；A is selected from C 3-8 carbocyclyl, phenyl ring, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 selected from O, S or heteroatoms of N;
F各自独立地选自C3-7单环碳环基、C4-10并环碳环基、C5-12螺环碳环基、C5-10桥环碳环基、4-7元杂单环基、4-10元杂并环基、8-15元三环杂并环基、12-17元四环杂并环基、5-17元杂螺环基、C6-14芳基、5-10元杂芳基、所述杂单环基、杂并环基、杂螺环基、杂桥环基或杂芳基含有1至4个选自O、S或N的杂原子；F is each independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 paracyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered Heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 aromatic base, 5-10 membered heteroaryl group, The heteromonocyclic group, heteroacyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
表示环选自芳香环基或非芳香环；Indicates that the ring is selected from aromatic ring groups or non-aromatic rings;
E各自独立地选自C3-10碳环基、苯环基、4-12元杂环基、5-12元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；Each E is independently selected from C 3-10 carbocyclyl, phenyl ring, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 selected from Heteroatom of O, S or N;
Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或4-7元杂环，所述的杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O) NR q - or 4-7 membered heterocycle, the heterocycle is optionally composed of 1 to 4 members selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1 Substituted with a substituent of -4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
Rq选自H或C1-4烷基；R q is selected from H or C 1-4 alkyl;
Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH或NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkyl Oxygen group, the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ;
或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环基或3-7元杂环，所述碳环基或杂环任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclyl or 3-7 membered heterocycle. , the carbocyclyl or heterocycle is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1 -4 Alkoxy substituents substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
Rk4各自独立的选自H、OH、NH2、CF3、CN或C1-4烷基；R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
Rk5各自独立地选自C(CH3)2、C(＝O)、CH2、CH2CH2、S(＝O)2、 R k5 are each independently selected from C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 , S(=O) 2 ,
Rk6各自独立地选自C(＝O)、CH、S(＝O)、S(＝O)2、CH2或N；R k6 is each independently selected from C(=O), CH, S(=O), S(=O) 2 , CH 2 or N;
Rk7各自独立地选自C(CH3)2、C(＝O)、CH、N、CH2、O、S、NRk7a；R k7 are each independently selected from C(CH 3 ) 2 , C(=O), CH, N, CH 2 , O, S, NR k7a ;
Rk8各自独立地选自C、N或CH； Rk8 is each independently selected from C, N or CH;
Rk9各自独立地选自键、C(CH3)2、C(＝O)、CH2、CH2CH2或S(＝O)2；R k9 are each independently selected from keys, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ;
Rka选自O、S或NH；R ka is selected from O, S or NH;
Rk7a选自H、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷 基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl alkyl The base and heterocycloalkyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2 Substituted with -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;
Rk14选自 R k14 selected from
其余基团定义与本发明第一、二、或三种实施方案相同。The definitions of the remaining groups are the same as in the first, second, or third embodiment of the present invention.
作为本发明的第五种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
B选自 B is selected from
V选自键、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、O-(Q2)v2-、-(Q2)v2-O、-(Q2)v2-；V is selected from bonds, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , O-(Q 2 ) v2 -, -(Q 2 ) v2 -O, -(Q 2 ) v2 -;
v2、v4各自独立地选自1、2、3或4；v 2 and v 4 are each independently selected from 1, 2, 3 or 4;
Y1、Y3各自独立地选自键、O、S、NRb5a；Y 1 and Y 3 are each independently selected from bond, O, S, NR b5a ;
Y2、Y4各自独立地选自O、S、NRb5a；Y 2 and Y 4 are each independently selected from O, S, NR b5a ;
Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S -, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -C≡ C- or bond, the -CH 2 -, -CH=CH- is optionally replaced by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, methane Substituted with a substituent of base, ethyl, methoxy or ethoxy;
q各自独立的选自0、1、2或3；q is independently selected from 0, 1, 2 or 3;
RL各自独立的选自H或C1-4烷基；R L are each independently selected from H or C 1-4 alkyl;
K1选自 K1 is selected from
K4选自 K4 is selected from
Q选自键、C(＝O)；Q is selected from bond, C(=O);
Qa选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 Qa is selected from bonds, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ),
Qb选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；Qb is selected from bonds, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);
E、A各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基或噁唑环；E and A are each independently selected from benzene ring group, pyridine ring group, pyridazine ring group, pyrazine ring group, pyrimidine ring group, pyrrole ring group, pyrazole ring group, imidazole ring group, thiazole ring group, furan ring group , thiophene ring or oxazole ring;
F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡唑、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、吲哚并吡啶、吲哚并噻吩、吲哚并呋喃、 其左侧与L直接连接；F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridimidazolyl, benzimidazole base, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazole Pyridazinyl, pyrazopyridinyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimido Pyrimidinyl, pyridopyridyl, pyridopyrazole, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyridazinyl, pyrazinopyrazinyl, indolopyridine , indolothiophene, indolofuran, Its left side is directly connected to L;
Rka选自O、S或NH；R ka is selected from O, S or NH;
Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代； Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl Substituted with substituents of C 3-6 cycloalkyl group;
p1或p2各自独立的选自0、1、2或3；p1 or p2 are each independently selected from 0, 1, 2 or 3;
其余基团定义与本发明第二、三或四种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third or fourth embodiments of the present invention.
作为本发明的第六种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
RL选自H、甲基或乙基；R L is selected from H, methyl or ethyl;
q各自独立的选自0、1或2；q is independently selected from 0, 1 or 2;
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、吡啶基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷 基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropyl cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl and cyclopentyl , cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocycle Butyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclohexyl Propylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl , cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl base, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidine Azetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, Cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, nitrogen Heterocyclidylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidine Spiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, by 1 to 4 R L2 ;
RL2各自独立地选自F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene -OC 1-2 alkyl, -OC 1-2 alkylene -OC 3-6 carbocyclyl, - C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl, so The above-mentioned alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic or heterocyclic groups are optionally selected from 1 to 4 F, Cl, Br, I, OH, COOH, CN, NH 2. NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, Substituted with C 1-4 alkoxy or halogen-substituted C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
B1选自取代或未取代的如下基团之一：苯基、萘基、噻吩、呋喃、吡咯、吡唑、咪唑、吡啶、2-吡啶酮、嘧啶、吡嗪、哒嗪、喹啉、异喹啉、喹唑啉、3,4-二氢-1H-苯并吡喃、1,2,3,4-四氢喹啉、苯并呋喃、苯并噻吩、苯并吡咯、苯并噁唑、苯并噻唑、苯并咪唑、苯并吡唑、吗啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、咔唑，当被取代时，被1至4个Rb1取代；B 1 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, Isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzox Azole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidine Base, carbazole, when substituted, is substituted by 1 to 4 R b1 ;
或者B1选自任选取代的如下结构之一： 当被取代时，被1至4个Rb1取代； Or B 1 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b1 ;
或者B1选自B1A；or B 1 is selected from B 1A ;
B2选自取代或未取代的如下基团之一：苯环基、萘基、喹啉、吡唑、吡啶、咪唑、三氮唑、噻唑、噁唑、异噁唑、噻吩、苯并吡咯、吲哚、苯并咪唑、苯并吡唑、苯并噻吩、苯并噻唑、吡唑并四氢吡咯、3-哒嗪酮、2-吡啶酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基，当被取代时，被1至4个Rb2取代；B 2 is selected from one of the following substituted or unsubstituted groups: phenyl ring, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole , indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquin Phenoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 ;
或者B2选自任选取代的如下结构之一： 当被取代时，被1至4个Rb2取代；Or B 2 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b2 ;
或者B2选自B2A；or B 2 is selected from B 2A ;
B1A、B2A各自独立地选自任选取代的如下结构之一： 当被取代时，B1A被1至4个Rb1取代，B2A被1至4个Rb2取代；B 1A and B 2A are each independently selected from one of the optionally substituted following structures: When substituted, B 1A is replaced by 1 to 4 R b1 and B 2A is replaced by 1 to 4 R b2 ;
B3选自取代或未取代的如下基团之一：氧杂环丁基、环丁基、环戊基、环己基、氮杂环丁基、四氢呋喃基、苯基、吡啶、萘基、吡唑、吡咯、吡咯烷基、哌啶、哌嗪、氮杂环己烯基、四氢吡喃基、咪唑、噻吩、噻唑、噁唑、异噁唑、三氮唑、2-吡啶酮、苯并吡咯、苯并吡咯烷、苯并噻吩、苯并噻唑、苯并吡唑、苯并咪唑、吡唑并四氢吡咯、3-哒嗪酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、环丁基螺哌啶基，当被取代时，被1至4个Rb3取代；B 3 is selected from one of the following substituted or unsubstituted groups: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyridyl Azole, pyrrole, pyrrolidinyl, piperidine, piperazine, azepine, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzene Pyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline , 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiroazetidinyl Butylspiropiperidinyl, when substituted, is substituted by 1 to 4 R b3 ;
或者B3选自任选取代的如下结构之一： 当被取代时，被1至4个Rb3取代；Or B 3 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b3 ;
V选自键、O、S、NRb5a、NRb5a-C1-4亚烷基、C1-4亚烷基-NRb5a、O-C1-4亚烷基、C1-4亚烷基-O、C1-4亚烷基，所述的亚烷基任选被1至4个Rb4或Rb5所取代；V is selected from bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene-NR b5a , OC 1-4 alkylene, C 1-4 alkylene- O. C 1-4 alkylene group, the alkylene group is optionally substituted by 1 to 4 R b4 or R b5 ;
Rb1各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-NH-环丙基、-NH-环丁基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b1 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , - C(＝O)NH-CH 3 , -C(＝O)N(CH 3 ) 2 , -S(＝O) 2 NH 2 , -P(＝O) 2 (CH 3 ) 2 , -S(＝ O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclo Propyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxolanyl, oxetanyl, morpholine, pyrrolidinyl Cyclopentyl, azetidinylspirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
Rb3各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、N(CH3)2、NHCH3、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-O-CH2-环丙基、-O-CH2-环丁基、-O-CH2CH2-甲氧基、-O-CH2CH2-O-环丙基、-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-甲氧基、-CH2-O-CH2CH2-O-环丙基、-CH2-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-NH-甲基、-CH2-甲氧基、-CH2-乙氧基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b3 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , N(CH 3 ) 2 , NHCH 3 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl , -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -O-CH 2 -cyclopropyl, -O- CH 2 -cyclobutyl , -O-CH 2 CH 2 -methoxy, -O-CH 2 CH 2 -O-cyclopropyl, -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -methoxy, - CH 2 -O-CH 2 CH 2 -O-cyclopropyl, -CH 2 -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -NH-methyl, - CH 2 -methoxy, -CH 2 -ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinyl And cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、-CH2-环丙基、-CH2-环丁基、-CH2-吗啉、-CH2-吡唑、-OCH2- 环丙基、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基、-CH2OCH2CH2-NH-甲基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、CH2OH、甲基、乙基、异丙基、甲氧基、乙氧基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、吡咯烷基、哌啶基、吡唑基、吗啉基的取代基所取代；R b2 is each independently selected from H, F, Cl, Br, I, =O, =S, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3. -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O )(CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, Propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, nitrogen Heterocyclylbutyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, Cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, -CH 2 -cyclopropyl, -CH 2 - Cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 - Cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O -Cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -NH-methyl, When substituted, from 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CH 2 F, CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 OH , methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyrazolyl, ? Substituted by a phenol substituent;
作为选择，Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环，所述的碳环基或者杂环任选被1至4个选自F、Cl、Br、I、OH、-NH2、CN、CH2F、CHF2、CF3、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；Alternatively, any one of R b1 and R b3 , R b2 and R b3 is directly connected to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic ring, and the carbocyclic group or heterocyclic ring is optionally substituted by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, OH, -NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy, said The heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
K选自表K-1所示的结构片段之一；K is selected from one of the structural fragments shown in Table K-1;
其余基团定义与本发明第二、三、四或五种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
RL2各自独立地选自F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、OCHF2、OCF3、甲基、甲氧基、＝O、CH2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代；R L2 is each independently selected from F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl , isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -Cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, by 1 to 4 selected from F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , methyl, methoxy, =O, CH 2 Substituted with OH, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituents;
B选自表B-1、表B-2或表B-3所示的结构片段之一，其右侧与L连接，b1、b2各自独立地选自0、1或2；B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, its right side is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2;
K选自表K-2所示的结构片段之一；K is selected from one of the structural fragments shown in Table K-2;
其余基团定义与本发明第二、三、四、五或六种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.
作为本发明的第八种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、 -Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2- Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3- Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3- Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, - Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4- , -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1- Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4- , -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3- Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5- ,-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH=CH-, -CH＝C(CN)-, -CH＝C(F)-, -C(CN)＝CH-, -C(F)＝CH-, -C≡C-, -C(CH 3 ) 2 - , -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH- , -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;
V选自键、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S；V is selected from bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C(CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O, S;
其余基团定义与本发明第二、三、四、五或六种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.
作为本发明的第九种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the ninth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自键或表L-1或表L-2或表L-3所示的结构片段之一，其中基团左侧与B连接其余基团定义与本发明第二、三、四、五或六种实施方案中任意一种相同。L is selected from a bond or one of the structural fragments shown in Table L-1, Table L-2 or Table L-3, in which the left side of the group is connected to B and the remaining groups are defined as in the second, third, fourth and fifth of the present invention. Or the same in any of the six embodiments.
本发明涉及一种下述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1结构之一。The present invention relates to a following compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
表E-1

























Table E-1

























本发明涉及一种药物组合物，包括本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.
本发明涉及一种药物组合物，包括治疗有效量的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
在一些实施方案中，本发明的药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如抑制或降解AR或AR剪切突变体相关疾病如前列腺癌)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、 1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate the disease or condition being treated to some extent (e.g., inhibit or degrade AR or AR cleavage). One or more symptoms of mutant-related diseases such as prostate cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25- 600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75- 500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200- 400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10- 200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
在一些实施方案中，该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选抑制或降解AR或AR剪切突变体相关疾病(如前列腺癌)。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable The salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical The amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the above-mentioned pharmaceutical composition for the preparation of treatment and AR Or application in drugs for diseases related to the activity or expression of AR splicing mutants.
本发明涉及一种本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产 物、药学上可接受的盐或共晶、或者上述药物组合物在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs and metabolites. The use of substances, pharmaceutically acceptable salts or co-crystals, or the above pharmaceutical compositions in the preparation of drugs for the treatment of diseases related to inhibition or degradation of AR or AR splicing mutants.
本发明涉及的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶、或者上述药物组合物的应用，其中，所述的疾病选自前列腺癌。The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions, wherein: The disease is selected from prostate cancer.
本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.
除非有其他的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“卤素”是指F、Cl、Br或I。"Halogen" refers to F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halogenated."
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
“烃基”是指取代的或者未取代的、直链或支链的、饱和或不饱和的由碳、氢原子组成的基团。烃基可以是一价、二价、三价或四价。"Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环基或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring group or a spiro ring. Non-limiting examples include Epoxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl , piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但 不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6, or 2 to 4 carbon atoms, alkenyl examples include but Not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3 -Pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl base, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-Decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this article Definition consistent. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，包括但不限于在主链包括2至10个碳原子、2至6个碳原子、2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"Alkynyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1- Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent .
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环基或者非芳香环，芳香环基或者非芳香环可以是3至8元的单环基、4至12元双环基或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环基或者非芳香环任选为单环基、桥环基或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环基、萘环基、“碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring group or non-aromatic ring. The aromatic ring group or non-aromatic ring can be a 3 to 8-membered monocyclic group, 4 To a 12-membered bicyclic group or a 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring group or non-aromatic ring is optionally a monocyclic group, a bridged ring group or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, phenyl ring group, naphthyl ring group, "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环基或者非芳香环，芳香环基或者非芳香环可以是3至8元的单环基、4至12元双环基或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的C、N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环基或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring group or non-aromatic ring. The aromatic ring group or non-aromatic ring can be a 3 to 8-membered monocyclic group, 4 to a 12-membered bicyclic group or a 10- to 15-membered tricyclic system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, heterocyclic group The selectively substituted C, N, and S in the ring can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring group or a spiro ring. Non-limiting examples include ethylene oxide. base, aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, Azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thio Morpholinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl Pyryl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene base, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, aza Bicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3] heptyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n的杂原子。"Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any may contain 0 to 5 heteroatoms selected from N, O or S(=O) n .
“螺环”或“螺环基”可以是一价、二价、三价或四价。 "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S (=O) n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include
立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。 Cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。 "Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system.
“杂并环”、“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。"Heterocyclyl", "cycloheterocyclyl" or "heterocyclyl" refers to a "paracyclyl" containing heteroatoms.
“杂螺环”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。"Heterospirocycle", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing heteroatoms.
“杂桥环”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。"Heterobridged ring", "bridged heterocyclyl" or "heterobridged ringyl" refers to a "bridged ring" containing heteroatoms.
“芳基”或“芳环”是指取代的或者未取代的具有单环基或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环基或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环基、萘环基、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic group or a fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclyl or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include phenyl ring, naphthyl ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶、吡啶酮、吡嗪酮、等。所述杂芳基环可以稠合于饱和或不饱和的碳环基或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, pyridone, pyrazinone, wait. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclyl or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
“5元环并5元杂芳基”是指5并5元的稠合杂芳基，2个并环中至少有1个环基含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了吡咯并吡咯环基、吡唑并吡咯环基、吡唑并吡唑环基、吡咯并呋喃环基、吡唑并呋喃环基、吡咯并噻吩环基、吡唑并噻吩环。"5-membered 5-membered heteroaryl" refers to a 5-membered fused heteroaryl. At least one of the two cyclic rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole ring group, pyrazolopyrrole ring group, pyrazolopyrazole ring group, pyrrolofuran ring group, pyrazofuran ring group , pyrrolothiophene ring, pyrazolothiophene ring.
“5并6元杂芳基”是指5并6元的稠合杂芳基，2个并环中至少有1个环基含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了苯并5元杂芳基、6元杂芳基并5元杂芳基。"5- and 6-membered heteroaryl" refers to a 5- and 6-membered fused heteroaryl group. At least one of the two cyclic rings contains more than one heteroatom (including but not limited to O, S or N ), the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基，Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。 "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m - C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , -(CH 2 ) m S(=O) n R a , -(CH 2 ) m -ene Base -R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n is 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethyl Sulfonyl group, as an option, R b and R c can form a five- or six-membered cycloalkyl or heterocyclyl group, and R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl group, heterocyclic group, carbonyl group, ester group, bridged cyclic group, spirocyclic group or paracyclic group.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
“1至X个选自…..取代基所取代”是指被1、2、3….X个选自…..取代基所取代，X选自1至10之间的任意整数。如“1至4个Rk取代”是指被1、2、3或4个Rk取代。如“1至5个选自…..取代基所取代”是指被1、2、3、4或5个选自…..取代基所取代。如“杂桥环任选被1至4个选自H或F的取代基所取代”是指杂桥环任选被1、2、3或4个选自H或F的取代基所取代。"Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... For example, "1 to 4 R k substituted" means substituted with 1, 2, 3 or 4 R k . For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from... For example, "the hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the hetero-bridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.
X-Y元的环(X、Y为整数，且3≤X＜Y，X＜Y≤20选自4至20之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。The ring of X-Y elements (X and Y are integers, and 3 ≤ X+4….Y-element ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
Cx-y碳环(包括芳基、环烷基、单环碳环基、螺环碳环基、并环碳环基或桥环碳环)包括了Cx、Cx+1、Cx+2、Cx+3、Cx+4….Cy元的环(x为整数，且3≤x＜y，y选自4至20之间的任意整数)，例如C3-6环烷基”是指C3、C4、C5或C6环烷基。C xy carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclyl, spirocyclic carbocyclyl, paracyclic carbocyclyl or bridged carbocyclic ring) includes C x , C x+1 , C x+2 , C x+3 , C x+4 ....C y -membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), such as C 3-6 cycloalkyl ” refers to C 3 , C 4 , C 5 or C 6 cycloalkyl.
当某一个基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团连接。当该化学键的连接方式是不定位的，且可连接位点存在氢原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。例如表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，也包括了例如表示该哌啶基上的R基团可以位于C上，可以位于N上，至少包括了 When a certain group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned, and there are hydrogen atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of connected chemical bonds and become the corresponding valence. group. For example Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if H atoms are drawn on -N-, Also included For example It means that the R group on the piperidinyl group can be located on C or N, including at least
当所列举的连接基团没有指明其连接方向时，其连接方向包括了从左向右和从右向左的读取顺序的方向进行连接，例如A-L-B，L选自-M-W-时，包括了A-M-W-B和A-W-M-B。When the listed linking groups do not specify the linking direction, the linking direction includes the reading order direction from left to right and right to left, for example, A-L-B. When L is selected from -M-W-, it includes A-M-W-B. and A-W-M-B.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。 "Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对映异构体和构象异构体。"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"Tautomers" refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。“IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) by half.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited to these.
本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的，起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from formal commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-–0.5mm；Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. -–0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
SEM:THP:Boc：叔丁氧基羰基；Ms：TBS:Bn:DIPEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；DMAc：N,N-二甲基乙酰胺；DMSO：二甲基亚砜；DCM：二氯甲烷；Cbz:NMP：N-甲基吡咯烷酮；TEA：三乙胺；MsCl:甲磺酰氯。SEM: THP: Boc: tert-butoxycarbonyl; Ms: TBS: Bn: DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane ;Cbz: NMP: N-methylpyrrolidone; TEA: triethylamine; MsCl: methanesulfonyl chloride.
中间体1的合成：
Synthesis of intermediate 1:
第一步：1B盐酸盐的制备Step 1: Preparation of 1B hydrochloride
将1A(90g,0.50mol)溶于500mL 2mol/L盐酸乙酸乙酯溶液中，室温反应5h。将反应体系减压浓缩，得粗品1B的盐酸盐(59g)。Dissolve 1A (90g, 0.50mol) in 500mL 2mol/L hydrochloric acid ethyl acetate solution and react at room temperature for 5h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude product 1B (59g).
LCMS m/z＝82.3[M+1]+ LCMS m/z＝82.3[M+1] +
第二步：中间体1的制备 Step 2: Preparation of Intermediate 1
将粗品1B的盐酸盐(59g)溶于500mL DMSO中，加入碳酸氢钠(42g，0.50mol)，室温搅拌10min后，加入100mL DIPEA和1C(165.6g，0.60mol)，85℃反应5h。将反应液冷却至室温，加入5L水，过滤，收集固体，用500mL水洗涤，将固体鼓风干燥，得粗品中间体1(40g)。Dissolve the hydrochloride salt of crude product 1B (59g) in 500mL DMSO, add sodium bicarbonate (42g, 0.50mol), stir at room temperature for 10min, add 100mL DIPEA and 1C (165.6g, 0.60mol), and react at 85°C for 5h. The reaction solution was cooled to room temperature, 5 L of water was added, filtered, the solid was collected, washed with 500 mL of water, and the solid was air-dried to obtain crude intermediate 1 (40 g).
实施例1：化合物1的制备
Example 1: Preparation of Compound 1
第一步：1b的制备Step 1: Preparation of 1b
将1a(1.0g，3.4mmol)(合成方法见WO2012123745)、1A(0.92g，5.1mmol)、TEA(2.06g，20.4mmol)、碘化亚铜(130mg，0.68mmol)和(PPh3)2PdCl2(240mg，0.34mmol)加入到反应瓶中，在氮气保护下，加入5mL DMF，升至50℃反应0.5h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到1b(1.0g，收率：85％)。1a (1.0g, 3.4mmol) (see WO2012123745 for synthesis method), 1A (0.92g, 5.1mmol), TEA (2.06g, 20.4mmol), copper iodide (130mg, 0.68mmol) and (PPh 3 ) 2 PdCl 2 (240 mg, 0.34 mmol) was added to the reaction bottle, and under nitrogen protection, 5 mL DMF was added, and the temperature was raised to 50°C for 0.5 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 1b (1.0g, yield: 85%).
第二步：1c的制备Step 2: Preparation of 1c
将1b(1.0g，2.88mmol)和碳酸钠(0.61g，5.76mmol)加入到10mL DMF中，升温至85℃反应1.5h。将反应液冷却至室温，加入到100mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到1c(0.6g，收率：84％)。Add 1b (1.0g, 2.88mmol) and sodium carbonate (0.61g, 5.76mmol) to 10mL DMF, raise the temperature to 85°C and react for 1.5h. Cool the reaction solution to room temperature, add it to 100 mL of ethyl acetate, wash with saturated sodium chloride aqueous solution (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v)=1:0-1:2) to obtain 1c (0.6g, yield: 84%).
LCMS m/z＝248.2[M+1]+ LCMS m/z＝248.2[M+1] +
第三步：1e的制备Step 3: Preparation of 1e
将1c(0.58g，2.33mmol)、1d(0.95g，2.33mmol)(合成方法见Journal of Organic Chemistry,2003,68,8075-8079)、碘化亚铜(89mg，0.47mmol)和(1S,2S)-(+)-N,N’二甲基-1,2-环己二胺(CAS:87583-89-9)(0.71g，4.99mmol)加入到反应瓶中，在氮气保护下加入10mL DMF，升至100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到1e(0.6g，收率：49％)。1c (0.58g, 2.33mmol), 1d (0.95g, 2.33mmol) (for synthesis methods, see Journal of Organic Chemistry, 2003, 68, 8075-8079), copper iodide (89mg, 0.47mmol) and (1S, 2S)-(+)-N,N'dimethyl-1,2-cyclohexanediamine (CAS:87583-89-9) (0.71g, 4.99mmol) was added to the reaction bottle under nitrogen protection. 10mL DMF, raised to 100℃ and reacted for 2h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (50 mL Ethyl ester (v/v)=1:0-1:2), obtaining 1e (0.6g, yield: 49%).
LCMS m/z＝526.1[M+1]+ LCMS m/z＝526.1[M+1] +
第四步：化合物1的制备Step 4: Preparation of Compound 1
将1e(0.2g，0.38mmol)和对甲苯磺酸(0.19g，1.10mmol)溶于5mL乙腈中，室温反应12h。将反应液减压浓缩，得粗品。将上述粗品、1f(0.1g，0.36mmol)和DIPEA(0.29g，2.24mmol)溶于5mL DMF中，升温至80℃反应5h。将反应液冷却到室温，加入100mL乙酸乙酯，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物1(0.1g，收率：39％)。 Dissolve 1e (0.2g, 0.38mmol) and p-toluenesulfonic acid (0.19g, 1.10mmol) in 5mL acetonitrile and react at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain crude product. The above crude product, 1f (0.1g, 0.36mmol) and DIPEA (0.29g, 2.24mmol) were dissolved in 5mL DMF, and the temperature was raised to 80°C for 5h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate was added, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /v)=1:0-1:2), compound 1 (0.1g, yield: 39%) was obtained.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.98(s,1H),7.90(s,1H),7.86(s,1H),7.80–7.64(m,4H),6.86–6.78(m,1H),6.57(dd,1H),5.01–4.89(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.94–3.76(m,1H),2.98–2.63(m,3H),2.23–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.05(s,1H),7.98(s,1H),7.90(s,1H),7.86(s,1H),7.80–7.64(m,4H),6.86– 6.78(m,1H),6.57(dd,1H),5.01–4.89(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.94–3.76(m,1H), 2.98–2.63(m,3H),2.23–2.06(m,1H).
LCMS m/z＝682.1[M+1]+ LCMS m/z＝682.1[M+1] +
实施例2：化合物2的三氟乙酸盐制备
Example 2: Preparation of trifluoroacetate salt of compound 2
第一步：2b的制备Step 1: Preparation of 2b
将2a(5.0g，25.57mmol)加入到50mL水中，缓慢加入15mL浓硫酸，60℃反应1h。将反应液冷却到0℃，滴加5mL亚硝酸钠(1.76g，25.51mmol)的水溶液，保持在0-5℃搅拌30min。将反应液升温到40℃，滴加10mL碘化钾(8.49g，51.14mmol)的水溶液，在50℃下反应1h。将反应液冷却到室温，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用1mol/L盐酸水溶液(50mL)洗涤，再用50mL饱和硫代硫酸钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-100:1)，得到2b(5.0g，收率：64％)。Add 2a (5.0g, 25.57mmol) to 50mL of water, slowly add 15mL of concentrated sulfuric acid, and react at 60°C for 1 hour. Cool the reaction solution to 0°C, add 5 mL of sodium nitrite (1.76g, 25.51 mmol) aqueous solution dropwise, and stir at 0-5°C for 30 minutes. The reaction solution was heated to 40°C, 10 mL of potassium iodide (8.49g, 51.14mmol) aqueous solution was added dropwise, and the reaction was carried out at 50°C for 1 hour. Cool the reaction solution to room temperature, extract with ethyl acetate (50mL Dry and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-100:1) to obtain 2b (5.0 g, yield: 64%).
第二步：2d的制备Step 2: Preparation of 2d
将2c(5.0g，49.93mmol)溶于50mL乙酸中，室温下加入碘(12.67g，49.92mmol)，室温反应12h。将反应液加入到200mL水中，用固体碳酸钾调pH至8，用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用50mL饱和硫代硫酸钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-5:1)，得到2d(2.0g，收率：18％)。Dissolve 2c (5.0g, 49.93mmol) in 50mL acetic acid, add iodine (12.67g, 49.92mmol) at room temperature, and react at room temperature for 12 hours. Add the reaction solution to 200 mL of water, adjust the pH to 8 with solid potassium carbonate, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash the organic phase with 50 mL of saturated sodium thiosulfate aqueous solution, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-5:1) to obtain 2d (2.0 g, yield: 18%).
第三步：2e的制备Step 3: Preparation of 2e
将2d(2.0g，8.85mmol)和1-氯-2-异氰酸基乙烷(0.95g，9.0mmol)加入到20mL乙腈中，升温至90℃回流2h。将反应液冷却到室温，加入5mL甲醇，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-2:1)，得到2e(2.0g，收率：73％)。2d (2.0g, 8.85mmol) and 1-chloro-2-isocyanatoethane (0.95g, 9.0mmol) were added to 20mL acetonitrile, and the temperature was raised to 90°C and refluxed for 2h. The reaction solution was cooled to room temperature, 5 mL of methanol was added, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-2:1) to obtain 2e (2.0 g, Yield: 73%).
第四步：2f的制备Step 4: Preparation of 2f
将2e(2.0g，6.03mmol)和碳酸钾(1.25g，9.04mmol)加入到20mL乙腈中，升温至80℃回流12h。将反应液冷却到室温，加入5mL甲醇，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到2f(1.5g，收率：84％)。Add 2e (2.0g, 6.03mmol) and potassium carbonate (1.25g, 9.04mmol) to 20mL acetonitrile, raise the temperature to 80°C and reflux for 12h. The reaction solution was cooled to room temperature, 5 mL of methanol was added, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-1:2) to obtain 2f (1.5 g, Yield: 84%).
LCMS m/z＝296.2[M+1]+ LCMS m/z＝296.2[M+1] +
第五步：2g的制备Step 5: Preparation of 2g
将2f(1.0g，3.39mmol)、1A(0.92g，5.08mmol)、TEA(2.06g，20.36mmol)、碘化亚铜(130mg，0.68mmol)和(PPh3)2PdCl2(240mg，0.34mmol)加入到反应瓶中，在氮气保护下加入5mL DMF，升至50℃反应0.5h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/ 乙酸乙酯(v/v)＝1:0-1:2)，得到2g(0.8g，收率：68％)。2f (1.0g, 3.39mmol), 1A (0.92g, 5.08mmol), TEA (2.06g, 20.36mmol), copper iodide (130mg, 0.68mmol) and (PPh 3 ) 2 PdCl 2 (240mg, 0.34 mmol) into the reaction bottle, add 5 mL DMF under nitrogen protection, and raise to 50°C for reaction for 0.5 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL / Ethyl acetate (v/v)=1:0-1:2), obtaining 2g (0.8g, yield: 68%).
LCMS m/z＝349.3[M+1]+ LCMS m/z＝349.3[M+1] +
第六步：2h的制备Step 6: Preparation for 2h
将2g(0.6g，1.72mmol)、2b(0.6g，1.96mmol)、碘化亚铜(59mg，0.31mmol)和(1S,2S)-(+)-N,N’-二甲基-1,2-环己二胺(0.6g，4.22mmol)加入到反应瓶中，在氮气保护下，加入6mL DMF，升至100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到2h(0.6g，收率：66％)。2g (0.6g, 1.72mmol), 2b (0.6g, 1.96mmol), copper iodide (59mg, 0.31mmol) and (1S,2S)-(+)-N,N'-dimethyl-1 , 2-cyclohexanediamine (0.6g, 4.22mmol) was added to the reaction bottle, under nitrogen protection, 6mL DMF was added, and the temperature was raised to 100°C for 2 hours. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 2h (0.6g, yield: 66%).
LCMS m/z＝527.1[M+1]+ LCMS m/z＝527.1[M+1] +
第七步：化合物2三氟乙酸盐的制备Step 7: Preparation of compound 2 trifluoroacetate
将2h(0.2g，0.38mmol)和对甲苯磺酸(0.26g，1.51mmol)溶于10mL乙腈中，室温反应12h。将反应液减压浓缩，得粗品。将上述粗品、1f(0.1g，0.36mmol)和DIPEA(0.3g，2.32mmol)溶于5mL DMF中，升温至80℃反应5h。将反应液冷却到室温，加入100mL乙酸乙酯，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩后粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得到化合物2的三氟乙酸盐(0.05g)。Dissolve 2h (0.2g, 0.38mmol) and p-toluenesulfonic acid (0.26g, 1.51mmol) in 10 mL acetonitrile and react at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain crude product. Dissolve the above crude product, 1f (0.1g, 0.36mmol) and DIPEA (0.3g, 2.32mmol) in 5mL DMF, raise the temperature to 80°C and react for 5h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate was added, the organic phase was washed with saturated aqueous sodium chloride solution (50 mL Glison GX-281 preparation liquid phase, preparation column model is Sunfire C18, 5μm, inner diameter × length = 30mm × 150mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 2 (0.05g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.05(s,1H),7.90–7.79(m,2H),7.74–7.62(m,2H),6.90–6.82(m,1H),6.71(dd,1H),5.13–5.01(m,1H),4.45–4.32(m,2H),4.32–4.15(m,2H),4.15–3.90(m,5H),2.98–2.80(m,1H),2.69–2.50(m,2H),2.09–1.96(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.06(s,1H),8.05(s,1H),7.90–7.79(m,2H),7.74–7.62(m,2H),6.90–6.82(m ,1H),6.71(dd,1H),5.13–5.01(m,1H),4.45–4.32(m,2H),4.32–4.15(m,2H),4.15–3.90(m,5H),2.98–2.80 (m,1H),2.69–2.50(m,2H),2.09–1.96(m,1H).
LCMS m/z＝683.0[M+1]+ LCMS m/z＝683.0[M+1] +
实施例3：化合物3的制备
Example 3: Preparation of Compound 3
第一步：3b的制备Step 1: Preparation of 3b
将3a(4.1g,19.80mmol)和4-碘-1H-吡唑(4.22g,21.75mmol)溶解在40mL乙腈中，加入固体碳酸铯(9.68g,29.70mmol)，80℃反应3h。将反应液冷却至室温，加入30mL水和100mL乙酸乙酯，分液，有机相用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:9)，得到3b(2.40g，收率：38％)。Dissolve 3a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add solid cesium carbonate (9.68g, 29.70mmol), and react at 80°C for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v)=1:9), 3b (2.40g, yield: 38%) was obtained.
第二步：3c的制备Step 2: Preparation of 3c
将3b(2.30g,7.18mmol)溶解在20mL四氢呋喃中，加入4mL水，再加入一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L稀盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品1(2.0g)。将4-(三氟甲基)苯-1,2-二胺(1.0g，5.7mmol)溶于10mL吡啶中，加入上述粗品1(1.6g)和亚磷酸三苯酯(5.3g，17.1mmol)，升温至200℃微波反应20min。将反应液冷却至室温，加入 80mL乙酸乙酯，有机相用水洗涤(100mL×3)，再用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝68:32)，得3c(0.3g，收率：12％)。Dissolve 3b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, then add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1( 2.0g). Dissolve 4-(trifluoromethyl)benzene-1,2-diamine (1.0g, 5.7mmol) in 10mL pyridine, add the above crude product 1 (1.6g) and triphenyl phosphite (5.3g, 17.1mmol) ), raise the temperature to 200°C and microwave for 20 minutes. Cool the reaction solution to room temperature and add 80 mL of ethyl acetate, the organic phase was washed with water (100 mL v/v)=68:32), 3c (0.3g, yield: 12%) was obtained.
LCMS m/z＝433.2[M+1]+ LCMS m/z＝433.2[M+1] +
第三步：化合物3的制备Step 3: Preparation of Compound 3
将3c(100mg，0.23mmol)加入到50mL单口瓶中，加入8mL干燥DMF，加入粗品中间体1(116mg)、三乙胺(70mg，0.69mmol)，置换氮气三次，加入(PPh3)2PdCl2(16mg，0.023mmol)和碘化亚铜(8mg，0.042mmol)，置换氮气三次，50℃反应2h。将反应体系冷却至室温，缓慢加入100mL饱和氯化铵水溶液，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝12:88)，得化合物3(50mg，收率：34％)。Add 3c (100 mg, 0.23 mmol) into a 50 mL single-neck bottle, add 8 mL of dry DMF, add crude intermediate 1 (116 mg), triethylamine (70 mg, 0.69 mmol), replace nitrogen three times, and add (PPh 3 ) 2 PdCl 2 (16 mg, 0.023 mmol) and copper iodide (8 mg, 0.042 mmol), replace nitrogen three times, and react at 50°C for 2 hours. Cool the reaction system to room temperature, slowly add 100 mL saturated aqueous ammonium chloride solution, extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, and reduce pressure. Concentrate, and the crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=12:88) to obtain compound 3 (50 mg, yield: 34%).
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.20–7.30(m,6H),6.84–6.72(m,1H),6.54(dd,1H),5.00–4.88(m,1H),4.40–4.28(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),3.34–3.07(m,2H),3.05–2.62(m,5H),2.43–2.06(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.31(s,1H),8.20–7.30(m,6H),6.84–6.72(m,1H),6.54(dd,1H),5.00–4.88(m,1H ),4.40–4.28(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),3.34–3.07(m,2H),3.05–2.62(m,5H),2.43–2.06 (m,3H).
LCMS m/z＝642.4[M+1]+ LCMS m/z＝642.4[M+1] +
实施例5：制备化合物5
Example 5: Preparation of Compound 5
第一步：5b的制备将5a(4.1g,19.80mmol)和4-碘-1H-吡唑(4.22g,21.75mmol)溶解在40mL乙腈中，加入碳酸铯(9.68g,29.70mmol)，80℃反应3h。将反应液冷却至室温，加入30mL水和100mL乙酸乙酯，分液，有机相用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:9)，得到5b(2.40g，收率：38％)。Step 1: Preparation of 5b Dissolve 5a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add cesium carbonate (9.68g, 29.70mmol), 80 ℃ reaction for 3h. The reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v)=1:9), 5b (2.40g, yield: 38%) was obtained.
第二步：5c的制备Step 2: Preparation of 5c
将5b(2.30g,7.18mmol)溶解在20mL四氢呋喃中，加入4mL水，加入一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L稀盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品(2.0g)。将上述粗品(2.0g)冷却至0℃，缓慢加入40mL硼烷四氢呋喃溶液(1.0mol/L)，室温反应16h。将反应液冷却至0℃，缓慢滴加甲醇直至无气泡产生，将体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到5c(1.1g，收率：55％)。Dissolve 5b (2.30g, 7.18mmol) in 20mL tetrahydrofuran, add 4mL water, add lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Cool the above crude product (2.0g) to 0°C, slowly add 40mL borane tetrahydrofuran solution (1.0mol/L), and react at room temperature for 16h. The reaction solution was cooled to 0°C, methanol was slowly added dropwise until no bubbles were generated, the system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain 5c (1.1g, yield: 55%).
LCMS m/z＝279.1[M+1]+ LCMS m/z＝279.1[M+1] +
第三步：5d的制备Step 3: Preparation of 5d
将5c(0.4g，1.44mmol)溶于15mL二氯甲烷中，加入三乙胺(0.44g，4.35mmol)，冷却至0℃，缓慢滴加MsCl(0.2g，1.75mmol)，室温反应16h。向反应体系中加入50mL水，用100mL乙酸乙酯萃取，有机相用50mL饱和碳酸氢钠水溶液洗涤，再用50mL 0.5mol/L盐酸洗涤，无 水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得5d(0.5g，收率：98％)。Dissolve 5c (0.4g, 1.44mmol) in 15mL dichloromethane, add triethylamine (0.44g, 4.35mmol), cool to 0°C, slowly add MsCl (0.2g, 1.75mmol) dropwise, and react at room temperature for 16h. Add 50 mL of water to the reaction system, extract with 100 mL of ethyl acetate, wash the organic phase with 50 mL of saturated aqueous sodium bicarbonate solution, and then wash with 50 mL of 0.5 mol/L hydrochloric acid. Dry over sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain 5d (0.5g, yield: 98%).
LCMS m/z＝357.0[M+1]+ LCMS m/z＝357.0[M+1] +
第四步：5e的制备Step 4: Preparation of 5e
将5-(三氟甲基)-1H-吲唑(0.2g，1.07mmol)溶于5mL DMF中，加入碳酸铯(0.70g，2.15mmol)，升温至90℃，缓慢分批加入5d(0.46g，1.29mmol)，90℃反应16h。将反应体系冷却至室温，加入50mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到5e(0.25g，收率：52％)。Dissolve 5-(trifluoromethyl)-1H-indazole (0.2g, 1.07mmol) in 5mL DMF, add cesium carbonate (0.70g, 2.15mmol), raise the temperature to 90°C, and slowly add it in batches for 5d (0.46 g, 1.29mmol), reacted at 90°C for 16h. The reaction system was cooled to room temperature, 50 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=5:1), 5e (0.25g, yield: 52%) was obtained.
第五步：化合物5的制备Step 5: Preparation of Compound 5
将5e(0.15g，0.34mmol)、粗品中间体1(0.14g)、TEA(0.10g，0.99mmol)、CuI(7mg，0.037mmol)和PdCl2(PPh3)2(24mg，0.034mmol)加入到反应瓶中，在氮气保护下，加入5mL DMF，50℃反应1h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物5(0.12g，收率：54％)。5e (0.15g, 0.34mmol), crude intermediate 1 (0.14g), TEA (0.10g, 0.99mmol), CuI (7mg, 0.037mmol) and PdCl 2 (PPh 3 ) 2 (24mg, 0.034mmol) were added Into the reaction bottle, under nitrogen protection, add 5 mL DMF and react at 50°C for 1 hour. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v)=1:1) to obtain compound 5 (0.12g, yield: 54%).
1H NMR(400MHz,CDCl3)δ8.13–8.04(m,2H),7.96(s,1H),7.69–7.62(m,1H),7.59–7.53(m,1H),7.40–7.33(m,1H),6.80–6.74(m,1H),6.72–6.62(m,2H),6.51(dd,1H),4.99–4.87(m,1H),4.83(s,2H),4.34–4.20(m,2H),4.00–3.87(m,2H),3.75–3.60(m,1H),2.95–2.65(m,5H),2.65–2.46(m,2H),2.26–2.00(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.13–8.04(m,2H),7.96(s,1H),7.69–7.62(m,1H),7.59–7.53(m,1H),7.40–7.33(m ,1H),6.80–6.74(m,1H),6.72–6.62(m,2H),6.51(dd,1H),4.99–4.87(m,1H),4.83(s,2H),4.34–4.20(m ,2H),4.00–3.87(m,2H),3.75–3.60(m,1H),2.95–2.65(m,5H),2.65–2.46(m,2H),2.26–2.00(m,3H).
LCMS m/z＝656.6[M+1]+ LCMS m/z＝656.6[M+1] +
实施例6：制备化合物6
Example 6: Preparation of Compound 6
第一步：6b的制备Step 1: Preparation of 6b
将化合物6a(1.00g，4.12mmol)和6A(1.01g，4.5mmol)溶于四氢呋喃(50mL)，加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(CAS:161265-03-8)(0.24g，0.415mmol)、磷酸钾(2.62g，12.34mmol)和醋酸钯(0.05g，0.22mmol)，置换氮气三次，80℃反应16h。将反应液冷却至室温，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝4:1)，得到6b(1.00g，产率：71％)。Compound 6a (1.00g, 4.12mmol) and 6A (1.01g, 4.5mmol) were dissolved in tetrahydrofuran (50mL), and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (CAS: 161265-03-8) (0.24g, 0.415mmol), potassium phosphate (2.62g, 12.34mmol) and palladium acetate (0.05g, 0.22mmol), replace nitrogen three times, and react at 80°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 6b (1.00 g, yield: 71%).
第二步：6c的制备Step 2: Preparation of 6c
在250mL反应瓶中，依次加入6b(1.00g，2.92mmol)、1c(0.72g，2.91mmol)、CuI(0.11g，0.58mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.17g，1.2mmol)、磷酸钾(1.86g，8.76mmol)和DMF(30mL)，100℃反应16h。将反应液冷却至室温，加入100mL乙酸乙酯，有机相用水洗涤(100mL×3)和30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)，得到6c(0.72g，产率49％)。 In a 250mL reaction bottle, add 6b (1.00g, 2.92mmol), 1c (0.72g, 2.91mmol), CuI (0.11g, 0.58mmol), trans-(1R,2R)-N,N'dimethyl 1,2-Cyclohexanediamine (CAS: 67579-81-1) (0.17g, 1.2mmol), potassium phosphate (1.86g, 8.76mmol) and DMF (30mL) were reacted at 100°C for 16h. Cool the reaction solution to room temperature, add 100 mL of ethyl acetate, wash the organic phase with water (100 mL Ether/ethyl acetate (v/v)=3:1), 6c (0.72g, yield 49%) was obtained.
第三步：6d的制备Step 3: Preparation of 6d
在50mL反应瓶中，将6c(0.50g，0.98mmol)溶于20mL乙腈，加入对甲苯磺酸一水合物(0.51g，2.68mmol)，25℃反应16h。将反应液用饱和碳酸氢钠水溶液调pH至9，用30mL二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，得到粗品6d(0.38g)。In a 50 mL reaction bottle, dissolve 6c (0.50 g, 0.98 mmol) in 20 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.51 g, 2.68 mmol), and react at 25°C for 16 hours. The reaction solution was adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, extracted with 30 mL of methylene chloride, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6d (0.38g).
LCMS m/z＝409.4[M+1]+ LCMS m/z＝409.4[M+1] +
第四步：化合物6的制备Step 4: Preparation of Compound 6
在50mL反应瓶中，依次加入上述粗品6d(0.15g)、1f(0.12g，0.43mmol)、DIPEA(0.10g，0.77mmol)和DMSO(10mL)，90℃反应3h。将反应液冷却至室温，加10mL水，有黄色固体析出，抽滤，将滤饼用水洗涤(5mL×3)后用二氯甲烷/甲醇(v/v)＝10:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝15:1)，得到化合物6(0.13g，产率：25％)。In a 50 mL reaction bottle, add the above crude product 6d (0.15g), 1f (0.12g, 0.43mmol), DIPEA (0.10g, 0.77mmol) and DMSO (10mL) in sequence, and react at 90°C for 3 hours. Cool the reaction solution to room temperature, add 10 mL of water, a yellow solid precipitates, filter with suction, wash the filter cake with water (5 mL × 3) and dissolve it with a mixed solvent of dichloromethane/methanol (v/v) = 10:1. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1) to obtain compound 6 (0.13g, yield: 25%).
1H NMR(400MHz,CDCl3)δ8.56–8.46(m,2H),7.92(s,1H),7.85–7.61(m,5H),6.86–6.79(m,1H),6.58(dd,1H),5.00–4.89(m,1H),4.42–4.31(m,2H),4.18–4.05(m,2H),3.94–3.79(m,1H),3.04–2.60(m,3H),2.22–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.56–8.46(m,2H),7.92(s,1H),7.85–7.61(m,5H),6.86–6.79(m,1H),6.58(dd,1H ),5.00–4.89(m,1H),4.42–4.31(m,2H),4.18–4.05(m,2H),3.94–3.79(m,1H),3.04–2.60(m,3H),2.22–2.08 (m,1H).
实施例7：化合物7的制备
Example 7: Preparation of Compound 7
第一步：7b的制备Step 1: Preparation of 7b
在1L反应瓶中，将粗品中间体1(10.00g)、7a(8.72g，29.65mmol)溶于DMF(200mL)，加入PdCl2(PPh3)2(2.08g，2.96mmol)、CuI(1.13g，5.93mmol)和TEA(18.00g，177.88mmol)，置换氮气三次，55℃反应1h。将反应液冷却至室温，加入500mL乙酸乙酯，加入100mL水，有絮状固体析出，抽滤，将滤液静置分层，有机相用水洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用50mL二氯甲烷/甲基叔丁基醚(v/v)＝1:5的混合溶剂打浆纯化，过滤，得到粗品7b(7.00g)。In a 1L reaction bottle, dissolve crude intermediate 1 (10.00g) and 7a (8.72g, 29.65mmol) in DMF (200mL), add PdCl 2 (PPh 3 ) 2 (2.08g, 2.96mmol), CuI (1.13 g, 5.93mmol) and TEA (18.00g, 177.88mmol), replaced with nitrogen three times, and reacted at 55°C for 1 hour. Cool the reaction solution to room temperature, add 500 mL of ethyl acetate, and add 100 mL of water. A flocculent solid will precipitate, filter it with suction, let the filtrate stand and separate into layers, wash the organic phase with water (50 mL × 3), dry over anhydrous sodium sulfate, and reduce Concentrate under pressure, and the crude product is slurried and purified with 50 mL of a mixed solvent of methylene chloride/methyl tert-butyl ether (v/v) = 1:5, and filtered to obtain crude product 7b (7.00g).
LCMS m/z＝504.7[M+1]+ LCMS m/z＝504.7[M+1] +
第二步：7c的制备Step 2: Preparation of 7c
将上述粗品7b(2.00g)溶于二氯甲烷(30mL)，室温下加入三氟乙酸(30mL)，25℃反应2h。将反应体系减压浓缩，加入200mL二氯甲烷，用饱和碳酸氢钠水溶液调pH至9，分液，水相用二氯甲烷萃取(50mL×2)，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝12:1)，得7c(1.54g，从化合物7a算两步收率：45％)。Dissolve the above crude product 7b (2.00g) in dichloromethane (30mL), add trifluoroacetic acid (30mL) at room temperature, and react at 25°C for 2 hours. Concentrate the reaction system under reduced pressure, add 200 mL of dichloromethane, adjust the pH to 9 with saturated sodium bicarbonate aqueous solution, separate the liquids, extract the aqueous phase with dichloromethane (50 mL × 2), combine the organic phases, and use anhydrous sulfuric acid for the organic phase Dried over sodium and concentrated under reduced pressure, the crude product was separated and purified by silica gel chromatography column (dichloromethane/methanol (v/v) = 12:1) to obtain 7c (1.54g, two-step yield calculated from compound 7a: 45%).
LCMS m/z＝404.1[M+1]+ LCMS m/z＝404.1[M+1] +
第三步：7f的制备Step 3: Preparation of 7f
向玻璃封管中加入7d(2.00g，8.23mmol)和7e(15mL)，50℃密封反应16h。将反应体系冷却至室温，加入100mL乙酸乙酯，用水洗涤(50mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，得粗品7f(1.95g)。 Add 7d (2.00g, 8.23mmol) and 7e (15mL) to the glass sealed tube, and seal for 16 hours at 50°C. The reaction system was cooled to room temperature, 100 mL of ethyl acetate was added, washed with water (50 mL × 3) and 50 mL of saturated sodium chloride aqueous solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 7f (1.95 g).
LCMS m/z＝249.1[M+1]+ LCMS m/z＝249.1[M+1] +
第四步：化合物7的制备Step 4: Preparation of Compound 7
在50mL反应瓶中，依次加入上述粗品7f(0.025g)、7c(0.04g，0.099mmol)、CuI(0.004g，0.021mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.006g，0.042mmol)、磷酸钾(0.063g，0.297mmol)和DMF(10mL)，100℃反应16h。将反应液冷却至室温，加入乙酸乙酯(50mL)，用水洗涤(50mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物7(0.015g，收率：27％)。In a 50mL reaction bottle, add the above crude products 7f (0.025g), 7c (0.04g, 0.099mmol), CuI (0.004g, 0.021mmol), trans-(1R,2R)-N,N'dimethyl 1 in sequence , 2-cyclohexanediamine (CAS: 67579-81-1) (0.006g, 0.042mmol), potassium phosphate (0.063g, 0.297mmol) and DMF (10mL), react at 100°C for 16h. Cool the reaction solution to room temperature, add ethyl acetate (50 mL), wash with water (50 mL × 3) and 50 mL of saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by a silica gel chromatography column. (Petroleum ether/ethyl acetate (v/v)=1:1), compound 7 (0.015g, yield: 27%) was obtained.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),7.72–7.63(m,2H),6.85–6.78(m,1H),6.72–6.52(m,2H),4.98–4.89(m,1H),4.36(t,2H),4.09(t,2H),3.88–3.77(m,5H),3.54–3.45(m,4H),2.95–2.64(m,3H),2.19–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.25(s,1H),7.93(s,1H),7.72–7.63(m,2H),6.85–6.78(m,1H),6.72–6.52(m,2H ),4.98–4.89(m,1H),4.36(t,2H),4.09(t,2H),3.88–3.77(m,5H),3.54–3.45(m,4H),2.95–2.64(m,3H ),2.19–2.08(m,1H).
实施例8：化合物8的制备
Example 8: Preparation of Compound 8
第一步：8c的制备Step One: Preparation of 8c
将8a(0.20g，0.65mmol)与8b(0.13g，0.65mmol)加入到玻璃封管中，加入甲苯(3mL)与甲醇(3mL)，加入四(三苯基膦)钯(0.015g，0.013mmol)和碳酸钠(0.14g，1.32mmol)，置换氮气三次，110℃反应2h。将反应液冷却至室温，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚)，得到8c(0.115g，收率：53％)。Add 8a (0.20g, 0.65mmol) and 8b (0.13g, 0.65mmol) into a glass sealed tube, add toluene (3mL) and methanol (3mL), and add tetrakis(triphenylphosphine)palladium (0.015g, 0.013 mmol) and sodium carbonate (0.14g, 1.32mmol), replaced with nitrogen three times, and reacted at 110°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether) to obtain 8c (0.115 g, yield: 53%).
第二步：化合物8的制备Step 2: Preparation of Compound 8
在50mL反应瓶中，依次加入8c(0.11g，0.33mmol)、7c(0.133g，0.33mmol)、CuI(0.013g，0.068mmol)、反-(1R,2R)-N,N’-二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.019g，0.13mmol)、磷酸钾(0.21g，0.99mmol)和DMF(15mL)，100℃反应16h。将反应液冷却至室温，加入乙酸乙酯(100mL)，用水洗涤(100mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物8(0.025g，产率：12％)。In a 50mL reaction bottle, add 8c (0.11g, 0.33mmol), 7c (0.133g, 0.33mmol), CuI (0.013g, 0.068mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (CAS: 67579-81-1) (0.019g, 0.13mmol), potassium phosphate (0.21g, 0.99mmol) and DMF (15mL) were reacted at 100°C for 16h. Cool the reaction solution to room temperature, add ethyl acetate (100 mL), wash with water (100 mL × 3) and 50 mL of saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product with a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=1:1) gave compound 8 (0.025g, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.92(s,1H),7.82–7.73(m,4H),7.68(d,1H),7.63–7.45(m,4H),6.85–6.81(m,1H),6.58(dd,1H),5.00–4.89(m,1H),4.45–4.33(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H),2.98–2.65(m,3H),2.20–2.09(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.07(s,1H),7.92(s,1H),7.82–7.73(m,4H),7.68(d,1H),7.63–7.45(m,4H), 6.85–6.81(m,1H),6.58(dd,1H),5.00–4.89(m,1H),4.45–4.33(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H ),2.98–2.65(m,3H),2.20–2.09(m,1H).
实施例9：化合物9的制备
Example 9: Preparation of Compound 9
化合物9以化合物9a和9b为原料，参照实施例8的合成方法得到。 Compound 9 was obtained by referring to the synthesis method of Example 8 using compounds 9a and 9b as raw materials.
’1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.93(s,1H),7.82–7.47(m,8H),7.42–7.36(m,1H),6.84–6.80(m,1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.30(m,2H),4.17–4.05(m,2H),3.93–3.76(m,1H),2.96–2.69(m,3H),2.18–2.08(m,1H).' 1 H NMR (400MHz, CDCl 3 ) δ8.05(s,1H),7.93(s,1H),7.82–7.47(m,8H),7.42–7.36(m,1H),6.84–6.80(m, 1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.30(m,2H),4.17–4.05(m,2H),3.93–3.76(m,1H),2.96–2.69( m,3H),2.18–2.08(m,1H).
LCMS m/z＝658.0[M+1]+ LCMS m/z＝658.0[M+1] +
实施例10：化合物10的制备
Example 10: Preparation of Compound 10
第一步：10b的制备Step One: Preparation of 10b
在250mL反应瓶中，将10a(5.00g，25.77mmol)溶于无水四氢呋喃(50mL)，冷却至0℃，分批加入60％氢化钠(1.55g)，继续在0℃反应1h后，滴加2-(三甲基硅烷基)乙氧甲基氯(5.17g，31.00mmol)，25℃反应2h。向反应液加入30mL水和200mL乙酸乙酯，有机相用水洗涤(30mL×3)和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得到10b(6.97g，产率：83％)。In a 250mL reaction bottle, dissolve 10a (5.00g, 25.77mmol) in anhydrous tetrahydrofuran (50mL), cool to 0°C, add 60% sodium hydride (1.55g) in batches, continue to react at 0°C for 1 hour, and then drop Add 2-(trimethylsilyl)ethoxymethyl chloride (5.17g, 31.00mmol) and react at 25°C for 2 hours. Add 30 mL water and 200 mL ethyl acetate to the reaction solution, wash the organic phase with water (30 mL (Petroleum ether/ethyl acetate (v/v)=10:1), 10b (6.97g, yield: 83%) was obtained.
LCMS m/z＝325.0[M+1]+ LCMS m/z＝325.0[M+1] +
第二步：10c的制备Step 2: Preparation of 10c
在100mL反应瓶中，依次加入化合物10b(0.51g，1.57mmol)、7c(0.58g，1.44mmol)、CuI(0.14g，0.735mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.20g，1.41mmol)、磷酸钾(0.92g，4.33mmol)和DMF(20mL)，置换氮气三次，120℃反应8h。将反应液冷却至室温，加入乙酸乙酯(300mL)，用水洗涤(100mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到10c(0.43g，产率：50％)。In a 100mL reaction bottle, add compound 10b (0.51g, 1.57mmol), 7c (0.58g, 1.44mmol), CuI (0.14g, 0.735mmol), trans-(1R,2R)-N,N' dimethyl 1,2-cyclohexanediamine (CAS: 67579-81-1) (0.20g, 1.41mmol), potassium phosphate (0.92g, 4.33mmol) and DMF (20mL), replaced with nitrogen three times, and reacted at 120°C for 8 hours . Cool the reaction solution to room temperature, add ethyl acetate (300 mL), wash with water (100 mL × 3) and 50 mL of saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product with a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=1:1) gave 10c (0.43g, yield: 50%).
第三步：10d的制备Step 3: Preparation of 10d
向100mL反应瓶中加入10c(0.43g，0.72mmol)和二氯甲烷(10mL)，滴加三氟乙酸(10mL)，25℃反应1h。将反应液减压浓缩，用碳酸氢钠水溶液调pH至9，析出黄色固体，抽滤，滤饼用10mL水洗涤3次后用二氯甲烷/甲醇(v/v)＝10:1)的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(二氯甲烷/甲醇(v/v)＝10:1)，得到10d(0.25g，产率：74％)。Add 10c (0.43g, 0.72mmol) and dichloromethane (10mL) to the 100mL reaction bottle, add trifluoroacetic acid (10mL) dropwise, and react at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 9 with sodium bicarbonate aqueous solution. A yellow solid precipitated and was filtered with suction. The filter cake was washed three times with 10 mL of water and then washed with dichloromethane/methanol (v/v) = 10:1). Dissolve the mixed solvent, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1) to obtain 10d (0.25g, yield: 74%) .
LCMS m/z＝470.2[M+1]+ LCMS m/z＝470.2[M+1] +
第四步：10f的制备Step 4: Preparation of 10f
在100mL反应瓶中，依次加入10e(2.00g，8.20mmol)、环丙基硼酸(1.06g，12.34mmol)、磷酸钾(9.04g，42.59mmol)、三环己基膦(0.46g，1.64mmol)、醋酸钯(0.31g，1.38mmol)，加入甲苯(20mL)和水(1mL)，置换氮气三次，氮气保护下100℃反应16h。将反应液冷却至室温，析出固体，加入200mL水，用300mL乙酸乙酯萃取，有机相用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝4:1)，得到10f(1.15g，产率：89％)。 In a 100mL reaction bottle, add 10e (2.00g, 8.20mmol), cyclopropylboronic acid (1.06g, 12.34mmol), potassium phosphate (9.04g, 42.59mmol), and tricyclohexylphosphine (0.46g, 1.64mmol) in sequence. , palladium acetate (0.31g, 1.38mmol), add toluene (20mL) and water (1mL), replace nitrogen three times, and react at 100°C for 16h under nitrogen protection. Cool the reaction solution to room temperature, precipitate a solid, add 200 mL of water, extract with 300 mL of ethyl acetate, wash the organic phase with 50 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v)=4:1) to obtain 10f (1.15g, yield: 89%).
LCMS m/z＝159.2[M+1]+ LCMS m/z＝159.2[M+1] +
第五步：10g的制备Step 5: Preparation of 10g
在100mL反应瓶中，加入10f(0.50g，3.16mmol)和乙腈(15mL)，冷却至0℃，加入亚硝酸异戊酯(0.52g，4.44mmol)，在0℃继续反应10min后，加入溴化铜(0.90g，4.03mmol)，25℃反应16min。向反应液中加入50mL水，加入200mL乙酸乙酯，用水洗涤(50mL×3)和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到10g(0.70g，产率：99％)。In a 100mL reaction bottle, add 10f (0.50g, 3.16mmol) and acetonitrile (15mL), cool to 0°C, add isoamyl nitrite (0.52g, 4.44mmol), continue the reaction at 0°C for 10 minutes, then add bromine Copper (0.90g, 4.03mmol) was reacted at 25°C for 16 minutes. Add 50 mL of water to the reaction solution, add 200 mL of ethyl acetate, wash with water (50 mL (Petroleum ether/ethyl acetate (v/v)=10:1), 10 g (0.70 g, yield: 99%) was obtained.
第六步：化合物10的制备Step 6: Preparation of Compound 10
在100mL反应瓶中，依次加入10g(0.044g，0.20mmol)、10d(0.096g，0.20mmol)、CuI(0.008g，0.042mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.011g，0.077mmol)、磷酸钾(0.13g，0.61mmol)和DMF(10mL)，置换氮气三次，110℃反应16h。将反应液冷却至室温，加入乙酸乙酯(100mL)，用水洗涤(50mL×3)和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物10(0.025g，产率：20％)。In a 100mL reaction bottle, add 10g (0.044g, 0.20mmol), 10d (0.096g, 0.20mmol), CuI (0.008g, 0.042mmol), trans-(1R,2R)-N,N'dimethyl 1,2-Cyclohexanediamine (CAS: 67579-81-1) (0.011g, 0.077mmol), potassium phosphate (0.13g, 0.61mmol) and DMF (10mL) were replaced with nitrogen three times and reacted at 110°C for 16h. Cool the reaction solution to room temperature, add ethyl acetate (100 mL), wash with water (50 mL × 3) and 30 mL of saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product with a silica gel chromatography column. Purification (petroleum ether/ethyl acetate (v/v)=1:1) gave compound 10 (0.025g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.20–8.15(m,1H),8.02–7.95(m,2H),7.84(s,1H),7.73(s,1H),7.68(d,1H),7.62–7.54(m,2H),7.41–7.36(m,1H),6.85–6.78(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.30(m,2H),4.15–4.03(m,2H),3.92–3.77(m,1H),2.99–2.65(m,3H),2.18–2.08(m,1H),2.06–1.94(m,1H),1.10–1.00(m,2H),0.80–0.72(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.20–8.15(m,1H),8.02–7.95(m,2H),7.84(s,1H),7.73(s,1H),7.68(d,1H), 7.62–7.54(m,2H),7.41–7.36(m,1H),6.85–6.78(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.30(m,2H ),4.15–4.03(m,2H),3.92–3.77(m,1H),2.99–2.65(m,3H),2.18–2.08(m,1H),2.06–1.94(m,1H),1.10–1.00 (m,2H),0.80–0.72(m,2H).
实施例11：化合物11的制备
Example 11: Preparation of Compound 11
第一步：11b的制备Step One: Preparation of 11b
在100mL反应瓶中，将11a(2.00g，8.33mmol)溶于盐酸(15mL)，冷却至0℃，加入亚硝酸钠(0.63g，9.13mmol)，0℃反应1.5h后，加入10mL碘化钾(4.15g，25.00mmol)的水溶液，25℃反应16h。将反应液倒入20mL 6mol/L氢氧化钠水溶液中，用30mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(纯石油醚)，得到11b(2.31g，产率：79％)。In a 100mL reaction bottle, dissolve 11a (2.00g, 8.33mmol) in hydrochloric acid (15mL), cool to 0°C, add sodium nitrite (0.63g, 9.13mmol), react at 0°C for 1.5h, add 10mL potassium iodide ( 4.15g, 25.00mmol) aqueous solution, react at 25°C for 16h. Pour the reaction solution into 20mL 6mol/L sodium hydroxide aqueous solution, extract with 30mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (pure petroleum ether) to obtain 11b (2.31g, yield: 79%).
第二步：11c的制备Step 2: Preparation of 11c
在玻璃封管中，依次加入11b(2.30g，6.55mmol)、PdCl2(PPh3)2(0.46g，0.66mmol)、CuI(0.25g，1.31mmol)、TEA(3.98g，39.33mmol)和1mol/L丙炔的四氢呋喃溶液(7.21mL，7.21mmol)，加入DMF(10mL)，置换氮气三次，氮气保护下25℃密封反应2h。向反应液中加入乙酸乙酯(100mL)，用水洗涤(100mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚)，得到11c(0.88g，产率：51％)。In a glass sealed tube, add 11b (2.30g, 6.55mmol), PdCl 2 (PPh 3 ) 2 (0.46g, 0.66mmol), CuI (0.25g, 1.31mmol), TEA (3.98g, 39.33mmol) and 1 mol/L propyne in tetrahydrofuran solution (7.21 mL, 7.21 mmol), add DMF (10 mL), replace nitrogen three times, and seal for 2 hours at 25°C under nitrogen protection. Add ethyl acetate (100 mL) to the reaction solution, wash with water (100 mL ether) to obtain 11c (0.88g, yield: 51%).
第三步：化合物11的制备Step 3: Preparation of Compound 11
在100mL反应瓶中，依次加入11c(0.053g，0.20mmol)、10d(0.096g，0.20mmol)、CuI(0.008g，0.042mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.011g，0.077mmol)、磷酸钾(0.13g，0.61mmol)和DMF(10mL)，置换氮气三次，110℃反应16h。将反应液冷却至 室温，加入乙酸乙酯(100mL)，用水洗涤(50mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物11(0.011g，产率：8％)。In a 100mL reaction bottle, add 11c (0.053g, 0.20mmol), 10d (0.096g, 0.20mmol), CuI (0.008g, 0.042mmol), trans-(1R,2R)-N,N'dimethyl 1,2-Cyclohexanediamine (CAS: 67579-81-1) (0.011g, 0.077mmol), potassium phosphate (0.13g, 0.61mmol) and DMF (10mL) were replaced with nitrogen three times and reacted at 110°C for 16h. Cool the reaction solution to At room temperature, add ethyl acetate (100 mL), wash with water (50 mL Ethyl acetate (v/v)=1:1) to obtain compound 11 (0.011g, yield: 8%).
1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.92–7.87(m,2H),7.82(d,1H),7.77–7.72(m,2H),7.67(s,1H),7.64–7.53(m,2H),6.78–6.73(m,1H),6.50(dd,1H),4.93–4.83(m,1H),4.38–4.26(m,2H),4.10–3.96(m,2H),3.86–3.70(m,1H),2.90–2.57(m,3H),2.15–1.98(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.65(s,1H),7.92–7.87(m,2H),7.82(d,1H),7.77–7.72(m,2H),7.67(s,1H), 7.64–7.53(m,2H),6.78–6.73(m,1H),6.50(dd,1H),4.93–4.83(m,1H),4.38–4.26(m,2H),4.10–3.96(m,2H ),3.86–3.70(m,1H),2.90–2.57(m,3H),2.15–1.98(m,4H).
实施例12：化合物12的制备
Example 12: Preparation of Compound 12
第一步：12b的制备Step One: Preparation of 12b
在50mL反应瓶中，将12a(2.00g，8.91mmol)溶于无水四氢呋喃(15mL)，冷却至0℃，滴加硼烷四氢呋喃络合物(1.15g，13.38mmol)，25℃反应16h。向反应液中加入20mL饱和氯化铵水溶液，加入300mL乙酸乙酯，用水洗涤(20mL×3)和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，得到粗品12b(1.87g)。In a 50mL reaction bottle, 12a (2.00g, 8.91mmol) was dissolved in anhydrous tetrahydrofuran (15mL), cooled to 0°C, borane tetrahydrofuran complex (1.15g, 13.38mmol) was added dropwise, and the reaction was carried out at 25°C for 16h. Add 20 mL saturated aqueous ammonium chloride solution to the reaction solution, add 300 mL ethyl acetate, wash with water (20 mL × 3) and 30 mL saturated aqueous sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 12b. (1.87g).
第二步：12c的制备Step 2: Preparation of 12c
在50mL反应瓶中，加入上述粗品12b(0.50g)和二氯甲烷(15mL)，加入DMF(0.017g)以及SOCl2(0.56g)，25℃反应2h。将反应液减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得到12c(376mg，从化合物12a算两步产率：69％)。In a 50mL reaction bottle, add the above crude product 12b (0.50g) and dichloromethane (15mL), add DMF (0.017g) and SOCl 2 (0.56g), and react at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain 12c (376 mg, two-step yield calculated from compound 12a: 69%).
第三步：化合物12的制备Step 3: Preparation of Compound 12
在50mL反应瓶中，依次加入10d(0.096g，0.20mmol)、碳酸铯(0.11g，0.34mmol)和DMF(10mL)，冷却至0℃，加入12c(0.04g，0.17mmol)，25℃反应3h。向反应液中加入20mL水，加入100mL乙酸乙酯，用水洗涤(30mL×3)和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用prep-TLC制备纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物12(34mg，产率：26％)。In a 50mL reaction bottle, add 10d (0.096g, 0.20mmol), cesium carbonate (0.11g, 0.34mmol) and DMF (10mL) in sequence, cool to 0°C, add 12c (0.04g, 0.17mmol), and react at 25°C 3h. Add 20 mL water to the reaction solution, add 100 mL ethyl acetate, wash with water (30 mL (Petroleum ether/ethyl acetate (v/v)=1:1), compound 12 (34 mg, yield: 26%) was obtained.
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.76–7.66(m,3H),7.65–7.56(m,3H),7.47–7.40(m,1H),7.18–7.11(m,1H),6.76–6.72(m,1H),6.49(dd,1H),5.41(s,2H),4.91–4.81(m,1H),4.35–4.24(m,2H),4.07–3.96(m,2H),3.83–3.69(m,1H),2.90–2.55(m,3H),2.14–2.00(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.93(s,1H),7.76–7.66(m,3H),7.65–7.56(m,3H),7.47–7.40(m,1H),7.18–7.11(m ,1H),6.76–6.72(m,1H),6.49(dd,1H),5.41(s,2H),4.91–4.81(m,1H),4.35–4.24(m,2H),4.07–3.96(m ,2H),3.83–3.69(m,1H),2.90–2.55(m,3H),2.14–2.00(m,1H).
LCMS m/z＝662.8[M+1]+ LCMS m/z＝662.8[M+1] +
实施例13：化合物13的制备
Example 13: Preparation of Compound 13
第一步：13c的制备Step One: Preparation of 13c
将DMF(3mL)加入到13a(0.30g，2.04mmol)中，室温搅拌下加入13b(0.58g，2.49mmol) 和碳酸钾(0.86g，6.22mmol)，置换氮气三次，80℃反应2h。将反应液冷却至室温，加入20mL乙酸乙酯和20mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20-1:10)，得到13c(0.65g，产率：89％)。DMF (3mL) was added to 13a (0.30g, 2.04mmol), and 13b (0.58g, 2.49mmol) was added under stirring at room temperature. and potassium carbonate (0.86g, 6.22mmol), replaced with nitrogen three times, and reacted at 80°C for 2 hours. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:10) gave 13c (0.65g, yield: 89%).
第二步：13e的制备Step 2: Preparation of 13e
在50mL反应瓶中，依次加入13c(0.70g，1.94mmol)、1c(0.57g，2.30mmol)、CuI(0.074g，0.39mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.11g，0.77mmol)、磷酸钾(1.23g，5.79mmol)和DMF(10mL)，置换氮气三次，130℃微波反应5h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20-1:3)，得到13e(0.05g，产率：5％)。In a 50mL reaction bottle, add 13c (0.70g, 1.94mmol), 1c (0.57g, 2.30mmol), CuI (0.074g, 0.39mmol), trans-(1R,2R)-N,N'dimethyl 1,2-Cyclohexanediamine (CAS: 67579-81-1) (0.11g, 0.77mmol), potassium phosphate (1.23g, 5.79mmol) and DMF (10mL), replace nitrogen three times, and react under microwave at 130°C for 5 hours . Cool the reaction solution to room temperature, add 50 mL ethyl acetate and 50 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:3) gave 13e (0.05g, yield: 5%).
第三步：13f的对甲苯磺酸盐的制备Step 3: Preparation of p-toluenesulfonate of 13f
将乙腈(3mL)加入到13e(0.05g，0.095mmol)中，室温搅拌下加入对甲苯磺酸(0.05g，0.29mmol)，25℃反应15h。将反应液减压浓缩，得到粗品13f的对甲苯磺酸盐(0.04g)。Acetonitrile (3mL) was added to 13e (0.05g, 0.095mmol), p-toluenesulfonic acid (0.05g, 0.29mmol) was added under stirring at room temperature, and the reaction was carried out at 25°C for 15h. The reaction liquid was concentrated under reduced pressure to obtain the p-toluenesulfonate salt of crude product 13f (0.04g).
第四步：化合物13的制备Step 4: Preparation of Compound 13
将DMF(5mL)加入到上述粗品13f的对甲苯磺酸盐(0.035g)中，室温搅拌下加入1f(0.023g，0.083mmol)和DIPEA(0.074g，0.57mmol)，置换氮气三次，80℃室温3h。将反应液冷却至室温，加入20mL乙酸乙酯和20mL水，分离出有机相，有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到化合物13(0.006g，产率：11％)。Add DMF (5mL) to the p-toluenesulfonate (0.035g) of the above crude product 13f, add 1f (0.023g, 0.083mmol) and DIPEA (0.074g, 0.57mmol) with stirring at room temperature, replace nitrogen three times, 80°C Room temperature 3h. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:10-1:1) gave compound 13 (0.006g, yield: 11%).
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.97(s,1H),7.84–7.63(m,4H),7.47–7.41(m,1H),7.28–7.23(m,1H),6.86–6.80(m,1H),6.57(dd,1H),5.00–4.88(m,1H),4.45–4.32(m,2H),4.18–4.06(m,2H),3.92–3.79(m,1H),2.98–2.64(m,3H),2.20–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.30(s,1H),7.97(s,1H),7.84–7.63(m,4H),7.47–7.41(m,1H),7.28–7.23(m,1H ),6.86–6.80(m,1H),6.57(dd,1H),5.00–4.88(m,1H),4.45–4.32(m,2H),4.18–4.06(m,2H),3.92–3.79(m ,1H),2.98–2.64(m,3H),2.20–2.08(m,1H).
实施例14：化合物14的制备
Example 14: Preparation of Compound 14
第一步：14b的制备Step One: Preparation of 14b
将1,4-二氧六环(15mL)加入到环戊-2-烯-1-酮(0.50g，6.09mmol)、14a(2.05g，9.14mmol)和(1,5-环辛二烯)氯铑(I)二聚体(CAS:12092-47-6)(0.09g，0.18mmol)中，室温搅拌下加入碳酸钠(1.03g，9.72mmol)的水(5mL)溶液，置换氮气三次，90℃反应4h。将反应液冷却至室温，加入30mL乙酸乙酯和30mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:10)，得到14b(0.80g，产率：50％)。1,4-dioxane (15 mL) was added to cyclopent-2-en-1-one (0.50 g, 6.09 mmol), 14a (2.05 g, 9.14 mmol) and (1,5-cyclooctadiene ) to rhodium (I) chloride dimer (CAS: 12092-47-6) (0.09g, 0.18mmol), add sodium carbonate (1.03g, 9.72mmol) in water (5mL) with stirring at room temperature, and replace nitrogen three times. , react at 90°C for 4 hours. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:10) gave 14b (0.80g, yield: 50%).
第二步：14c的制备 Step 2: Preparation of 14c
将甲醇(15mL)加入到14b(0.80g，3.05mmol)中，冷却至0℃，加入硼氢化钠(0.23g，6.08mmol)，25℃反应2h。将反应液冷却至0℃，加入10mL饱和氯化铵水溶液，加入30mL乙酸乙酯和20mL水，分离出有机相，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:3)，得到粗品1(0.40g)。将二氯甲烷(10mL)加入到粗品1(0.25g)中，冷却至0℃，加入甲基磺酰氯(0.22g，1.92mmol)和三乙胺(0.29g，2.87mmol)，25℃反应2h。将反应液冷却至0℃，加入饱和10mL饱和碳酸氢钠水溶液，加入30mL二氯甲烷和20mL水，分离出有机相，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到粗品2(0.40g)。在50mL反应瓶中，依次加入上述粗品2(0.27g)、1c(0.23g，0.93mmol)、碳酸铯(0.77g，2.36mmol)和DMF(10mL)，80℃反应5h。将反应液冷却至室温，加入30mL乙酸乙酯和30mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到14c(0.27g，产率：59％)。Methanol (15 mL) was added to 14b (0.80 g, 3.05 mmol), cooled to 0°C, sodium borohydride (0.23g, 6.08 mmol) was added, and the reaction was carried out at 25°C for 2 hours. Cool the reaction solution to 0°C, add 10 mL saturated aqueous ammonium chloride solution, add 30 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with 20 mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v)=1:20-1:3) to obtain crude product 1 (0.40g). Add dichloromethane (10 mL) to crude product 1 (0.25 g), cool to 0°C, add methylsulfonyl chloride (0.22g, 1.92mmol) and triethylamine (0.29g, 2.87mmol), and react at 25°C for 2 hours. . Cool the reaction solution to 0°C, add 10 mL of saturated aqueous sodium bicarbonate solution, add 30 mL of dichloromethane and 20 mL of water, separate the organic phase, wash the organic phase with 20 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and reduce pressure. Concentrate, and the crude product is separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v)=1:20-1:4) to obtain crude product 2 (0.40g). In a 50mL reaction bottle, add the above crude product 2 (0.27g), 1c (0.23g, 0.93mmol), cesium carbonate (0.77g, 2.36mmol) and DMF (10mL) in sequence, and react at 80°C for 5h. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:4) gave 14c (0.27g, yield: 59%).
第三步：14d的对甲苯磺酸盐的制备Step 3: Preparation of 14d p-toluenesulfonate
将乙腈(10mL)加入到14c(0.25g，0.51mmol)中，室温搅拌下加入对甲苯磺酸(0.26g，1.51mmol)，25℃反应15h。将反应液减压浓缩，得到粗品14d的对甲苯磺酸盐(0.18g)。Acetonitrile (10 mL) was added to 14c (0.25 g, 0.51 mmol), p-toluenesulfonic acid (0.26 g, 1.51 mmol) was added under stirring at room temperature, and the reaction was carried out at 25°C for 15 h. The reaction liquid was concentrated under reduced pressure to obtain crude product 14d p-toluenesulfonate (0.18g).
第四步：化合物14的制备Step 4: Preparation of Compound 14
将DMF(10mL)加入到上述粗品14d的对甲苯磺酸盐(0.18g)中，室温搅拌下加入1f(0.13g，0.47mmol)和DIPEA(0.42g，3.25mmol)，置换氮气三次，80℃反应5h。将反应液冷却至室温，加入20mL乙酸乙酯和20mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到的粗品用prep-TLC制备纯化(DCM:MeOH(v/v)＝35:1)，得到化合物14(0.02g，产率：7％)。Add DMF (10 mL) to the p-toluenesulfonate (0.18g) of the above crude product 14d, add 1f (0.13g, 0.47mmol) and DIPEA (0.42g, 3.25mmol) with stirring at room temperature, replace nitrogen three times, 80°C Reaction 5h. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel Column separation and purification (ethyl acetate/petroleum ether (v/v) = 1:10-1:1), and the crude product obtained was preparative and purified by prep-TLC (DCM:MeOH (v/v) = 35:1) to obtain Compound 14 (0.02g, yield: 7%).
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.72–7.56(m,4H),7.56–7.36(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.99–4.81(m,2H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.98–3.75(m,2H),2.96–2.65(m,3H),2.62–2.07(m,6H),1.89–1.74(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.97(s,1H),7.72–7.56(m,4H),7.56–7.36(m,2H),6.84–6.78(m,1H),6.55(dd,1H ),4.99–4.81(m,2H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.98–3.75(m,2H),2.96–2.65(m,3H),2.62–2.07 (m,6H),1.89–1.74(m,1H).
实施例15：化合物15的制备
Example 15: Preparation of Compound 15
第一步：15c的制备Step One: Preparation of 15c
在50mL反应瓶中，依次加入15a(1.00g，5.04mmol)、15b(0.48g，5.51mmol)、碳酸铯(3.28g，10.07mmol)和DMF(20mL)，80℃反应3h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，分离出有机相，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到15c(0.55g，产率：41％)。In a 50 mL reaction bottle, add 15a (1.00g, 5.04mmol), 15b (0.48g, 5.51mmol), cesium carbonate (3.28g, 10.07mmol) and DMF (20mL) in sequence, and react at 80°C for 3 hours. Cool the reaction solution to room temperature, add 50 mL ethyl acetate and 50 mL water, separate the organic phase, wash the organic phase with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:20-1:4) gave 15c (0.55g, yield: 41%).
第二步：15d的制备Step 2: Preparation of 15d
将二氯甲烷(15mL)加入到15c(0.55g，2.07mmol)中，冷却至0℃，加入甲基磺酰氯(0.47 g，4.10mmol)和三乙胺(0.63g，6.22mmol)，25℃反应2h。将反应液冷却至0℃，加入10mL饱和碳酸氢钠水溶液，加入40mL二氯甲烷和20mL水，分离出有机相，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到15d(0.61g，产率：86％)。Dichloromethane (15 mL) was added to 15c (0.55 g, 2.07 mmol), cooled to 0°C, and methylsulfonyl chloride (0.47 g, 4.10mmol) and triethylamine (0.63g, 6.22mmol), reacted at 25°C for 2h. Cool the reaction solution to 0°C, add 10 mL of saturated aqueous sodium bicarbonate solution, add 40 mL of dichloromethane and 20 mL of water, separate the organic phase, wash the organic phase with 20 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20-1:4) to obtain 15d (0.61g, yield: 86%).
第三步：15e的制备Step 3: Preparation of 15e
在50mL反应瓶中，依次加入15d(0.20g，0.58mmol)、1c(0.17g，0.69mmol)、碳酸铯(0.57g，1.75mmol)和DMF(10mL)，80℃反应5h。将反应液冷却至室温，加入30mL乙酸乙酯和30mL水，分离出有机相，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到15e(0.27g，产率：94％)。In a 50mL reaction bottle, 15d (0.20g, 0.58mmol), 1c (0.17g, 0.69mmol), cesium carbonate (0.57g, 1.75mmol) and DMF (10mL) were added in sequence, and the reaction was carried out at 80°C for 5h. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the organic phase, wash the organic phase with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:20-1:4) gave 15e (0.27g, yield: 94%).
第四步：15f的对甲苯磺酸盐的制备Step 4: Preparation of p-toluenesulfonate of 15f
将乙腈(10mL)加入到15e(0.27g，0.55mmol)中，室温搅拌下加入对甲苯磺酸(0.28g，1.63mmol)，25℃反应15h。将反应液减压浓缩，得到粗品15f的对甲苯磺酸盐(0.22g)。Acetonitrile (10 mL) was added to 15e (0.27 g, 0.55 mmol), p-toluenesulfonic acid (0.28 g, 1.63 mmol) was added under stirring at room temperature, and the reaction was carried out at 25°C for 15 h. The reaction liquid was concentrated under reduced pressure to obtain the p-toluenesulfonate salt of crude product 15f (0.22g).
第五步：化合物15的制备Step 5: Preparation of Compound 15
将DMF(10mL)加入到上述粗品15f的对甲苯磺酸盐(0.15g)中，室温搅拌下加入1f(0.11g，0.399mmol)和DIPEA(0.49g，3.79mmol)，置换氮气三次，80℃反应5h。将反应液冷却至室温，加入20mL乙酸乙酯和20mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到的粗品用prep-TLC制备纯化(DCM:MeOH(v/v)＝35:1)，得到化合物15(0.05g，产率：19％)。Add DMF (10 mL) to the p-toluenesulfonate (0.15g) of the above crude product 15f, add 1f (0.11g, 0.399mmol) and DIPEA (0.49g, 3.79mmol) with stirring at room temperature, replace nitrogen three times, 80°C Reaction 5h. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is chromatographed on silica gel Column separation and purification (ethyl acetate/petroleum ether (v/v) = 1:10-1:1), and the crude product obtained was preparative and purified by prep-TLC (DCM:MeOH (v/v) = 35:1) to obtain Compound 15 (0.05g, yield: 19%).
1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.74–7.50(m,4H),7.44–7.33(m,1H),6.93–6.84(m,1H),6.84–6.75(m,1H),6.54(dd,1H),5.07–4.88(m,2H),4.44–4.27(m,2H),4.15–3.70(m,6H),3.64–3.47(m,1H),3.00–2.64(m,3H),2.60–2.35(m,2H),2.20–2.05(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.14(s,1H),7.74–7.50(m,4H),7.44–7.33(m,1H),6.93–6.84(m,1H),6.84–6.75(m ,1H),6.54(dd,1H),5.07–4.88(m,2H),4.44–4.27(m,2H),4.15–3.70(m,6H),3.64–3.47(m,1H),3.00–2.64 (m,3H),2.60–2.35(m,2H),2.20–2.05(m,1H).
LCMS m/z＝651.2[M+1]+ LCMS m/z＝651.2[M+1] +
实施例16：化合物16的制备
Example 16: Preparation of Compound 16
第一步：16c的制备Step One: Preparation of 16c
在玻璃微波管中，依次加入16a(1.00g，3.26mmol)、16b(0.28g，3.29mmol)、CuI(0.13g，0.68mmol)、反-(1R,2R)-N,N’二甲基1,2-环己烷二胺(CAS:67579-81-1)(0.19g，1.34mmol)、磷酸钾(2.10g，9.90mmol)和DMF(20mL)，置换氮气三次，140℃微波反应5h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:3)，得到16c(0.35g，产率：41％)。In the glass microwave tube, add 16a (1.00g, 3.26mmol), 16b (0.28g, 3.29mmol), CuI (0.13g, 0.68mmol), trans-(1R,2R)-N,N' dimethyl 1,2-Cyclohexanediamine (CAS: 67579-81-1) (0.19g, 1.34mmol), potassium phosphate (2.10g, 9.90mmol) and DMF (20mL), replace nitrogen three times, and react under microwave at 140°C for 5 hours . Cool the reaction solution to room temperature, add 50 mL ethyl acetate and 50 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:3) gave 16c (0.35g, yield: 41%).
第二步：16d的制备Step 2: Preparation of 16d
将无水四氢呋喃(15mL)加入到16c(0.30g，1.14mmol)中，置换氮气三次，-78℃下加入双三甲基硅基胺基锂(0.38g，2.27mmol)，继续在-78℃反应1h后，加入N-溴代丁二酰亚胺(0.24 g，1.35mmol)，加完后在-78℃下搅拌3h。向反应液中加入20mL饱和氯化铵水溶液，加入30mL乙酸乙酯和20mL水，分离出有机相，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到16d(0.11g，产率：28％)。Add anhydrous tetrahydrofuran (15 mL) to 16c (0.30 g, 1.14 mmol), replace nitrogen three times, add lithium bistrimethylsilylamide (0.38 g, 2.27 mmol) at -78°C, and continue at -78°C. After reacting for 1 hour, add N-bromosuccinimide (0.24 g, 1.35 mmol), stir at -78°C for 3 hours after completion. Add 20 mL saturated aqueous ammonium chloride solution to the reaction solution, add 30 mL ethyl acetate and 20 mL water, separate the organic phase, wash the organic phase with 20 mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel for the crude product Chromatographic column separation and purification (ethyl acetate/petroleum ether (v/v)=1:20-1:4) was performed to obtain 16d (0.11g, yield: 28%).
第三步：化合物16的制备Step 3: Preparation of Compound 16
在25mL反应瓶中，依次加入16d(0.10g，0.29mmol)、7c(0.12g，0.30mmol)、碳酸铯(0.28g，0.86mmol)和DMF(5mL)，60℃反应3h。将反应液冷却至室温，加入30mL乙酸乙酯和30mL水，分离出有机相，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到的粗品用prep-TLC制备纯化(DCM:MeOH(v/v)＝20:1)，得到化合物16(0.05g，产率：26％)。In a 25mL reaction bottle, add 16d (0.10g, 0.29mmol), 7c (0.12g, 0.30mmol), cesium carbonate (0.28g, 0.86mmol) and DMF (5mL) in sequence, and react at 60°C for 3 hours. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (ethyl acetate/petroleum ether (v/v)=1:10-1:1), and the crude product obtained is preparative and purified by prep-TLC (DCM:MeOH (v/v)=20:1) to obtain Compound 16 (0.05g, yield: 26%).
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.80–7.72(m,2H),7.70–7.56(m,3H),7.54–7.44(m,1H),6.84–6.77(m,1H),6.55(dd,1H),5.13–5.02(m,1H),5.01–4.86(m,1H),4.42–4.30(m,2H),4.12–4.03(m,2H),4.03–3.90(m,2H),3.88–3.75(m,1H),2.98–2.65(m,5H),2.18–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.09(s,1H),7.80–7.72(m,2H),7.70–7.56(m,3H),7.54–7.44(m,1H),6.84–6.77(m ,1H),6.55(dd,1H),5.13–5.02(m,1H),5.01–4.86(m,1H),4.42–4.30(m,2H),4.12–4.03(m,2H),4.03–3.90 (m,2H),3.88–3.75(m,1H),2.98–2.65(m,5H),2.18–2.08(m,1H).
LCMS m/z＝665.1[M+1]+ LCMS m/z＝665.1[M+1] +
实施例17：化合物17的制备
Example 17: Preparation of Compound 17
化合物17以化合物17a和10d为原料，参照实施例10的合成方法得到。Compound 17 was obtained by referring to the synthesis method of Example 10 using compounds 17a and 10d as raw materials.
’1H NMR(400MHz,CDCl3)δ8.42–8.34(m,1H),8.19(s,1H),8.14(d,1H),8.10(s,1H),8.02(d,1H),7.95(s,1H),7.89(s,1H),7.85–7.61(m,5H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.93–3.77(m,1H),2.97–2.65(m,3H),2.19–2.07(m,1H).' 1 H NMR (400MHz, CDCl 3 ) δ8.42–8.34(m,1H),8.19(s,1H),8.14(d,1H),8.10(s,1H),8.02(d,1H),7.95 (s,1H),7.89(s,1H),7.85–7.61(m,5H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.88(m,1H),4.45–4.32 (m,2H),4.17–4.05(m,2H),3.93–3.77(m,1H),2.97–2.65(m,3H),2.19–2.07(m,1H).
LCMS m/z＝621.2[M+1]+ LCMS m/z＝621.2[M+1] +
实施例18：化合物18的制备
Example 18: Preparation of Compound 18
化合物18以化合物18a为原料，参照实施例10的合成方法得到。Compound 18 was obtained by referring to the synthesis method of Example 10 using compound 18a as a raw material.
’1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.92(s,1H),7.86(s,1H),7.78(s,1H),7.69–7.58(m,3H),7.55–7.51(m,1H),7.24–7.19(m,1H),6.75(d,1H),6.50(dd,1H),4.92–4.82(m,1H),4.35–4.27(m,2H),4.07–3.97(m,2H),3.83–3.69(m,1H),2.89–2.58(m,3H),2.12–2.02(m,1H),2.02–1.91(m,1H),1.08–1.00(m,2H),0.85–0.70(m,2H).' 1 H NMR (400MHz, CDCl 3 ) δ8.22(s,1H),7.92(s,1H),7.86(s,1H),7.78(s,1H),7.69–7.58(m,3H),7.55 –7.51(m,1H),7.24–7.19(m,1H),6.75(d,1H),6.50(dd,1H),4.92–4.82(m,1H),4.35–4.27(m,2H),4.07 –3.97(m,2H),3.83–3.69(m,1H),2.89–2.58(m,3H),2.12–2.02(m,1H),2.02–1.91(m,1H),1.08–1.00(m, 2H),0.85–0.70(m,2H).
实施例19：化合物19的制备
Example 19: Preparation of Compound 19
第一步：19b的制备Step One: Preparation of 19b
在50mL反应瓶中，依次加入19a(0.50g，2.52mmol)、19A(0.25g，2.47mmol)、碳酸铯(1.64g，5.03mmol)和DMF(10mL)，80℃反应3h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到19b(0.06g，产率：9％)。In a 50 mL reaction bottle, add 19a (0.50 g, 2.52 mmol), 19A (0.25 g, 2.47 mmol), cesium carbonate (1.64 g, 5.03 mmol) and DMF (10 mL) in sequence, and react at 80°C for 3 hours. Cool the reaction solution to room temperature, add 50 mL of ethyl acetate and 50 mL of water, wash the organic phase with saturated brine (30 mL /petroleum ether (v/v)=1:20-1:4) to obtain 19b (0.06g, yield: 9%).
第二步：19c的制备Step 2: Preparation of 19c
将二氯甲烷(5mL)加入到19b(0.06g，0.21mmol)中，冷却至0℃，加入甲基磺酰氯(0.048g，0.42mmol)和三乙胺(0.064g，0.63mmol)，25℃反应2h。将反应体系冷却至室温，加入10mL饱和碳酸氢钠水溶液，加入10mL二氯甲烷和10mL水，有机相用饱和食盐水洗涤(20mL)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到19c(0.058g，产率：77％)。Add dichloromethane (5mL) to 19b (0.06g, 0.21mmol), cool to 0°C, add methylsulfonyl chloride (0.048g, 0.42mmol) and triethylamine (0.064g, 0.63mmol), 25°C Reaction 2h. Cool the reaction system to room temperature, add 10 mL of saturated sodium bicarbonate aqueous solution, add 10 mL of dichloromethane and 10 mL of water, wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is used on a silica gel chromatography column. Separate and purify (ethyl acetate/petroleum ether (v/v)=1:20-1:4) to obtain 19c (0.058g, yield: 77%).
第三步：化合物19的制备Step 3: Preparation of Compound 19
在25mL反应瓶中，依次加入19c(0.061g，0.17mmol)、7c(0.07g，0.17mmol)、碳酸铯(0.17g，0.52mmol)和DMF(4mL)，80℃反应5h。将反应液冷却至室温，加入20mL乙酸乙酯和10mL水，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到化合物19(0.02g，产率：18％)。In a 25 mL reaction bottle, add 19c (0.061g, 0.17mmol), 7c (0.07g, 0.17mmol), cesium carbonate (0.17g, 0.52mmol) and DMF (4mL) in sequence, and react at 80°C for 5 hours. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 10 mL water, wash the organic phase with saturated sodium chloride aqueous solution (10 mL Ethyl ester/petroleum ether (v/v)=1:10-1:1) to obtain compound 19 (0.02g, yield: 18%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.74–7.57(m,4H),7.52–7.42(m,1H),7.15–7.07(m,1H),6.86–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.20(m,3H),4.15–4.00(m,2H),3.90–3.75(m,1H),3.66–3.50(m,2H),3.04–2.60(m,5H),2.35–2.06(m,5H). 1 H NMR (400MHz, CDCl 3 ) δ8.02(s,1H),7.74–7.57(m,4H),7.52–7.42(m,1H),7.15–7.07(m,1H),6.86–6.77(m ,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.20(m,3H),4.15–4.00(m,2H),3.90–3.75(m,1H),3.66–3.50 (m,2H),3.04–2.60(m,5H),2.35–2.06(m,5H).
LCMS m/z＝665.2[M+1]+ LCMS m/z＝665.2[M+1] +
实施例20：化合物20的制备
Example 20: Preparation of Compound 20
第一步：20b的制备Step One: Preparation of 20b
在25mL反应瓶中，依次加入20a(0.10g，0.48mmol)、20A(41.82mg，0.48mmol)和1,2-二氯乙烷(5mL)，室温搅拌5min后，加入三乙酰氧基硼氢化钠(152.60mg，0.72mmol)，室温反应3h。加入20mL乙酸乙酯和10mL饱和碳酸氢钠水溶液，有机相用10mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:1)，得到20b(83mg，产率：62％)。In a 25mL reaction bottle, add 20a (0.10g, 0.48mmol), 20A (41.82mg, 0.48mmol) and 1,2-dichloroethane (5mL) in sequence. After stirring at room temperature for 5 minutes, add triacetoxyborane. Sodium (152.60 mg, 0.72 mmol), react at room temperature for 3 hours. Add 20 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate solution, wash the organic phase with 10 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (ethyl acetate/petroleum ether (v /v)=1:20-1:1), obtaining 20b (83 mg, yield: 62%).
第二步：20c的制备Step 2: Preparation of 20c
将二氯甲烷(5mL)加入到20b(0.08g，0.29mmol)中，冷却至0℃，加入甲基磺酰氯(0.066g，0.58mmol)和三乙胺(0.088g，0.87mmol)，25℃反应2h。将反应液冷却至0℃，加入10mL 饱和碳酸氢钠水溶液，加入10mL二氯甲烷和10mL水，分离出有机相，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:3)，得到20c(0.09g，产率：87％)。Add dichloromethane (5mL) to 20b (0.08g, 0.29mmol), cool to 0°C, add methylsulfonyl chloride (0.066g, 0.58mmol) and triethylamine (0.088g, 0.87mmol), 25°C Reaction 2h. Cool the reaction solution to 0°C and add 10 mL To the saturated aqueous sodium bicarbonate solution, add 10 mL of dichloromethane and 10 mL of water to separate the organic phase. The organic phase is washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (acetic acid Ethyl ester/petroleum ether (v/v)=1:20-1:3) to obtain 20c (0.09g, yield: 87%).
第三步：化合物20的制备Step 3: Preparation of Compound 20
在25mL反应瓶中，依次加入20c(0.061g，0.17mmol)、7c(0.07g，0.17mmol)、碳酸铯(0.17g，0.52mmol)和DMF(4mL)，80℃反应5h。将反应液冷却至室温，加入20mL乙酸乙酯和10mL水，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，所得粗品再用prep-HPLC制备纯化(二氯甲烷:甲醇(v/v)＝30:1)，得到化合物20(0.02g，产率：18％)。In a 25mL reaction bottle, add 20c (0.061g, 0.17mmol), 7c (0.07g, 0.17mmol), cesium carbonate (0.17g, 0.52mmol) and DMF (4mL) in sequence, and react at 80°C for 5 hours. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 10 mL water, wash the organic phase with saturated sodium chloride aqueous solution (10 mL Ethyl ester/petroleum ether (v/v)=1:10-1:1), and the obtained crude product was purified by prep-HPLC (dichloromethane:methanol (v/v)=30:1) to obtain compound 20 ( 0.02g, yield: 18%).
1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.78–7.42(m,6H),6.84–6.76(m,1H),6.55(dd,1H),5.00–4.84(m,2H),4.45–4.30(m,2H),4.13–4.02(m,2H),3.95–3.75(m,3H),3.15–2.40(m,8H),2.23–2.07(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.07(s,1H),7.78–7.42(m,6H),6.84–6.76(m,1H),6.55(dd,1H),5.00–4.84(m,2H ),4.45–4.30(m,2H),4.13–4.02(m,2H),3.95–3.75(m,3H),3.15–2.40(m,8H),2.23–2.07(m,2H).
LCMS m/z＝665.8[M+1]+ LCMS m/z＝665.8[M+1] +
实施例21：化合物21的制备
Example 21: Preparation of Compound 21
化合物21以化合物21a和21A为原料，参照实施例20的合成方法得到。Compound 21 was obtained by referring to the synthesis method of Example 20 using compounds 21a and 21A as raw materials.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.77–7.41(m,6H),6.84–6.76(m,1H),6.59–6.50(m,1H),4.99–4.87(m,1H),4.44–4.27(m,2H),4.25–4.00(m,3H),3.88–3.64(m,3H),3.15–2.65(m,4H),2.49–1.93(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.77–7.41(m,6H),6.84–6.76(m,1H),6.59–6.50(m,1H),4.99–4.87(m ,1H),4.44–4.27(m,2H),4.25–4.00(m,3H),3.88–3.64(m,3H),3.15–2.65(m,4H),2.49–1.93(m,8H).
LCMS m/z＝679.3[M+1]+ LCMS m/z＝679.3[M+1] +
实施例22：化合物22的制备
Example 22: Preparation of Compound 22
在25mL反应瓶中，依次加入22a(10.25mg，0.052mmol)、10d(20mg，0.043mmol)、碳酸铯(28.02mg，0.086mmol)和DMF(3mL)，80℃反应3h。将反应液冷却至室温，加入20mL乙酸乙酯和10mL水，分液，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用prep-TLC制备纯化(DCM:MeOH(v/v)＝30:1)，得到化合物22(0.01g，产率：36％)。In a 25mL reaction bottle, add 22a (10.25mg, 0.052mmol), 10d (20mg, 0.043mmol), cesium carbonate (28.02mg, 0.086mmol) and DMF (3mL) in sequence, and react at 80°C for 3 hours. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 10 mL water, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (10 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is prepared by prep-TLC. Purification (DCM:MeOH (v/v)=30:1) gave compound 22 (0.01g, yield: 36%).
1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.10–7.95(m,2H),7.90–7.60(m,6H),6.86–6.78(m,1H),6.62–6.52(m,1H),4.99–4.89(m,1H),4.45–4.30(m,2H),4.18–4.02(m,2H),3.94–3.76(m,1H),3.04–2.61(m,3H),2.22–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.32(s,1H),8.10–7.95(m,2H),7.90–7.60(m,6H),6.86–6.78(m,1H),6.62–6.52(m ,1H),4.99–4.89(m,1H),4.45–4.30(m,2H),4.18–4.02(m,2H),3.94–3.76(m,1H),3.04–2.61(m,3H),2.22 –2.06(m,1H).
实施例23：化合物23的制备
Example 23: Preparation of Compound 23
第一步：23b的制备Step One: Preparation of 23b
在50mL反应瓶中，加入23a(0.5g，2.52mmol)、23A(0.61g，2.54mmol)和碳酸钾(0.7g，5.07mmol)，加入10mL DMSO，100℃反应4h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到23b(0.5g，收率：48％)。In a 50mL reaction bottle, add 23a (0.5g, 2.52mmol), 23A (0.61g, 2.54mmol) and potassium carbonate (0.7g, 5.07mmol), add 10mL DMSO, and react at 100°C for 4 hours. Cool the reaction solution to room temperature, add it to 50 mL of ethyl acetate, wash with saturated sodium chloride aqueous solution (50 mL Ether/ethyl acetate (v/v)=1:0-1:2) to obtain 23b (0.5g, yield: 48%).
LCMS m/z＝418.5[M+1]+ LCMS m/z＝418.5[M+1] +
第二步：23c的制备Step 2: Preparation of 23c
将23b(0.5g，1.20mmol)、1c(0.29g,1.17mmol)、CuI(45mg，0.24mmol)和(1S,2S)-(+)-N,N'’二甲基-1,2-环己二胺(CAS:87583-89-9)(0.36g，2.53mmol)加入到反应瓶中，在氮气保护下，加入10mL DMF，100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到23c(0.4g，收率：59％)。23b (0.5g, 1.20mmol), 1c (0.29g, 1.17mmol), CuI (45mg, 0.24mmol) and (1S,2S)-(+)-N,N''dimethyl-1,2- Cyclohexanediamine (CAS: 87583-89-9) (0.36g, 2.53mmol) was added to the reaction bottle. Under nitrogen protection, 10mL DMF was added and the reaction was carried out at 100°C for 2 hours. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated aqueous sodium chloride solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain 23c (0.4g, yield: 59%).
LCMS m/z＝585.2[M+1]+ LCMS m/z＝585.2[M+1] +
第三步：23d的对甲苯磺酸盐的制备Step 3: Preparation of 23d p-toluenesulfonate
将23c(0.2g，0.34mmol)和对甲苯磺酸(0.19g，1.10mmol)溶于5mL乙腈中，室温反应12h。将反应体系减压浓缩，得到粗品23d的对甲苯磺酸盐(0.2g)。Dissolve 23c (0.2g, 0.34mmol) and p-toluenesulfonic acid (0.19g, 1.10mmol) in 5 mL acetonitrile and react at room temperature for 12 hours. The reaction system was concentrated under reduced pressure to obtain crude product 23d p-toluenesulfonate (0.2g).
LCMS m/z＝485.2[M+1]+ LCMS m/z＝485.2[M+1] +
第四步：化合物23的制备Step 4: Preparation of compound 23
将上述粗品23d的对甲苯磺酸盐(0.2g)、1f(0.094g，0.34mmol)和DIPEA(0.26g，2.01mmol)溶于5mL DMF中，90℃反应2h。将反应体系冷却到室温，加入到100mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物23(0.05g，收率：20％)。Dissolve the p-toluenesulfonate (0.2g), 1f (0.094g, 0.34mmol) and DIPEA (0.26g, 2.01mmol) of the above crude product 23d in 5mL DMF, and react at 90°C for 2h. Cool the reaction system to room temperature, add it to 100 mL of ethyl acetate, wash with saturated aqueous sodium chloride solution (50 mL /v)=1:0-1:2) to obtain compound 23 (0.05g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.98(s,1H),7.91–7.86(m,1H),7.77(s,1H),7.72(dd,1H),7.70–7.65(m,2H),7.60–7.53(m,1H),7.41(dd,1H),6.84–6.80(m,1H),6.60–6.53(m,2H),4.98–4.88(m,1H),4.43–4.32(m,2H),4.15–4.04(m,2H),3.90–3.76(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.62–1.52(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.02(s,1H),7.98(s,1H),7.91–7.86(m,1H),7.77(s,1H),7.72(dd,1H),7.70– 7.65(m,2H),7.60–7.53(m,1H),7.41(dd,1H),6.84–6.80(m,1H),6.60–6.53(m,2H),4.98–4.88(m,1H), 4.43–4.32(m,2H),4.15–4.04(m,2H),3.90–3.76(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.62–1.52(m ,6H).
LCMS m/z＝741.2[M+1]+ LCMS m/z＝741.2[M+1] +
实施例24：化合物24的制备
Example 24: Preparation of Compound 24
第一步：24b的制备Step One: Preparation of 24b
在100mL反应瓶中，将24a(3.00g，23.79mmol)溶于无水四氢呋喃(30mL)中，冷却至0℃，加入60％氢化钠(1.14g)，0℃搅拌1h后，滴加2-(三甲基硅烷基)乙氧甲基氯(4.36g，26.15mmol)，室温反应3h。向反应体系中加入50mL水，加入500mL乙酸乙酯，用水洗涤(50mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得到24b(3.87g，产率：64％)。In a 100 mL reaction bottle, dissolve 24a (3.00 g, 23.79 mmol) in anhydrous tetrahydrofuran (30 mL), cool to 0°C, add 60% sodium hydride (1.14g), stir at 0°C for 1 hour, and add 2- (Trimethylsilyl)ethoxymethyl chloride (4.36g, 26.15mmol), react at room temperature for 3 hours. Add 50 mL water to the reaction system, add 500 mL ethyl acetate, wash with water (50 mL (Petroleum ether/ethyl acetate (v/v)=10:1), 24b (3.87g, yield: 64%) was obtained.
LCMS m/z＝257.1[M+1]+ LCMS m/z＝257.1[M+1] +
第二步：24c的制备Step 2: Preparation of 24c
在100mL反应瓶中，将24b(2.00g，7.81mmol)溶于无水四氢呋喃(40mL)中，0℃下加入氢化铝锂(0.44g，11.59mmol)，0℃反应3h。向反应体系中加入20mL水，加入200mL乙酸乙酯，用水洗涤(50mL×3)和50mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1)，得到24c(1.75g，产率：98％)。In a 100 mL reaction bottle, 24b (2.00 g, 7.81 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), lithium aluminum hydride (0.44 g, 11.59 mmol) was added at 0°C, and the reaction was carried out at 0°C for 3 hours. Add 20 mL of water to the reaction system, add 200 mL of ethyl acetate, wash with water (50 mL (Petroleum ether/ethyl acetate (v/v)=5:1), 24c (1.75g, yield: 98%) was obtained.
LCMS m/z＝229.1[M+1]+ LCMS m/z＝229.1[M+1] +
第三步：24d的制备Step 3: Preparation of 24d
在50mL反应瓶中，0℃下依次加入24c(0.5g，2.19mmol)、三乙胺(0.45g，4.45mmol)和甲烷磺酰氯(0.37g，3.23mmol)，0℃下反应16h。将反应液用20mL饱和氯化铵水溶液淬灭，用100mL乙酸乙酯萃取，有机相用20mL饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得到24d(0.28g，产率：52％)。In a 50mL reaction bottle, 24c (0.5g, 2.19mmol), triethylamine (0.45g, 4.45mmol) and methane sulfonyl chloride (0.37g, 3.23mmol) were added in sequence at 0°C, and the reaction was carried out at 0°C for 16 hours. The reaction solution was quenched with 20 mL saturated aqueous ammonium chloride solution, extracted with 100 mL ethyl acetate, the organic phase was washed with 20 mL saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether /ethyl acetate (v/v)=10:1) to obtain 24d (0.28g, yield: 52%).
第四步：24e的制备Step 4: Preparation of 24e
在50mL反应瓶中，依次加入7c(0.28g，0.69mmol)、碳酸铯(0.37g，1.14mmol)和DMF(15mL)，滴加24d(0.14g，0.57mmol)，25℃反应2h。向反应体系中加入25mL水，加入100mL乙酸乙酯，用水洗涤(25mL×3)和25mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到24e(0.10g，产率：29％)。In a 50mL reaction bottle, add 7c (0.28g, 0.69mmol), cesium carbonate (0.37g, 1.14mmol) and DMF (15mL) in sequence, add 24d (0.14g, 0.57mmol) dropwise, and react at 25°C for 2 hours. Add 25 mL water to the reaction system, add 100 mL ethyl acetate, wash with water (25 mL (Petroleum ether/ethyl acetate (v/v)=1:1), 24e (0.10 g, yield: 29%) was obtained.
LCMS m/z＝614.8[M+1]+ LCMS m/z＝614.8[M+1] +
第五步：24f的制备Step 5: Preparation of 24f
在50mL反应瓶中，依次加入24e(0.15g，0.24mmol)和二氯甲烷(10mL)，滴加三氟乙酸(10mL)，25℃反应1h。将反应液减压浓缩，加入100mL二氯甲烷，用饱和碳酸氢钠水溶液调pH至9，用100mL二氯甲烷萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝12:1)，得到24f(0.10g，产率：86％)。 In a 50mL reaction bottle, add 24e (0.15g, 0.24mmol) and dichloromethane (10mL) in sequence, add trifluoroacetic acid (10mL) dropwise, and react at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, 100 mL of dichloromethane was added, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, and extracted with 100 mL of dichloromethane. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated on a silica gel chromatography column. Purification (dichloromethane/methanol (v/v) = 12:1) gave 24f (0.10 g, yield: 86%).
LCMS m/z＝484.7[M+1]+ LCMS m/z＝484.7[M+1] +
第六步：化合物24的制备Step 6: Preparation of compound 24
在50mL反应瓶中，依次加入24f(0.046g，0.095mmol)、碳酸铯(0.057g，0.17mmol)和DMF(5mL)，滴加24A(0.02g，0.087mmol)(合成方法见WO2007018314)，25℃反应2h。向反应体系中加入10mL水，加入100mL乙酸乙酯，用水洗涤(10mL×3)和10mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物24(0.036g，产率：61％)。In a 50mL reaction bottle, add 24f (0.046g, 0.095mmol), cesium carbonate (0.057g, 0.17mmol) and DMF (5mL) in sequence, and add 24A (0.02g, 0.087mmol) dropwise (see WO2007018314 for the synthesis method), 25 ℃ reaction for 2h. Add 10 mL of water to the reaction system, add 100 mL of ethyl acetate, wash with water (10 mL (Petroleum ether/ethyl acetate (v/v)=1:1), compound 24 (0.036g, yield: 61%) was obtained.
1H NMR(400MHz,CDCl3)δ7.74–7.54(m,6H),7.52–7.43(m,1H),7.28–7.24(m,1H),7.09(d,1H),6.77(s,1H),6.55(dd,1H),5.44(s,2H),5.00–4.82(m,3H),4.42–4.30(m,2H),4.14–4.01(m,2H),3.89–3.72(m,1H),3.04–2.85(m,1H),2.85–2.64(m,2H),2.14–2.00(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.74–7.54(m,6H),7.52–7.43(m,1H),7.28–7.24(m,1H),7.09(d,1H),6.77(s,1H ),6.55(dd,1H),5.44(s,2H),5.00–4.82(m,3H),4.42–4.30(m,2H),4.14–4.01(m,2H),3.89–3.72(m,1H ),3.04–2.85(m,1H),2.85–2.64(m,2H),2.14–2.00(m,1H).
LCMS m/z＝676.2[M+1]+ LCMS m/z＝676.2[M+1] +
实施例25：化合物25的制备
Example 25: Preparation of Compound 25
第一步：25b的制备Step One: Preparation of 25b
将DMF(5mL)加入到25a(0.20g，0.85mmol)中，室温搅拌下缓慢加入NBS(0.15g，0.84mmol)，室温反应1h。向反应液中加入20mL乙酸乙酯和20mL水，分液，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20-1:10)，得到25b(0.20g，产率：76％)。DMF (5 mL) was added to 25a (0.20 g, 0.85 mmol), NBS (0.15 g, 0.84 mmol) was slowly added with stirring at room temperature, and the reaction was carried out at room temperature for 1 h. Add 20 mL ethyl acetate and 20 mL water to the reaction solution, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (10 mL Ethyl ester/petroleum ether (v/v)=1:20-1:10) to obtain 25b (0.20g, yield: 76%).
第二步：25c的制备Step 2: Preparation of 25c
在微波管中，依次加入25b(0.20g，0.64mmol)、1c(0.16g，0.64mmol)、CuI(0.024g，0.13mmol)、反-(1R,2R)-N,N'二甲基1,2-环己烷二胺(0.036g，0.25mmol)、磷酸钾(0.41g，1.93mmol)和DMF(4mL)，加完后140℃微波反应5h。将反应液冷却至室温，加入30mL乙酸乙酯和30mL水，分液，有机相用饱和氯化钠水溶液洗涤(20mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:20-1:3)，得到25c(0.03g，产率：10％)。In the microwave tube, add 25b (0.20g, 0.64mmol), 1c (0.16g, 0.64mmol), CuI (0.024g, 0.13mmol), trans-(1R,2R)-N,N'dimethyl 1 , 2-cyclohexanediamine (0.036g, 0.25mmol), potassium phosphate (0.41g, 1.93mmol) and DMF (4mL), after adding, microwave reaction at 140°C for 5h. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:20-1:3) gave 25c (0.03g, yield: 10%).
第三步：25d的对甲苯磺酸盐的制备Step 3: Preparation of 25d p-toluenesulfonate
将乙腈(3mL)加入到25c(0.04g，0.083mmol)中，室温搅拌下加入对甲苯磺酸(0.043g，0.25mmol)，25℃反应15h。将反应液减压浓缩，得到粗品25d的对甲苯磺酸盐(0.02g)。Acetonitrile (3mL) was added to 25c (0.04g, 0.083mmol), p-toluenesulfonic acid (0.043g, 0.25mmol) was added under stirring at room temperature, and the reaction was carried out at 25°C for 15h. The reaction liquid was concentrated under reduced pressure to obtain crude product 25d of p-toluenesulfonate (0.02g).
第四步：化合物25的制备Step 4: Preparation of compound 25
将DMF(3mL)加入到上述粗品25d的对甲苯磺酸盐(0.03g)中，室温搅拌下加入1f(0.022g，0.08mmol)和DIPEA(0.10g，0.77mmol)，置换氮气三次，80℃反应3h。将反应液冷却至室温，加入20mL乙酸乙酯和20mL水，分液，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到化合物25(0.006g，产率：12％)。Add DMF (3mL) to the p-toluenesulfonate (0.03g) of the above crude product 25d, add 1f (0.022g, 0.08mmol) and DIPEA (0.10g, 0.77mmol) with stirring at room temperature, replace nitrogen three times, 80°C Reaction 3h. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 20 mL water, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (10 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:10-1:1) gave compound 25 (0.006g, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.39–8.32(m,2H),8.10(s,1H),8.01(s,1H),7.82(s, 1H),7.77(dd,1H),7.73–7.62(m,2H),7.58–7.48(m,2H),6.82–6.74(m,1H),6.55(dd,1H),4.99–4.90(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.49(s,1H),8.39–8.32(m,2H),8.10(s,1H),8.01(s,1H),7.82(s, 1H),7.77(dd,1H),7.73–7.62(m,2H),7.58–7.48(m,2H),6.82–6.74(m,1H),6.55(dd,1H),4.99–4.90(m, 1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.06(m,1H).
实施例26：化合物26的制备
Example 26: Preparation of Compound 26
化合物26以化合物26a和26A为原料，参照实施例19的合成方法得到。Compound 26 was obtained by referring to the synthesis method of Example 19 using compounds 26a and 26A as raw materials.
1H NMR(400MHz,CDCl3)δ8.20–7.28(m,6H),6.86–6.76(m,1H),6.63–6.40(m,2H),5.01–4.89(m,1H),4.45–4.30(m,3H),4.30–4.02(m,5H),4.01–3.73(m,3H),3.28–2.60(m,4H),2.18–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.20–7.28(m,6H),6.86–6.76(m,1H),6.63–6.40(m,2H),5.01–4.89(m,1H),4.45–4.30 (m,3H),4.30–4.02(m,5H),4.01–3.73(m,3H),3.28–2.60(m,4H),2.18–2.06(m,1H).
实施例27：化合物27的制备
Example 27: Preparation of Compound 27
第一步：27b的制备Step One: Preparation of 27b
在25mL反应瓶中，依次加入27a(0.20g，1.01mmol)、27A的盐酸盐(0.14g)、碳酸铯(0.99g，3.04mmol)和DMF(5mL)，80℃反应15h。将反应液冷却至室温，加入30mL乙酸乙酯和20mL水，分液，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到27b(0.06g，产率：24％)。In a 25mL reaction bottle, add 27a (0.20g, 1.01mmol), 27A hydrochloride (0.14g), cesium carbonate (0.99g, 3.04mmol) and DMF (5mL) in sequence, and react at 80°C for 15h. Cool the reaction solution to room temperature, add 30 mL ethyl acetate and 20 mL water, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (10 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:20-1:4) gave 27b (0.06g, yield: 24%).
第二步：27c的制备Step 2: Preparation of 27c
将二氯甲烷(5mL)加入到27b(0.06g，0.24mmol)中，冷却至0℃，加入甲烷磺酰氯(0.055g，0.48mmol)和三乙胺(0.073g，0.72mmol)，25℃反应2h。将反应液冷却至0℃，加入20mL饱和碳酸氢钠水溶液，加入20mL二氯甲烷和10mL水，分液，有机相用20mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到27c(0.065g，产率：82％)。Add dichloromethane (5mL) to 27b (0.06g, 0.24mmol), cool to 0°C, add methanesulfonyl chloride (0.055g, 0.48mmol) and triethylamine (0.073g, 0.72mmol), and react at 25°C 2h. Cool the reaction solution to 0°C, add 20 mL of saturated aqueous sodium bicarbonate solution, add 20 mL of dichloromethane and 10 mL of water, separate the layers, wash the organic phase with 20 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Separate and purify using silica gel chromatography column (ethyl acetate/petroleum ether (v/v)=1:20-1:4) to obtain 27c (0.065g, yield: 82%).
第三步：化合物27的制备Step 3: Preparation of Compound 27
在25mL反应瓶中，依次加入27c(0.066g，0.20mmol)、7c(0.80g，0.20mmol)、碳酸铯(0.20g，0.61mmol)和DMF(4mL)，80℃反应15h。将反应液冷却至室温，加入20mL乙酸乙酯和10mL水，分液，有机相用饱和氯化钠水溶液洗涤(10mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，得到化合物27(0.025g，产率：20％)。In a 25mL reaction bottle, add 27c (0.066g, 0.20mmol), 7c (0.80g, 0.20mmol), cesium carbonate (0.20g, 0.61mmol) and DMF (4mL) in sequence, and react at 80°C for 15h. Cool the reaction solution to room temperature, add 20 mL ethyl acetate and 10 mL water, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (10 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate the crude product on a silica gel chromatography column. Purification (ethyl acetate/petroleum ether (v/v)=1:10-1:1) gave compound 27 (0.025g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.76–7.60(m,3H),7.52–7.45(m,1H),7.42–7.34(m,1H),6.84–6.77(m,1H),6.62–6.51(m,2H),5.23–5.10(m,1H),5.00–4.88(m,1H),4.70–4.58(m,2H),4.52–4.41(m,2H),4.40–4.28(m,2H),4.12–4.01(m,2H),3.88–3.74(m,1H),3.00–2.64(m,3H),2.20–2.05(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.07(s,1H),7.76–7.60(m,3H),7.52–7.45(m,1H),7.42–7.34(m,1H),6.84–6.77(m ,1H),6.62–6.51(m,2H),5.23–5.10(m,1H),5.00–4.88(m,1H),4.70–4.58(m,2H),4.52–4.41(m,2H),4.40 –4.28(m,2H),4.12–4.01(m,2H),3.88–3.74(m,1H),3.00–2.64(m,3H),2.20–2.05(m,1H).
实施例29：化合物29的制备
Example 29: Preparation of Compound 29
第一步：29b的制备Step 1: Preparation of 29b
将29a(4.1g,19.80mmol)和4-碘-1H-吡唑(4.22g,21.75mmol)溶于40mL乙腈中，加入碳酸铯(9.68g,29.70mmol)，80℃反应3h。将反应液冷却至室温，加入30mL水和100mL乙酸乙酯，分液，有机相用30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩后粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:9)，得到29b(2.40g，收率：38％)。Dissolve 29a (4.1g, 19.80mmol) and 4-iodo-1H-pyrazole (4.22g, 21.75mmol) in 40mL acetonitrile, add cesium carbonate (9.68g, 29.70mmol), and react at 80°C for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water and 100 mL of ethyl acetate were added, and the liquids were separated. The organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v) = 1:9), 29b (2.40 g, yield: 38%) was obtained.
1H NMR(400MHz,CDCl3)δ7.55(s,2H),4.19(q,2H),2.95–2.70(m,4H),2.26–1.96(m,2H),1.23(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.55(s,2H),4.19(q,2H),2.95–2.70(m,4H),2.26–1.96(m,2H),1.23(t,3H).
LCMS m/z＝321.1[M+1]+。LCMS m/z=321.1[M+1] + .
第二步：29c的制备Step 2: Preparation of 29c
将29b(2.30g,7.18mmol)溶于THF(20mL)中，加入4mL水和一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品1(2.0g)。将粗品1(0.51g)溶于DCM(10mL)中，缓慢滴加1-氯-N,N,2-三甲基丙烯胺(0.35g,2.62mmol)，室温反应2h。向反应液中加入TEA(0.53g,5.24mmol)和2-氯-4-(三氟甲基)苯胺(0.34g,1.74mmol)，室温反应3h。向反应液中加入20mL饱和碳酸氢钠水溶液，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(乙酸乙酯/石油醚(v/v)＝1:3)，得到29c(0.45g,收率：52％)。Dissolve 29b (2.30g, 7.18mmol) in THF (20mL), add 4mL of water and lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL of ethyl acetate, separate the layers, wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1 (2.0 g). Dissolve crude product 1 (0.51g) in DCM (10mL), slowly add 1-chloro-N,N,2-trimethylpropenylamine (0.35g, 2.62mmol) dropwise, and react at room temperature for 2h. TEA (0.53g, 5.24mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.34g, 1.74mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 3 hours. Add 20 mL saturated sodium bicarbonate aqueous solution to the reaction solution, extract with 100 mL ethyl acetate, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether) (v/v)=1:3), 29c (0.45g, yield: 52%) was obtained.
第三步：29d的制备Step 3: Preparation of 29d
将29c(2.0g，4.26mmol)溶于10mL THF中，冷却至0℃，加入1mol/L硼烷四氢呋喃溶液(8.5mL，8.5mmol)，室温反应18h。将反应液冷却至0℃，加入5mL甲醇，加入40mL乙酸乙酯和30mL水，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-3:1)，得到29d(1.5g，收率：77％)。Dissolve 29c (2.0g, 4.26mmol) in 10mL THF, cool to 0°C, add 1mol/L borane tetrahydrofuran solution (8.5mL, 8.5mmol), and react at room temperature for 18h. Cool the reaction solution to 0°C, add 5 mL of methanol, add 40 mL of ethyl acetate and 30 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). (v/v)=10:1-3:1), 29d (1.5g, yield: 77%) was obtained.
LCMS m/z＝456.4[M+1]+ LCMS m/z＝456.4[M+1] +
第四步：化合物29的制备Step 4: Preparation of compound 29
将29d(0.32g，0.70mmol)、粗品中间体1(0.35g)、TEA(0.21g，2.08mmol)、CuI(27mg，0.14mmol)和PdCl2(PPh3)2(98mg，0.14mmol)加入到反应瓶中，在氮气保护下加入8mL DMF，55℃反应3h。将反应液冷却至室温，加入40mL水，抽滤，滤饼用10mL水洗涤，将滤饼用100mL DCM/MeOH(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:1.5)，得化合物29(88mg，收率：19％)。29d (0.32g, 0.70mmol), crude intermediate 1 (0.35g), TEA (0.21g, 2.08mmol), CuI (27mg, 0.14mmol) and PdCl 2 (PPh 3 ) 2 (98mg, 0.14mmol) were added To the reaction bottle, add 8 mL DMF under nitrogen protection and react at 55°C for 3 hours. Cool the reaction solution to room temperature, add 40 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 100 mL of a mixed solvent of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and reduce The mixture was concentrated under pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:1.5) to obtain compound 29 (88 mg, yield: 19%).
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.70–7.60(m,2H),7.53(s,1H),7.48–7.42(m,1H),7.29(dd,1H),6.82–6.77(m,1H),6.54(dd,1H),6.45(d,1H),5.12–4.88(m,2H),4.39–4.27(m,2H),4.10–3.98(m,2H),3.85–3.72(m,1H),3.65(d,2H),2.95–2.55(m,5H),2.53–2.37(m,2H),2.23–1.97(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.03(s,1H),7.70–7.60(m,2H),7.53(s,1H),7.48–7.42(m,1H),7.29(dd,1H), 6.82–6.77(m,1H),6.54(dd,1H),6.45(d,1H),5.12–4.88(m,2H),4.39–4.27(m,2H),4.10–3.98(m,2H), 3.85–3.72(m,1H),3.65(d,2H),2.95–2.55(m,5H),2.53–2.37(m,2H),2.23–1.97(m,3H).
LCMS m/z＝665.2[M+1]+ LCMS m/z＝665.2[M+1] +
实施例30：化合物30的制备
Example 30: Preparation of Compound 30
化合物30以化合物30a和30A为原料，参照实施例23的合成方法得到。Compound 30 was obtained by referring to the synthesis method of Example 23 using compounds 30a and 30A as raw materials.
1H NMR(400MHz,CDCl3)δ8.04–7.95(m,2H),7.92(d,1H),7.79–7.72(m,2H),7.71–7.65(m,2H),7.60–7.54(m,1H),7.41(dd,1H),6.82(d,1H),6.61–6.53(m,2H),4.99–4.90(m,1H),4.44–4.32(m,2H),4.16–4.05(m,2H),3.92–3.77(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.58–1.53(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.04–7.95(m,2H),7.92(d,1H),7.79–7.72(m,2H),7.71–7.65(m,2H),7.60–7.54(m ,1H),7.41(dd,1H),6.82(d,1H),6.61–6.53(m,2H),4.99–4.90(m,1H),4.44–4.32(m,2H),4.16–4.05(m ,2H),3.92–3.77(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.58–1.53(m,6H).
实施例31：化合物31的制备
Example 31: Preparation of Compound 31
第一步：31b的制备Step One: Preparation of 31b
在50mL反应瓶中，加入亚硝酸钠(0.18g，2.61mmol)，于0℃下缓慢滴加浓硫酸(1.17g)，搅拌反应10min后，加入冰乙酸(0.59g，9.83mmol)，25℃反应1h后，滴加31a(0.50g，2.17mmol)的冰醋酸溶液(0.57mL)，25℃反应1h后，加入碘化钾(3.65g，22.00mmol)的水(5mL)溶液，25℃反应3h。将反应体系用1mol/L氢氧化钠水溶液调pH至10，用50mL乙酸乙酯萃取，有机相用30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(纯石油醚)，得到31b(0.28g，产率：38％)。In a 50mL reaction bottle, add sodium nitrite (0.18g, 2.61mmol), slowly add concentrated sulfuric acid (1.17g) dropwise at 0°C, stir for 10 minutes, then add glacial acetic acid (0.59g, 9.83mmol), 25°C After reacting for 1 hour, a solution of 31a (0.50g, 2.17mmol) in glacial acetic acid (0.57mL) was added dropwise. After reacting at 25°C for 1h, a solution of potassium iodide (3.65g, 22.00mmol) in water (5mL) was added, and the reaction was carried out at 25°C for 3h. Adjust the pH of the reaction system to 10 with 1 mol/L sodium hydroxide aqueous solution, extract with 50 mL ethyl acetate, wash the organic phase with 30 mL saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel for the crude product Chromatographic column separation and purification (pure petroleum ether) was performed to obtain 31b (0.28g, yield: 38%).
第二步：31c的制备Step 2: Preparation of 31c
在50mL反应瓶中，依次加入31b(0.50g，1.47mmol)、31A(0.19g，1.51mmol)、碳酸钾(0.61g，4.41mmol)和DMF(15mL)，90℃反应4h。将反应体系冷却至室温，加入10mL水和200mL乙酸乙酯，有机相用50mL水洗涤三次和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)，得到31c(0.09g，产率：18％)。In a 50mL reaction bottle, add 31b (0.50g, 1.47mmol), 31A (0.19g, 1.51mmol), potassium carbonate (0.61g, 4.41mmol) and DMF (15mL) in sequence, and react at 90°C for 4 hours. Cool the reaction system to room temperature, add 10 mL water and 200 mL ethyl acetate, wash the organic phase three times with 50 mL water and 30 mL saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column. After separation and purification (petroleum ether/ethyl acetate (v/v) = 10:1), 31c (0.09 g, yield: 18%) was obtained.
第三步：31d的制备Step 3: Preparation of 31d
在50mL反应瓶中，将31c(0.12g，0.35mmol)溶于无水四氢呋喃(5mL)中，0℃下加入 氢化铝锂(0.02g，0.53mmol)，0℃继续反应3h。向反应体系中加入10mL水和100mL乙酸乙酯，有机相用50mL水洗涤三次和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1)，得31d(0.08g，产率：74％)。In a 50mL reaction bottle, dissolve 31c (0.12g, 0.35mmol) in anhydrous tetrahydrofuran (5mL), and add Lithium aluminum hydride (0.02g, 0.53mmol) was used to react at 0°C for 3 hours. Add 10 mL water and 100 mL ethyl acetate to the reaction system, wash the organic phase three times with 50 mL water and 30 mL saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v)=5:1) to obtain 31d (0.08g, yield: 74%).
LCMS m/z＝311.0[M+1]+ LCMS m/z＝311.0[M+1] +
第四步：31e的制备Step 4: Preparation of 31e
在50mL反应瓶中，将31d(0.08g，0.26mmol)溶于二氯甲烷(5mL)，0℃下加入氯化亚砜(0.093g，0.78mmol)，0℃反应1h。将反应液减压浓缩，得到粗品31e(0.085g)。In a 50 mL reaction bottle, dissolve 31d (0.08g, 0.26mmol) in dichloromethane (5mL), add thionyl chloride (0.093g, 0.78mmol) at 0°C, and react at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude product 31e (0.085g).
第五步：化合物31的制备Step 5: Preparation of Compound 31
在50mL反应瓶中，依次加入7c(0.10g，0.248mmol)、碳酸铯(0.17g，0.52mmol)、DMF(5mL)，滴加上述粗品31e(0.085g)，25℃下反应2h。向反应体系中加入10mL水和100mL乙酸乙酯，有机相用50mL水洗涤三次和30mL饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)，得到化合物31(0.03g，产率：17％)。In a 50mL reaction bottle, add 7c (0.10g, 0.248mmol), cesium carbonate (0.17g, 0.52mmol), and DMF (5mL) in sequence, add the above crude product 31e (0.085g) dropwise, and react at 25°C for 2 hours. Add 10 mL water and 100 mL ethyl acetate to the reaction system, wash the organic phase three times with 50 mL water and 30 mL saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v)=1:1) to obtain compound 31 (0.03g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.10–7.47(m,7H),6.84–6.78(m,1H),6.61–6.52(m,1H),5.35–4.85(m,3H),4.44–4.30(m,2H),4.14–4.02(m,2H),3.90–3.75(m,1H),3.10–2.66(m,3H),2.20–2.04(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.10–7.47(m,7H),6.84–6.78(m,1H),6.61–6.52(m,1H),5.35–4.85(m,3H),4.44–4.30 (m,2H),4.14–4.02(m,2H),3.90–3.75(m,1H),3.10–2.66(m,3H),2.20–2.04(m,1H).
LCMS m/z＝696.1[M+1]+ LCMS m/z＝696.1[M+1] +
实施例32：化合物32的三氟乙酸盐的制备
Example 32: Preparation of trifluoroacetate salt of compound 32
化合物32的三氟乙酸盐以化合物32a和32A为原料，参照实施例23的合成方法，经酸性制备(乙腈/水(含0.1％TFA))冻干得到。The trifluoroacetate salt of compound 32 was prepared by acidic preparation (acetonitrile/water (containing 0.1% TFA)) by freeze-drying using compounds 32a and 32A as raw materials, referring to the synthesis method of Example 23.
’1H NMR(400MHz,CDCl3)δ7.99(s,2H),7.84(d,1H),7.79(s,1H),7.75–7.64(m,3H),7.55(dd,1H),7.47(dd,1H),7.04(d,1H),6.87–6.79(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.32(m,2H),4.17–4.05(m,2H),3.93–3.77(m,1H),3.00–2.64(m,3H),2.20–2.06(m,1H),1.53(s,6H).' 1 H NMR (400MHz, CDCl 3 ) δ7.99(s,2H),7.84(d,1H),7.79(s,1H),7.75–7.64(m,3H),7.55(dd,1H),7.47 (dd,1H),7.04(d,1H),6.87–6.79(m,1H),6.57(dd,1H),5.00–4.89(m,1H),4.45–4.32(m,2H),4.17–4.05 (m,2H),3.93–3.77(m,1H),3.00–2.64(m,3H),2.20–2.06(m,1H),1.53(s,6H).
实施例33：化合物33的制备
Example 33: Preparation of Compound 33
第一步：33a的制备Step 1: Preparation of 33a
将33A(4.0g,20.15mmol)、33B(3.91g,20.16mmol)和碳酸钾(2.78g，20.12mmol)加入到20mL DMSO中，100℃反应16h。将反应体系冷却至室温，加入到100mL乙酸乙酯，有机相用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:0-10:1)，得到33a(7.51g，收率：>99％)。Add 33A (4.0g, 20.15mmol), 33B (3.91g, 20.16mmol) and potassium carbonate (2.78g, 20.12mmol) to 20mL DMSO and react at 100°C for 16h. The reaction system was cooled to room temperature, and 100 mL of ethyl acetate was added. The organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=1:0-10:1), 33a (7.51g, yield: >99%) was obtained.
第二步：33b的制备Step 2: Preparation of 33b
将33a(1.0g，2.68mmol)和N-Boc-4-氨基苯硼酸频哪醇酯(CAS:330793-01-6)(0.86g，2.69mmol)加入到反应瓶中，氮气保护下加入10mL DME和3mL水，加入Pd(PPh3)4(62mg,0.054mmol)和Cs2CO3(2.18g,6.69mmol)，置换氮气三次，90℃微波反应4h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到33b(0.8g，收率：68％)。Add 33a (1.0g, 2.68mmol) and N-Boc-4-aminophenylboronic acid pinacol ester (CAS: 330793-01-6) (0.86g, 2.69mmol) into the reaction bottle, and add 10mL under nitrogen protection. DME and 3mL water, add Pd(PPh 3 ) 4 (62mg, 0.054mmol) and Cs 2 CO 3 (2.18g, 6.69mmol), replace nitrogen three times, and react under microwave at 90°C for 4h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v /v)=1:0-1:2) to obtain 33b (0.8g, yield: 68%).
LCMS m/z＝438.2[M+1]+ LCMS m/z＝438.2[M+1] +
第三步：33c的制备Step 3: Preparation of 33c
将33b(0.8g，1.83mmol)溶于10mL二氯甲烷和5mL三氟乙酸中，室温反应6h。将反应体系减压浓缩，加入50mL乙酸乙酯，用50mL饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到33c(0.4g，收率：65％)。Dissolve 33b (0.8g, 1.83mmol) in 10mL dichloromethane and 5mL trifluoroacetic acid, and react at room temperature for 6h. The reaction system was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with 50 mL of saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=1:0-1:2), 33c (0.4g, yield: 65%) was obtained.
第四步：33d的制备Step 4: Preparation of 33d
将33c(0.4g，1.18mmol)加入到5mL水中，缓慢加入浓硫酸(0.8mL)，60℃反应1h。将反应体系冷却至0℃，滴加5mL亚硝酸钠(0.081g，1.17mmol)的水溶液，5℃反应30min后，于40℃下滴加2mL KI(0.39g，2.35mmol)的水溶液，50℃反应1h。将反应体系冷却到室温，用乙酸乙酯萃取(50mL×3)，有机相用50mL 1mol/L盐酸水溶液和50mL饱和硫代硫酸钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-2:1)，得到33d(0.2g，收率：38％)。Add 33c (0.4g, 1.18mmol) to 5mL of water, slowly add concentrated sulfuric acid (0.8mL), and react at 60°C for 1 hour. Cool the reaction system to 0°C, add dropwise an aqueous solution of 5mL sodium nitrite (0.081g, 1.17mmol), react at 5°C for 30 minutes, then add 2mL of an aqueous solution of KI (0.39g, 2.35mmol) dropwise at 40°C, 50°C Reaction 1h. Cool the reaction system to room temperature, extract with ethyl acetate (50mL Chromatographic column separation and purification (petroleum ether/ethyl acetate (v/v) = 1:0-2:1) was performed to obtain 33d (0.2g, yield: 38%).
LCMS m/z＝449.3[M+1]+ LCMS m/z＝449.3[M+1] +
第五步：化合物33的制备Step 5: Preparation of compound 33
将33d(0.05g，0.11mmol)、上述粗品中间体1(0.056g)、TEA(0.067g，0.66mmol)、CuI(4.2mg，0.022mmol)和PdCl2(PPh3)2(7.7mg，0.011mmol)加入到反应瓶中，在氮气保护下加入2mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得化合物33(0.03g，收率：42％)。 33d (0.05g, 0.11mmol), the above crude intermediate 1 (0.056g), TEA (0.067g, 0.66mmol), CuI (4.2mg, 0.022mmol) and PdCl 2 (PPh 3 ) 2 (7.7mg, 0.011 mmol) into the reaction bottle, add 2 mL DMF under nitrogen protection, and react at 55°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/dichloromethane/ Ethyl acetate (v/v)=1:1:2) to obtain compound 33 (0.03g, yield: 42%).
1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.05(s,1H),7.94(s,1H),7.88–7.79(m,2H),7.73–7.63(m,2H),7.55–7.42(m,4H),6.83(d,1H),6.58(dd,1H),4.98–4.89(m,1H),4.45–4.35(m,2H),4.17–4.07(m,2H),3.94–3.82(m,1H),2.97–2.65(m,3H),2.20–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.25(s,1H),8.05(s,1H),7.94(s,1H),7.88–7.79(m,2H),7.73–7.63(m,2H), 7.55–7.42(m,4H),6.83(d,1H),6.58(dd,1H),4.98–4.89(m,1H),4.45–4.35(m,2H),4.17–4.07(m,2H), 3.94–3.82(m,1H),2.97–2.65(m,3H),2.20–2.06(m,1H).
LCMS m/z＝658.1[M+1]+ LCMS m/z＝658.1[M+1] +
实施例34：化合物34的制备
Example 34: Preparation of Compound 34
第一步：34b的制备Step 1: Preparation of 34b
将34a(0.2g，0.904mmol)(合成方法见WO2018066545)溶于2mL DMF中，室温下加入60％氢化钠(5.3mg)，室温反应15min后，加入4-碘苄基溴(0.32g，1.08mmol)，室温反应2h。将反应体系加入到50mL乙酸乙酯中，用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到34b(0.2g，收率：51％)。Dissolve 34a (0.2g, 0.904mmol) (see WO2018066545 for synthesis method) in 2mL DMF, add 60% sodium hydride (5.3mg) at room temperature, react at room temperature for 15min, then add 4-iodobenzyl bromide (0.32g, 1.08 mmol), react at room temperature for 2 h. The reaction system was added to 50 mL of ethyl acetate, washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-1:2) to obtain 34b (0.2g, yield: 51%).
第二步：化合物34的制备Step 2: Preparation of Compound 34
将34b(0.2g，0.46mmol)、上述粗品中间体1(0.23g)、TEA(0.28g，2.77mmol)、CuI(18mg，0.095mmol)和PdCl2(PPh3)2(32mg，0.046mmol)加入到反应瓶中，在氮气保护下加入2mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2，得到化合物34(0.05g，收率：17％)。34b (0.2g, 0.46mmol), the above crude intermediate 1 (0.23g), TEA (0.28g, 2.77mmol), CuI (18mg, 0.095mmol) and PdCl 2 (PPh 3 ) 2 (32mg, 0.046mmol) Add it to the reaction bottle, add 2 mL DMF under nitrogen protection, and react at 55°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/dichloromethane/ Ethyl acetate (v/v)=1:1:2 to obtain compound 34 (0.05g, yield: 17%).
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.76–7.62(m,3H),7.56–7.48(m,2H),7.46–7.36(m,2H),6.88(d,2H),6.82(d,1H),6.56(dd,1H),5.10(s,2H),4.99–4.87(m,1H),4.43–4.33(m,2H),4.16–4.05(m,2H),3.92–3.77(m,1H),2.97–2.65(m,3H),2.36(s,3H),2.24–2.06(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.92(s,1H),7.76–7.62(m,3H),7.56–7.48(m,2H),7.46–7.36(m,2H),6.88(d,2H ),6.82(d,1H),6.56(dd,1H),5.10(s,2H),4.99–4.87(m,1H),4.43–4.33(m,2H),4.16–4.05(m,2H), 3.92–3.77(m,1H),2.97–2.65(m,3H),2.36(s,3H),2.24–2.06(m,4H).
实施例35：化合物35的制备
Example 35: Preparation of Compound 35
第一步：35b的制备Step One: Preparation of 35b
在25mL反应瓶中，依次加入35A(0.18g，0.86mmol)、35a(0.21g，0.84mmol)(合成方法见WO2020211822)和1,2-二氯乙烷(6mL)，室温搅拌5min后，加入三乙酰氧基硼氢化钠(0.27g，1.27mmol)，室温反应16h。向反应液中加入30mL乙酸乙酯和10mL饱和碳酸氢钠水溶液，有机相用饱和氯化钠水溶液洗涤(20mL)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(乙酸乙酯/石油醚(v/v)＝1:20-1:4)，得到35b(0.16g，产率：43％)。In a 25mL reaction bottle, add 35A (0.18g, 0.86mmol), 35a (0.21g, 0.84mmol) (see WO2020211822 for synthesis method) and 1,2-dichloroethane (6mL) in sequence, stir at room temperature for 5 minutes, and then add Sodium triacetoxyborohydride (0.27g, 1.27mmol), react at room temperature for 16h. Add 30 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, wash the organic phase with saturated aqueous sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (ethyl acetate). Ester/petroleum ether (v/v)=1:20-1:4), 35b (0.16g, yield: 43%) was obtained.
第二步：化合物35的制备Step 2: Preparation of Compound 35
在25mL反应瓶中，依次加入35b(66.24mg，0.15mmol)、上述粗品中间体1(50mg)、PdCl2(PPh3)2(10.53mg，0.015mmol)、CuI(5.71mg，0.030mmol)、TEA(91.07mg，0.90mmol)和DMF(5mL)，氮气保护下55℃反应1h。将反应液冷却至室温，加入20mL乙酸乙酯和10mL水，有机相用饱和氯化钠水溶液洗涤(10mL)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离 提纯(乙酸乙酯/石油醚(v/v)＝1:10-1:1)，所得粗品再用prep-TLC分离纯化(乙酸乙酯/石油醚(v/v)＝2:1)，得到化合物35(0.015g，产率：15％)。In a 25mL reaction bottle, add 35b (66.24mg, 0.15mmol), the above crude intermediate 1 (50mg), PdCl 2 (PPh 3 ) 2 (10.53mg, 0.015mmol), CuI (5.71mg, 0.030mmol), and TEA (91.07 mg, 0.90 mmol) and DMF (5 mL) were reacted at 55°C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate and 10 mL of water were added, the organic phase was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated on a silica gel chromatography column. Purify (ethyl acetate/petroleum ether (v/v)=1:10-1:1), and the crude product is separated and purified by prep-TLC (ethyl acetate/petroleum ether (v/v)=2:1), Compound 35 was obtained (0.015 g, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.74–7.48(m,6H),6.85–6.77(m,1H),6.56(dd,1H),5.04–4.88(m,2H),4.44–4.27(m,2H),4.14–4.02(m,2H),3.99–3.75(m,5H),3.73–3.57(m,2H),2.97–2.63(m,3H),2.20–2.06(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.11(s,1H),7.74–7.48(m,6H),6.85–6.77(m,1H),6.56(dd,1H),5.04–4.88(m,2H ),4.44–4.27(m,2H),4.14–4.02(m,2H),3.99–3.75(m,5H),3.73–3.57(m,2H),2.97–2.63(m,3H),2.20–2.06 (m,1H).
实施例36：化合物36的制备
Example 36: Preparation of Compound 36
第一步：36B的制备Step One: Preparation of 36B
在氮气保护下将36A(2.0g，15.4mmol)加入到100mL三口瓶中，加入干燥二氯甲烷(40mL)，加入三乙胺(3.1g，30.64mmol)，冷却至0℃，缓慢加入甲磺酰氯(2.1g，18.33mmol)，室温反应16h。向反应体系中加入二氯甲烷(30mL)，加入饱和碳酸氢钠水溶液(10mL)，分离出有机相，有机相用饱和碳酸氢钠洗涤(100mL×2)、水洗涤(800mL×2)和饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，得到粗品36B(2.7g)。Under nitrogen protection, add 36A (2.0g, 15.4mmol) into a 100mL three-necked flask, add dry dichloromethane (40mL), add triethylamine (3.1g, 30.64mmol), cool to 0°C, and slowly add methanesulfonate Acid chloride (2.1g, 18.33mmol), reacted at room temperature for 16h. Add dichloromethane (30mL) to the reaction system, add saturated sodium bicarbonate aqueous solution (10mL), separate the organic phase, wash the organic phase with saturated sodium bicarbonate (100mL×2), water (800mL×2) and saturated Wash with sodium chloride aqueous solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 36B (2.7 g).
LCMS m/z＝209.1[M+1]+ LCMS m/z＝209.1[M+1] +
第二步：36b和36b′的制备Step 2: Preparation of 36b and 36b′
将上述粗品36B(1.0g)和碳酸钾(1.24g，8.97mmol)加入到100mL单口瓶中，加入干燥DMF(15mL)，加入36a(0.87g，4.48mmol)，85℃反应16h。将反应体系冷却至室温，缓慢倾倒入水(200mL)中，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝89:11)，分别得36b(0.46g，收率：33％)和36b′(0.33g，收率：24％)。Add the above crude product 36B (1.0g) and potassium carbonate (1.24g, 8.97mmol) into a 100mL single-neck bottle, add dry DMF (15mL), add 36a (0.87g, 4.48mmol), and react at 85°C for 16h. The reaction system was cooled to room temperature, slowly poured into water (200 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 89:11) to obtain 36b (0.46g, yield: 33%) and 36b′ (0.33g, yield: 24 %).
36b和36b′分别为结构36b-A或36b-B的其中一个异构体。36b and 36b′ are respectively one of the isomers of structure 36b-A or 36b-B.
第三步：36c的制备 Step 3: Preparation of 36c
将36b(0.46g，1.5mmol)溶于四氢呋喃(12mL)和水(3mL)的混合溶剂中，加入一水合氢氧化锂(315mg，7.51mmol)，室温反应16h。将反应体系用0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(40mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝42:58)，得粗品(0.31g)。将上述粗品(310mg)加入到50mL单口瓶中，加入干燥二氯甲烷(20mL)，加入1-氯-N,N,2-三甲基丙烯胺(213mg，1.59mmol)，室温反应1h后，依次加入三乙胺(321mg，3.17mmol)和2-氯-4-(三氟甲基)苯胺(206mg，1.05mmol)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得36c(200mg，收率：41％)。Dissolve 36b (0.46g, 1.5mmol) in a mixed solvent of tetrahydrofuran (12mL) and water (3mL), add lithium hydroxide monohydrate (315mg, 7.51mmol), and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid solution, extract with ethyl acetate (40 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 42:58) to obtain the crude product (0.31g). Add the above crude product (310mg) to a 50mL single-neck bottle, add dry dichloromethane (20mL), add 1-chloro-N,N,2-trimethylpropenylamine (213mg, 1.59mmol), and react at room temperature for 1 hour. Triethylamine (321 mg, 3.17 mmol) and 2-chloro-4-(trifluoromethyl)aniline (206 mg, 1.05 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=87:13) to obtain 36c (200 mg, yield: 41%).
LCMS m/z＝470.1[M+1]+ LCMS m/z＝470.1[M+1] +
36c为结构36c-A或36c-B的其中一个异构体。36c is one of the isomers of structure 36c-A or 36c-B.
第四步：36d的制备Step 4: Preparation of 36d
将36c(200mg，0.43mmol)加入到50mL单口瓶中，加入干燥四氢呋喃(4mL)，置换氮气三次，加入1mol/L硼烷的四氢呋喃溶液(0.86mL)，室温反应16h。向反应体系中加入10mL甲醇，加入0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(20mL×3)，有机相用饱和氯化钠水溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝42:58)，得36d(0.1g，收率：51％)。Add 36c (200 mg, 0.43 mmol) into a 50 mL single-neck bottle, add dry tetrahydrofuran (4 mL), replace nitrogen three times, add 1 mol/L borane solution in tetrahydrofuran (0.86 mL), and react at room temperature for 16 h. Add 10 mL methanol to the reaction system, add 0.5 mol/L hydrochloric acid solution to adjust the pH to 5, extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 2), and anhydrous sodium sulfate. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=42:58) to obtain 36d (0.1g, yield: 51%).
LCMS m/z＝456.1[M+1]+ LCMS m/z＝456.1[M+1] +
36d为结构36d-A或36d-B的其中一个异构体。36d is one of the isomers of structure 36d-A or 36d-B.
第五步：化合物36的制备Step 5: Preparation of compound 36
将36d(100mg，0.22mmol)加入到50mL单口瓶中，加入干燥DMF(10mL)，加入上述粗品中间体1(110mg)、三乙胺(66mg，0.65mmol)，置换氮气三次，加入PdCl2(PPh3)2(16mg，0.023mmol)和CuI(7mg，0.037mmol)，置换氮气三次，60℃反应3h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(80mL)，用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝22:78)，得化合物36(70mg，收率：48％)。Add 36d (100 mg, 0.22 mmol) into a 50 mL single-neck bottle, add dry DMF (10 mL), add the above crude intermediate 1 (110 mg), triethylamine (66 mg, 0.65 mmol), replace nitrogen three times, and add PdCl 2 ( PPh 3 ) 2 (16 mg, 0.023 mmol) and CuI (7 mg, 0.037 mmol) were replaced with nitrogen three times and reacted at 60°C for 3 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (80mL), extract with ethyl acetate (60mL×3), wash the organic phase with saturated aqueous sodium chloride solution (50mL×2), and dry over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 22:78) to obtain compound 36 (70 mg, yield: 48%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.75–7.63(m,1H),7.60(s,1H),7.53–7.47(m,2H),7.42–7.33(m,1H),6.80(d,1H),6.66(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.75–4.57(m,2H),4.41–4.30(m,2H),4.12–4.01(m,2H),3.88–3.75(m,1H),3.37(t,2H),2.99–2.63(m,5H),2.58–2.28(m,3H),2.20–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.75–7.63(m,1H),7.60(s,1H),7.53–7.47(m,2H),7.42–7.33(m,1H ),6.80(d,1H),6.66(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.75–4.57(m,2H),4.41–4.30(m,2H), 4.12–4.01(m,2H),3.88–3.75(m,1H),3.37(t,2H),2.99–2.63(m,5H),2.58–2.28(m,3H),2.20–2.07(m,1H ).
LCMS m/z＝665.1[M+1]+ LCMS m/z＝665.1[M+1] +
化合物36为结构36-A或36-B的其中一个异构体。Compound 36 is one of the isomers of structure 36-A or 36-B.
实施例37：化合物37的制备
Example 37: Preparation of Compound 37
第一步：37c的制备Step One: Preparation of 37c
将36b′(0.33g，1.08mmol)溶于四氢呋喃(12mL)和水(3mL)的混合溶剂中，加入一水合氢氧化锂(226.8mg，5.41mmol)，室温反应16h。将反应体系用0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(40mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝42:58)，得粗品(0.22g)。将上述粗品(220mg)加入到50mL单口瓶中，加入干燥二氯甲烷(20mL)，加入1-氯-N,N,2-三甲基丙烯胺(151mg，1.13mmol)，室温反应1h后，依次加入三乙胺(228mg，2.25mmol)和2-氯-4-(三氟甲基)苯胺(147mg，0.75mmol)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得37a(110mg，收率：31％)。Dissolve 36b' (0.33g, 1.08mmol) in a mixed solvent of tetrahydrofuran (12mL) and water (3mL), add lithium hydroxide monohydrate (226.8mg, 5.41mmol), and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid solution, extract with ethyl acetate (40 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 42:58) to obtain the crude product (0.22g). Add the above crude product (220mg) to a 50mL single-neck bottle, add dry dichloromethane (20mL), add 1-chloro-N,N,2-trimethylpropenylamine (151mg, 1.13mmol), and react at room temperature for 1 hour. Triethylamine (228 mg, 2.25 mmol) and 2-chloro-4-(trifluoromethyl)aniline (147 mg, 0.75 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 87:13) to obtain 37a (110 mg, yield: 31%).
LCMS m/z＝470.1[M+1]+ LCMS m/z＝470.1[M+1] +
37a为结构36c-A或36c-B的其中一个异构体。37a is one of the isomers of structure 36c-A or 36c-B.
第二步：37b的制备Step 2: Preparation of 37b
将37a(110mg，0.23mmol)加入到50mL单口瓶中，加入干燥四氢呋喃(4mL)，置换氮气三次，加入1mol/L硼烷四氢呋喃溶液(0.47mL)，室温反应16h。向反应体系中加入8mL甲醇，加入0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(20mL×3)，有机相用饱和氯化钠水溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝42:58)，得37b(0.017g，收率：16％)。Add 37a (110 mg, 0.23 mmol) into a 50 mL single-neck bottle, add dry tetrahydrofuran (4 mL), replace nitrogen three times, add 1 mol/L borane tetrahydrofuran solution (0.47 mL), and react at room temperature for 16 h. Add 8 mL methanol to the reaction system, add 0.5 mol/L hydrochloric acid solution to adjust the pH to 5, extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 2), and anhydrous sodium sulfate. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=42:58) to obtain 37b (0.017g, yield: 16%).
LCMS m/z＝456.1[M+1]+ LCMS m/z＝456.1[M+1] +
37b为结构36d-A或36d-B的其中一个异构体。37b is one of the isomers of structure 36d-A or 36d-B.
第三步：化合物37的制备Step 3: Preparation of Compound 37
将37b(17mg，0.037mmol)加入到50mL单口瓶中，加入干燥DMF(5mL)，加入上述粗品中间体1(19mg)、三乙胺(11mg，0.11mmol)，置换氮气三次，加入PdCl2(PPh3)2(3mg，0.0043mmol)和CuI(2mg，0.0105mmol)，置换氮气三次，60℃反应3h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(50mL)，用乙酸乙酯萃取(30mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝22:78)，得化合物37(5mg，收率：20％)。 Add 37b (17 mg, 0.037 mmol) into a 50 mL single-neck bottle, add dry DMF (5 mL), add the above crude intermediate 1 (19 mg), triethylamine (11 mg, 0.11 mmol), replace nitrogen three times, and add PdCl 2 ( PPh 3 ) 2 (3 mg, 0.0043 mmol) and CuI (2 mg, 0.0105 mmol) were replaced with nitrogen three times and reacted at 60°C for 3 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (50mL), extract with ethyl acetate (30mL×3), wash the organic phase with saturated aqueous sodium chloride solution (30mL×2), and dry over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=22:78) to obtain compound 37 (5 mg, yield: 20%).
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.67(d,1H),7.61(s,1H),7.56–7.48(m,2H),7.39(dd,1H),6.80(d,1H),6.69(d,1H),6.55(dd,1H),4.98–4.80(m,2H),4.61(br.s,1H),4.40–4.30(m,2H),4.12–4.02(m,2H),3.86–3.74(m,1H),3.38(d,2H),2.98–2.62(m,6H),2.50–2.31(m,2H),2.20–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.99(s,1H),7.67(d,1H),7.61(s,1H),7.56–7.48(m,2H),7.39(dd,1H),6.80( d,1H),6.69(d,1H),6.55(dd,1H),4.98–4.80(m,2H),4.61(br.s,1H),4.40–4.30(m,2H),4.12–4.02( m,2H),3.86–3.74(m,1H),3.38(d,2H),2.98–2.62(m,6H),2.50–2.31(m,2H),2.20–2.07(m,1H).
LCMS m/z＝665.1[M+1]+ LCMS m/z＝665.1[M+1] +
化合物37为结构36-A或36-B的其中一个异构体。Compound 37 is one of the isomers of structure 36-A or 36-B.
实施例38：化合物38的制备
Example 38: Preparation of Compound 38
第一步：38b的制备Step 1: Preparation of 38b
将38a(2.0g，9.66mmol)和碳酸钾(4g，28.94mmol)加入到100mL单口瓶中，加入干燥DMF(30mL)，加入38A(1.89g，9.74mmol)，85℃反应16h。将反应体系冷却至室温，缓慢倾倒入水(300mL)中，用乙酸乙酯萃取(80mL×3)，有机相用饱和氯化钠水溶液洗涤(80mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝92:8)，得38b(0.7g，收率：23％)，Add 38a (2.0g, 9.66mmol) and potassium carbonate (4g, 28.94mmol) into a 100mL single-neck bottle, add dry DMF (30mL), add 38A (1.89g, 9.74mmol), and react at 85°C for 16h. The reaction system was cooled to room temperature, slowly poured into water (300 mL), extracted with ethyl acetate (80 mL × 3), the organic phase was washed with saturated aqueous sodium chloride solution (80 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 92:8) to obtain 38b (0.7g, yield: 23%),
LCMS m/z＝321.1[M+1]+ LCMS m/z＝321.1[M+1] +
第二步：38c的制备Step 2: Preparation of 38c
将38b(0.7g，2.19mmol)溶于四氢呋喃(16mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(460mg，10.96mmol)，室温反应16h。将反应体系用0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝47:53)，得粗品(0.51g)。将上述粗品(300mg)加入到50mL单口瓶中，加入干燥二氯甲烷(10mL)，依次加入N,N,N'’N'’四甲基氯甲脒六氟磷酸盐(428mg，1.53mmol)和2-氯-4-(三氟甲基)苯胺(199mg，1.02mmol)，加入N-甲基咪唑(418mg，5.09mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝89:11)，得38c(200mg，收率：42％)。Dissolve 38b (0.7g, 2.19mmol) in a mixed solvent of tetrahydrofuran (16mL) and water (4mL), add lithium hydroxide monohydrate (460mg, 10.96mmol), and react at room temperature for 16h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid solution, extract with ethyl acetate (60 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 47:53) to obtain the crude product (0.51g). Add the above crude product (300mg) to a 50mL single-neck bottle, add dry dichloromethane (10mL), and add N, N, N''N'' tetramethylchloroformamidine hexafluorophosphate (428mg, 1.53mmol) in sequence. and 2-chloro-4-(trifluoromethyl)aniline (199 mg, 1.02 mmol), add N-methylimidazole (418 mg, 5.09 mmol), and react at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 89:11) to obtain 38c (200 mg, yield: 42%).
LCMS m/z＝470.1[M+1]+ LCMS m/z＝470.1[M+1] +
第三步：38d的制备Step 3: Preparation of 38d
将38c(200mg，0.43mmol)加入到50mL单口瓶中，加入干燥四氢呋喃(4mL)，置换氮气三次，加入1mol/L硼烷四氢呋喃溶液(0.86mL)，室温反应16h。向反应体系中加入5mL甲醇，加入0.5mol/L盐酸溶液调pH至5，用乙酸乙酯萃取(20mL×3)，有机相用饱和氯化钠水溶液洗涤(20mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝42:58)，得38d(80mg，收率：41％)。 Add 38c (200 mg, 0.43 mmol) into a 50 mL single-neck bottle, add dry tetrahydrofuran (4 mL), replace nitrogen three times, add 1 mol/L borane tetrahydrofuran solution (0.86 mL), and react at room temperature for 16 h. Add 5 mL methanol to the reaction system, add 0.5 mol/L hydrochloric acid solution to adjust the pH to 5, extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated sodium chloride aqueous solution (20 mL × 2), and anhydrous sodium sulfate. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=42:58) to obtain 38d (80 mg, yield: 41%).
LCMS m/z＝456.1[M+1]+ LCMS m/z＝456.1[M+1] +
第四步：化合物38的制备Step 4: Preparation of compound 38
将38d(80mg，0.176mmol)加入到50mL单口瓶中，加入干燥DMF(10mL)，加入上述粗品中间体1(91mg)和三乙胺(55mg，0.54mmol)，置换氮气三次，加入PdCl2(PPh3)2(13mg，0.0185mmol)和CuI(6mg，0.0315mmol)，置换氮气三次，60℃反应2h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(80mL)，用乙酸乙酯萃取(60mL×3)，有机相用饱和氯化钠水溶液洗涤(50mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝31:69)，得化合物38(50mg，收率：43％)。Add 38d (80 mg, 0.176 mmol) into a 50 mL single-neck bottle, add dry DMF (10 mL), add the above crude intermediate 1 (91 mg) and triethylamine (55 mg, 0.54 mmol), replace nitrogen three times, and add PdCl 2 ( PPh 3 ) 2 (13 mg, 0.0185 mmol) and CuI (6 mg, 0.0315 mmol) were replaced with nitrogen three times and reacted at 60°C for 2 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (80mL), extract with ethyl acetate (60mL×3), wash the organic phase with saturated aqueous sodium chloride solution (50mL×2), and dry over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 31:69) to obtain compound 38 (50 mg, yield: 43%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.70–7.64(m,1H),7.61(s,1H),7.53–7.45(m,2H),7.38–7.31(m,1H),6.81(d,1H),6.63–6.52(m,2H),4.98–4.89(m,1H),4.52–4.30(m,3H),4.12–4.00(m,2H),3.88–3.75(m,1H),3.44–3.32(m,1H),3.32–3.20(m,1H),3.16–3.01(m,1H),2.96–2.65(m,3H),2.57–2.30(m,2H),2.23–2.07(m,2H),1.80–1.62(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.70–7.64(m,1H),7.61(s,1H),7.53–7.45(m,2H),7.38–7.31(m,1H) ),6.81(d,1H),6.63–6.52(m,2H),4.98–4.89(m,1H),4.52–4.30(m,3H),4.12–4.00(m,2H),3.88–3.75(m ,1H),3.44–3.32(m,1H),3.32–3.20(m,1H),3.16–3.01(m,1H),2.96–2.65(m,3H),2.57–2.30(m,2H),2.23 –2.07(m,2H),1.80–1.62(m,1H).
LCMS m/z＝665.1[M+1]+ LCMS m/z＝665.1[M+1] +
实施例39：化合物39的制备
Example 39: Preparation of Compound 39
化合物39以化合物33a和3-(Boc-氨基)苯硼酸频哪酯为原料，参照实施例33的合成方法得到。Compound 39 was obtained by referring to the synthesis method of Example 33 using compound 33a and 3-(Boc-amino)phenylboronic acid pinacol ester as raw materials.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.04(s,1H),7.94(s,1H),7.87–7.79(m,2H),7.74–7.59(m,3H),7.55–7.47(m,1H),7.41–7.32(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.88(m,1H),4.46–4.32(m,2H),4.20–4.08(m,2H),3.94–3.80(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.25(s,1H),8.04(s,1H),7.94(s,1H),7.87–7.79(m,2H),7.74–7.59(m,3H), 7.55–7.47(m,1H),7.41–7.32(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.88(m,1H),4.46–4.32(m,2H), 4.20–4.08(m,2H),3.94–3.80(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H).
LCMS m/z＝658.2[M+1]+ LCMS m/z＝658.2[M+1] +
实施例40：化合物40的制备
Example 40: Preparation of Compound 40
第一步：40b的制备Step One: Preparation of 40b
将40a(1g，8.61mmol)溶于二甲基亚砜(20mL)中，冷却至0℃，加入60％氢化钠(62mg)，室温反应1h。将反应体系冷却至0℃，加入2-氯-1-氟-4-(三氟甲基)苯(1.7g，8.56mmol)，室温 反应2h。加入水(200mL)，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(40mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝74:26)，得40b(360mg，收率：14％)。Dissolve 40a (1g, 8.61mmol) in dimethyl sulfoxide (20mL), cool to 0°C, add 60% sodium hydride (62mg), and react at room temperature for 1 hour. Cool the reaction system to 0°C, add 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (1.7g, 8.56mmol), and keep at room temperature. Reaction 2h. Add water (200 mL), extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (40 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v) = 74:26) to obtain 40b (360 mg, yield: 14%).
LCMS m/z＝295.1[M+1]+ LCMS m/z＝295.1[M+1] +
第二步：40c的制备Step 2: Preparation of 40c
将40b(360mg，1.22mmol)加入到100mL单口瓶中，加入干燥二氯甲烷(20mL)，加入三乙胺(360mg，3.56mmol)，冷却至0℃，缓慢滴加甲磺酰氯(205mg，1.79mmol)，室温反应2h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝90:10)，得40c(0.31g，收率：68％)。Add 40b (360mg, 1.22mmol) into a 100mL single-mouth bottle, add dry dichloromethane (20mL), add triethylamine (360mg, 3.56mmol), cool to 0°C, slowly add methanesulfonyl chloride (205mg, 1.79 mmol), react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=90:10) to obtain 40c (0.31g, yield: 68%).
LCMS m/z＝373.1[M+1]+ LCMS m/z＝373.1[M+1] +
第三步：40d的制备Step 3: Preparation of 40d
将40c(310mg，0.83mmol)加入到100mL单口瓶中，加入干燥DMF(10mL)，加入碳酸钾(345mg，2.5mmol)，加入4-碘-1H-吡唑(161mg，0.83mmol)，85℃反应16h。将反应体系冷却至室温，加入到水(120mL)中，用乙酸乙酯萃取(30mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得40d(0.31g，收率：79％)。Add 40c (310mg, 0.83mmol) to a 100mL single-neck bottle, add dry DMF (10mL), add potassium carbonate (345mg, 2.5mmol), add 4-iodo-1H-pyrazole (161mg, 0.83mmol), 85°C Reaction 16h. The reaction system was cooled to room temperature, added to water (120 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 87:13) to obtain 40d (0.31g, yield: 79%).
LCMS m/z＝471.1[M+1]+ LCMS m/z＝471.1[M+1] +
40d为结构40d-A或40d-B的其中一个异构体。40d is one of the isomers of structure 40d-A or 40d-B.
第四步：化合物40的制备Step 4: Preparation of Compound 40
将40d(130mg，0.277mmol)加入到50mL单口瓶中，加入干燥DMF(10mL)，加入上述粗品中间体1(136mg)、三乙胺(52mg，0.51mmol)，置换氮气三次，加入PdCl2(PPh3)2(19mg，0.027mmol)和CuI(8mg，0.042mmol)，置换氮气三次，60℃反应3h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(50mL)，用乙酸乙酯萃取(40mL×3)，有机相用饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝28:72)，所得粗品用Prep-HPLC制备(仪器:waters 2767制备液相；色谱柱:SunFire@PrepC18(19×250nm)；流动相A：乙腈；流动相B：水(含5mmol/L氨水)；梯度洗脱：流动相A含量从40-90％；流速：12mL/min；柱温：室温；检测波长：210nm；样品用DMF溶解，用0.45um滤头过滤，制成样品液；洗脱时间：15min)，冻干得到化合物40(30mg，收率：16％)。Add 40d (130mg, 0.277mmol) into a 50mL single-neck bottle, add dry DMF (10mL), add the above crude intermediate 1 (136mg), triethylamine (52mg, 0.51mmol), replace nitrogen three times, add PdCl 2 ( PPh 3 ) 2 (19 mg, 0.027 mmol) and CuI (8 mg, 0.042 mmol) were replaced with nitrogen three times and reacted at 60°C for 3 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (50mL), extract with ethyl acetate (40mL×3), wash the organic phase with saturated aqueous sodium chloride solution (30mL×2), and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 28:72). The crude product is prepared by Prep-HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: SunFire@ PrepC18 (19×250nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5mmol/L ammonia); gradient elution: mobile phase A content from 40-90%; flow rate: 12mL/min; column temperature: room temperature ; Detection wavelength: 210nm; Dissolve the sample with DMF and filter it with a 0.45um filter to make a sample solution; elution time: 15min), freeze-dry to obtain compound 40 (30mg, yield: 16%).
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.72–7.53(m,4H),7.48(dd,1H),7.01(d,1H),6.81(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.80–4.70(m,1H),4.42–4.18(m,3H),4.14–4.01(m,2H),3.90–3.73(m,1H),2.95–2.64(m,3H),2.32–1.98(m,7H),1.85–1.69(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.09(s,1H),7.72–7.53(m,4H),7.48(dd,1H),7.01(d,1H),6.81(d,1H),6.55( dd,1H),4.99–4.88(m,1H),4.80–4.70(m,1H),4.42–4.18(m,3H),4.14–4.01(m,2H),3.90–3.73(m,1H), 2.95–2.64(m,3H),2.32–1.98(m,7H),1.85–1.69(m,2H).
实施例41：化合物41的制备
Example 41: Preparation of Compound 41
第一步：41b的制备Step One: Preparation of 41b
将41a(1.17g，3.4mmol)(合成方法见WO2016058544)、1A(0.92g，5.08mmol)、TEA(2.06g，20.4mmol)、CuI(130mg，0.68mmol)和PdCl2(PPh3)2(240mg，0.34mmol)，在氮气保护下加入5mL DMF，50℃反应0.5h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到41b(1.0g，收率：74％)。41a (1.17g, 3.4mmol) (see WO2016058544 for the synthesis method), 1A (0.92g, 5.08mmol), TEA (2.06g, 20.4mmol), CuI (130mg, 0.68mmol) and PdCl 2 (PPh 3 ) 2 ( 240 mg, 0.34 mmol), add 5 mL DMF under nitrogen protection, and react at 50°C for 0.5 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v) = 1:0-1:2) to obtain 41b (1.0 g, yield: 74%).
第二步：41c的制备Step 2: Preparation of 41c
将41b(1.0g，2.52mmol)和碳酸钠(0.53g，5.0mmol)加入到10mL DMF中，加入2mL水，85℃反应1.5h。将反应液冷却至室温，加入到100mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到41c(0.6g，收率：80％)。Add 41b (1.0g, 2.52mmol) and sodium carbonate (0.53g, 5.0mmol) to 10mL DMF, add 2mL water, and react at 85°C for 1.5h. The reaction solution was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain 41c (0.6g, yield: 80%).
第三步：41d的制备Step 3: Preparation of 41d
将41c(0.4g，1.35mmol)，33a(0.5g，1.34mmol)、CuI(13mg，0.068mmol)、(1S,2S)-(+)-N,N’二甲基-1,2-环己二胺(0.095g，0.67mmol)和碳酸钾(0.28g，2.03mmol)，在氮气保护下加入10mL DMF，100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到41d(0.4g，收率：55％)。41c (0.4g, 1.35mmol), 33a (0.5g, 1.34mmol), CuI (13mg, 0.068mmol), (1S,2S)-(+)-N,N'dimethyl-1,2-cyclo Hexamethylenediamine (0.095g, 0.67mmol) and potassium carbonate (0.28g, 2.03mmol) were added with 10mL DMF under nitrogen protection and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain 41d (0.4g, yield: 55%).
第四步：41e的对甲苯磺酸盐的制备Step 4: Preparation of p-toluenesulfonate of 41e
将41d(0.2g，0.37mmol)和一水合对甲苯磺酸(0.21g，1.10mmol)溶于5mL乙腈中，室温反应3h。将反应体系减压浓缩，得粗品41e的对甲苯磺酸盐(0.16g)。Dissolve 41d (0.2g, 0.37mmol) and p-toluenesulfonic acid monohydrate (0.21g, 1.10mmol) in 5 mL acetonitrile and react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure to obtain crude product 41e p-toluenesulfonate (0.16g).
第五步：化合物41的制备Step 5: Preparation of Compound 41
将上述粗品41e的对甲苯磺酸盐(0.16g)、1f(0.12g，0.43mmol)和DIPEA(0.29g，2.24mmol)溶于5mL DMF中，80℃反应5h。将反应体系冷却到室温，加入到100mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物41(0.05g，收率：17％)。Dissolve the p-toluenesulfonate (0.16g), 1f (0.12g, 0.43mmol) and DIPEA (0.29g, 2.24mmol) of the above crude product 41e in 5mL DMF, and react at 80°C for 5h. The reaction system was cooled to room temperature, added to 100 mL of ethyl acetate, washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain compound 41 (0.05g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.22(s,1H),8.00(s,1H),7.93–7.82(m,3H),7.75–7.62(m,3H),7.58–7.47(m,1H),7.37–7.29(m,1H),6.85(d,1H),6.59(dd,1H),4.99–4.90(m,1H),4.53–4.40(m,2H),4.30–4.17(m,2H),4.07–3.94(m,1H),2.97–2.64(m,3H),2.20–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.46(s,1H),8.22(s,1H),8.00(s,1H),7.93–7.82(m,3H),7.75–7.62(m,3H), 7.58–7.47(m,1H),7.37–7.29(m,1H),6.85(d,1H),6.59(dd,1H),4.99–4.90(m,1H),4.53–4.40(m,2H), 4.30–4.17(m,2H),4.07–3.94(m,1H),2.97–2.64(m,3H),2.20–2.07(m,1H).
实施例42：化合物42的制备
Example 42: Preparation of Compound 42
第一步：42b的制备Step One: Preparation of 42b
将42a(1.15g，4.96mmol)溶解在10mL 1,4-二氧六环中，加入42A(1.25g，5.94mmol)，加入1mL甲磺酸，100℃反应16h。将反应体系冷却至室温，滴加饱和碳酸氢钠水溶液调pH至9，用50mL乙酸乙酯萃取，有机相用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-9:1)，得42b(1.0g，产率：48％)。 Dissolve 42a (1.15g, 4.96mmol) in 10mL of 1,4-dioxane, add 42A (1.25g, 5.94mmol), add 1mL of methanesulfonic acid, and react at 100°C for 16h. Cool the reaction system to room temperature, add saturated aqueous sodium bicarbonate solution dropwise to adjust the pH to 9, extract with 50 mL of ethyl acetate, wash the organic phase with 30 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Separate and purify by column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 42b (1.0 g, yield: 48%).
LCMS m/z＝423.2[M+1]+ LCMS m/z＝423.2[M+1] +
第二步：化合物42的制备Step 2: Preparation of Compound 42
将42b(0.5g，1.18mmol)、上述粗品中间体1(0.52g)溶解在10mL DMF中，加入TEA(0.36g，3.56mmol)，氮气保护下加入CuI(0.034g，0.18mmol)、PdCl2(PPh3)2(0.12g，0.17mmol))50℃反应2h。将反应体系冷却至室温，加入10mL水，室温搅拌5min后，抽滤，将滤饼用5mL水洗涤，收集滤饼，将滤饼用50mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1-1:4)，得化合物42(0.2g，产率：27％)。Dissolve 42b (0.5g, 1.18mmol) and the above crude intermediate 1 (0.52g) in 10 mL DMF, add TEA (0.36g, 3.56mmol), and add CuI (0.034g, 0.18mmol) and PdCl 2 under nitrogen protection. (PPh 3 ) 2 (0.12g, 0.17mmol)) reacted at 50°C for 2h. Cool the reaction system to room temperature, add 10 mL of water, stir at room temperature for 5 minutes, then filter with suction, wash the filter cake with 5 mL of water, collect the filter cake, dissolve the filter cake with 50 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1-1:4) to obtain compound 42 (0.2g, yield: 27%).
1H NMR(400MHz,DMSO-d6)δ13.90–13.50(m,1H),11.06(s,1H),8.55–8.15(m,2H),8.14–7.55(m,5H),6.91(d,1H),6.75(dd,1H),5.13–5.03(m,1H),4.52–4.38(m,2H),4.19–3.92(m,3H),2.97–2.80(m,1H),2.67–2.50(m,2H),2.10–1.97(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ13.90–13.50(m,1H),11.06(s,1H),8.55–8.15(m,2H),8.14–7.55(m,5H),6.91(d ,1H),6.75(dd,1H),5.13–5.03(m,1H),4.52–4.38(m,2H),4.19–3.92(m,3H),2.97–2.80(m,1H),2.67–2.50 (m,2H),2.10–1.97(m,1H).
LCMS m/z＝632.6[M+1]+ LCMS m/z＝632.6[M+1] +
实施例43：化合物43的制备
Example 43: Preparation of Compound 43
第一步：43b的制备Step One: Preparation of 43b
将43a(1.0g，4.79mmol)溶解在10mL 1,4-二氧六环中，加入43A(1.35g，5.77mmol)，加入1mL甲磺酸，100℃反应16h。将反应体系冷却至室温，滴加饱和碳酸氢钠水溶液调pH至9，用50mL乙酸乙酯萃取，有机相用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-9:1)，得43b(0.86g，产率：43％)。Dissolve 43a (1.0g, 4.79mmol) in 10mL of 1,4-dioxane, add 43A (1.35g, 5.77mmol), add 1mL of methanesulfonic acid, and react at 100°C for 16h. Cool the reaction system to room temperature, add saturated aqueous sodium bicarbonate solution dropwise to adjust the pH to 9, extract with 50 mL of ethyl acetate, wash the organic phase with 30 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is washed with silica gel Separate and purify by column chromatography (petroleum ether/ethyl acetate (v/v)=1:0-9:1) to obtain 43b (0.86g, yield: 43%).
LCMS m/z＝423.0[M+1]+ LCMS m/z＝423.0[M+1] +
第二步：化合物43的制备Step 2: Preparation of compound 43
将43b(0.45g，1.07mmol)、上述粗品中间体1(0.46g)溶解在10mL DMF中，加入TEA(0.32g，3.16mmol)，氮气保护下加入CuI(0.03g，0.16mmol)、PdCl2(PPh3)2(0.11g，0.16mmol)，50℃反应2h。将反应体系冷却至室温，加入10mL水，室温搅拌5min后，抽滤，将滤饼用5mL水洗涤，收集滤饼，将滤饼用50mL二氯甲烷溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1-1:4)，得化合物43(0.18g，产率：27％)。Dissolve 43b (0.45g, 1.07mmol) and the above crude intermediate 1 (0.46g) in 10 mL DMF, add TEA (0.32g, 3.16mmol), and add CuI (0.03g, 0.16mmol) and PdCl 2 under nitrogen protection. (PPh 3 ) 2 (0.11g, 0.16mmol), reacted at 50°C for 2h. Cool the reaction system to room temperature, add 10 mL of water, stir at room temperature for 5 minutes, then filter with suction, wash the filter cake with 5 mL of water, collect the filter cake, dissolve the filter cake with 50 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1-1:4) to obtain compound 43 (0.18g, yield: 27%).
1H NMR(400MHz,DMSO-d6)δ13.13–12.98(m,1H),11.06(s,1H),8.20–8.13(m,1H),8.12–8.07(m,1H),7.96–7.55(m,4H),7.36(dd,1H),6.89(d,1H),6.74(dd,1H),5.13–5.02(m,1H),4.50–4.37(m,2H),4.17–4.05(m,2H),4.03–3.90(m,1H),2.97–2.81(m,1H),2.66–2.50(m,2H),2.08–1.96(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ13.13–12.98(m,1H),11.06(s,1H),8.20–8.13(m,1H),8.12–8.07(m,1H),7.96–7.55 (m,4H),7.36(dd,1H),6.89(d,1H),6.74(dd,1H),5.13–5.02(m,1H),4.50–4.37(m,2H),4.17–4.05(m ,2H),4.03–3.90(m,1H),2.97–2.81(m,1H),2.66–2.50(m,2H),2.08–1.96(m,1H).
LCMS m/z＝632.1[M+1]+ LCMS m/z＝632.1[M+1] +
实施例44：化合物44的制备
Example 44: Preparation of Compound 44
第一步：44b的制备Step One: Preparation of 44b
将44a(1.0g，4.1mmol)、二碳酸二叔丁酯(1.79g，8.20mmol)、TEA(0.82g，8.10mmol)、DMAP(0.1g，0.82mmol)溶于20mL二氯甲烷中，室温反应12h。将反应体系加入到50mL二氯甲烷中，有机相用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚/乙酸乙酯(v/v)＝1:0-9:1)，得到粗品1(1.2g)。将上述粗品1(1.17g)、3-乙炔基氮杂环丁-1-甲酸叔丁酯(0.92g，5.08mmol)、TEA(2.06g，20.36mmol)、CuI(130mg，0.68mmol)和PdCl2(PPh3)2(240mg，0.34mmol)加入到反应瓶中，在氮气保护下加入5mL DMF，50℃反应0.5h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到粗品2(1.1g)。将上述粗品2(1.0g)和碳酸钠(0.53g，5.0mmol)加入到10mL DMF中，加入2mL水，85℃反应12h。将反应液冷却至室温，加入到100mL乙酸乙酯中，用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到44b(0.6g,收率：56％)。Dissolve 44a (1.0g, 4.1mmol), di-tert-butyl dicarbonate (1.79g, 8.20mmol), TEA (0.82g, 8.10mmol), and DMAP (0.1g, 0.82mmol) in 20 mL dichloromethane, room temperature Reaction 12h. The reaction system was added to 50 mL of methylene chloride, the organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) )=1:0-9:1), and crude product 1 (1.2g) was obtained. The above crude product 1 (1.17g), 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (0.92g, 5.08mmol), TEA (2.06g, 20.36mmol), CuI (130mg, 0.68mmol) and PdCl 2 (PPh 3 ) 2 (240 mg, 0.34 mmol) was added to the reaction bottle, 5 mL DMF was added under nitrogen protection, and the reaction was carried out at 50°C for 0.5 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain crude product 2 (1.1g). Add the above crude product 2 (1.0g) and sodium carbonate (0.53g, 5.0mmol) to 10mL DMF, add 2mL water, and react at 85°C for 12h. Cool the reaction solution to room temperature, add it to 100 mL of ethyl acetate, wash with saturated sodium chloride aqueous solution (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v)=1:0-1:2) to obtain 44b (0.6g, yield: 56%).
第二步：44c的制备Step 2: Preparation of 44c
将44b(0.4g，1.35mmol)、33a(0.5g，1.34mmol)、CuI(13mg，0.068mmol)、(1S,2S)-(+)-N,N’二甲基-1,2-环己二胺(0.095g，0.67mmol)和碳酸钾(0.28g，2.03mmol)加入到反应瓶中，在氮气保护下加入10mL DMF，100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到44c(0.4g，收率：55％)。44b (0.4g, 1.35mmol), 33a (0.5g, 1.34mmol), CuI (13mg, 0.068mmol), (1S,2S)-(+)-N,N'dimethyl-1,2-cyclo Hexamethylenediamine (0.095g, 0.67mmol) and potassium carbonate (0.28g, 2.03mmol) were added to the reaction bottle, 10mL DMF was added under nitrogen protection, and the reaction was carried out at 100°C for 2 hours. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 44c (0.4g, yield: 55%).
第三步：44d的对甲苯磺酸的制备Step 3: Preparation of 44d p-toluenesulfonic acid
将44c(0.2g，0.37mmol)和对甲苯磺酸一水合物(0.21g，1.10mmol)溶于5mL乙腈中，室温反应3h。将反应体系减压浓缩，得到粗品44d的对甲苯磺酸盐(0.173g)。Dissolve 44c (0.2g, 0.37mmol) and p-toluenesulfonic acid monohydrate (0.21g, 1.10mmol) in 5 mL acetonitrile and react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure to obtain crude product 44d p-toluenesulfonate (0.173g).
LCMS m/z＝442.4[M+1]+ LCMS m/z＝442.4[M+1] +
第四步：化合物44的制备Step 4: Preparation of Compound 44
将上述粗品44d的对甲苯磺酸盐(0.173g)、1f(0.12g，0.43mmol)和DIPEA(0.29g，2.24mmol)溶于5mL DMF中，80℃反应5h。将反应体系冷却到室温，加入到100mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物44(0.06g，收率：20％)。Dissolve the p-toluenesulfonate (0.173g), 1f (0.12g, 0.43mmol) and DIPEA (0.29g, 2.24mmol) of the above crude product 44d in 5mL DMF, and react at 80°C for 5h. The reaction system was cooled to room temperature, added to 100 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain compound 44 (0.06g, yield: 20%).
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.27(s,1H),8.19(s,1H),7.96(s,1H),7.92–7.83(m,2H),7.74–7.66(m,2H),7.64–7.57(m,1H),7.48–7.39(m,1H),7.38–7.31(m,1H),6.89–6.84(m,1H),6.61(dd,1H),4.99–4.89(m,1H),4.53–4.40(m,2H),4.27–4.16(m,2H),4.05–3.93(m,1H), 2.98–2.65(m,3H),2.19–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.43(s,1H),8.27(s,1H),8.19(s,1H),7.96(s,1H),7.92–7.83(m,2H),7.74– 7.66(m,2H),7.64–7.57(m,1H),7.48–7.39(m,1H),7.38–7.31(m,1H),6.89–6.84(m,1H),6.61(dd,1H), 4.99–4.89(m,1H),4.53–4.40(m,2H),4.27–4.16(m,2H),4.05–3.93(m,1H), 2.98–2.65(m,3H),2.19–2.08(m,1H).
实施例45：化合物45的制备
Example 45: Preparation of Compound 45
第一步：45b的制备Step One: Preparation of 45b
在50mL反应瓶中，加入45a(1.0g，6.43mmol)、3,3-二甲基-5-硝基二氢吲哚-2-酮(1.32g，6.40mmol)和碳酸钾(1.77g，12.81mmol)，加入10mL DMSO，100℃反应4h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到45b(1.5g，收率：69％)。In a 50mL reaction bottle, add 45a (1.0g, 6.43mmol), 3,3-dimethyl-5-nitroindolin-2-one (1.32g, 6.40mmol) and potassium carbonate (1.77g, 12.81mmol), add 10mL DMSO, and react at 100°C for 4h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 45b (1.5g, yield: 69%).
第二步：45c的制备Step 2: Preparation of 45c
将45b(1.0g，2.93mmol)溶于20mL乙醇和10mL饱和氯化铵水溶液中，加入铁粉(1.64g，29.29mmol)，室温反应6h。将反应体系减压浓缩，加入50mL乙酸乙酯和50mL水，过滤，将滤液分液，有机相用无水硫酸钠干燥，减压浓缩，得到粗品45c(0.7g)。Dissolve 45b (1.0g, 2.93mmol) in 20mL ethanol and 10mL saturated aqueous ammonium chloride solution, add iron powder (1.64g, 29.29mmol), and react at room temperature for 6 hours. The reaction system was concentrated under reduced pressure, 50 mL of ethyl acetate and 50 mL of water were added, filtered, the filtrate was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 45c (0.7g).
LCMS m/z＝312.1[M+1]+ LCMS m/z＝312.1[M+1] +
第三步：45d的制备Step 3: Preparation of 45d
将上述粗品45c(0.37g)加入到5mL水中，缓慢加入0.8mL浓硫酸，60℃反应1h。将反应体系冷却至0℃，滴加5mL亚硝酸钠(0.081g，1.17mmol)的水溶液，5℃下反应30min后，40℃下滴加2mL KI(0.39g，2.35mmol)的水溶液，50℃反应1h。将反应体系冷却到室温，用乙酸乙酯萃取(50mL×3)，有机相依次用1mol/L盐酸水溶液(50mL)和饱和硫代硫酸钠水溶液洗涤(50mL)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-2:1)，得到45d(0.2g，从化合物45b算两步收率：31％)。Add the above crude product 45c (0.37g) to 5mL of water, slowly add 0.8mL of concentrated sulfuric acid, and react at 60°C for 1 hour. Cool the reaction system to 0℃, add 5mL of sodium nitrite (0.081g, 1.17mmol) aqueous solution dropwise, and after reacting for 30 minutes at 5℃, add 2mL of KI (0.39g, 2.35mmol) aqueous solution dropwise at 40℃, 50℃ Reaction 1h. The reaction system was cooled to room temperature, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with 1 mol/L hydrochloric acid aqueous solution (50 mL) and saturated sodium thiosulfate aqueous solution (50 mL), dried over anhydrous sodium sulfate, and reduced pressure. Concentrate, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-2:1) to obtain 45d (0.2g, two-step yield calculated from compound 45b: 31%).
LCMS m/z＝423.4[M+1]+ LCMS m/z＝423.4[M+1] +
第四步：化合物45的制备Step 4: Preparation of Compound 45
将45d(0.046g，0.11mmol)、上述粗品中间体1(0.056g)、TEA(0.067g，0.66mmol)、CuI(4.2mg，0.022mmol)和PdCl2(PPh3)2(7.7mg，0.011mmol)加入到反应瓶中，在氮气保护下加入2mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，将滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得到化合物45(0.02g，收率：29％)。45d (0.046g, 0.11mmol), the above crude intermediate 1 (0.056g), TEA (0.067g, 0.66mmol), CuI (4.2mg, 0.022mmol) and PdCl 2 (PPh 3 ) 2 (7.7mg, 0.011 mmol) into the reaction bottle, add 2 mL DMF under nitrogen protection, and react at 55°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 20 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether). /dichloromethane/ethyl acetate (v/v)=1:1:2) to obtain compound 45 (0.02g, yield: 29%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.87–7.77(m,1H),7.73–7.65(m,2H),7.52(dd,1H),7.39–7.30(m,2H),6.95–6.88(m,1H),6.85–6.81(m,1H),6.58(dd,1H),4.99–4.90(m,1H),4.44–4.35(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),2.96–2.66(m,3H),2.20–2.09(m,1H),1.48(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.87–7.77(m,1H),7.73–7.65(m,2H),7.52(dd,1H),7.39–7.30(m,2H ),6.95–6.88(m,1H),6.85–6.81(m,1H),6.58(dd,1H),4.99–4.90(m,1H),4.44–4.35(m,2H),4.18–4.07(m ,2H),3.93–3.80(m,1H),2.96–2.66(m,3H),2.20–2.09(m,1H),1.48(s,6H).
实施例46：化合物46的制备
Example 46: Preparation of Compound 46
第一步：46b的制备Step One: Preparation of 46b
向反应瓶中加入46a(1.0g，3.27mmol)(合成方法见WO2022003557)、4-碘吡唑(0.61g，3.14mmol)和碳酸钾(0.87g，6.30mmol)溶于10mL DMF中，80℃反应4h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到46b(0.4g，收率：32％)。Add 46a (1.0g, 3.27mmol) (see WO2022003557 for synthesis method), 4-iodopyrazole (0.61g, 3.14mmol) and potassium carbonate (0.87g, 6.30mmol) into the reaction flask. Dissolve in 10mL DMF, 80℃ Reaction 4h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 46b (0.4g, yield: 32%).
第二步：46c的三氟乙酸盐的制备Step 2: Preparation of 46c trifluoroacetate
将46b(0.4g，0.99mmol)溶于5mL二氯甲烷和5mL三氟乙酸中，室温反应2h。将反应体系减压浓缩，得到粗品46c的三氟乙酸盐(0.23g)。Dissolve 46b (0.4g, 0.99mmol) in 5mL dichloromethane and 5mL trifluoroacetic acid, and react at room temperature for 2h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 46c (0.23g).
第三步：46d的制备Step 3: Preparation of 46d
将上述粗品46c的三氟乙酸盐(0.23g)、3-氯-4-氟三氟甲苯(0.2g，1.0mmol)、碳酸钾(0.55g，3.98mmol)溶于5mL DMF中，80℃反应4h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到46d(0.04g，收率：8％)。Dissolve the above crude product 46c trifluoroacetate (0.23g), 3-chloro-4-fluorotrifluorotoluene (0.2g, 1.0mmol), and potassium carbonate (0.55g, 3.98mmol) in 5mL DMF, 80°C Reaction 4h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 46d (0.04g, yield: 8%).
LCMS m/z＝482.1[M+1]+ LCMS m/z＝482.1[M+1] +
第四步：化合物46的制备Step 4: Preparation of Compound 46
将46d(0.04g，0.083mmol)、上述粗品中间体1(0.042g)、TEA(0.05g，0.49mmol)、CuI(3.2mg，0.017mmol)和PdCl2(PPh3)2(5.8mg，0.0083mmol)加入到反应瓶中，在氮气保护下，加入2mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/二氯甲烷/乙酸乙酯(v/v)＝1:1:2)，得化合物46(0.02g，收率：35％)。46d (0.04g, 0.083mmol), the above crude intermediate 1 (0.042g), TEA (0.05g, 0.49mmol), CuI (3.2mg, 0.017mmol) and PdCl 2 (PPh 3 ) 2 (5.8mg, 0.0083 mmol) into the reaction bottle, under nitrogen protection, add 2 mL DMF, and react at 55°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water, and perform suction filtration. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/petroleum ether/ Dichloromethane/ethyl acetate (v/v)=1:1:2), compound 46 (0.02g, yield: 35%) was obtained.
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.71–7.63(m,1H),7.62–7.51(m,3H),7.47–7.40(m,1H),7.04(d,1H),6.84–6.76(m,1H),6.55(dd,1H),5.02–4.88(m,2H),4.43–4.26(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.48–3.38(m,2H),3.25–3.10(m,2H),3.07–2.95(m,2H),2.95–2.65(m,3H),2.50–2.35(m,2H),2.23–2.06(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.93(s,1H),7.71–7.63(m,1H),7.62–7.51(m,3H),7.47–7.40(m,1H),7.04(d,1H ),6.84–6.76(m,1H),6.55(dd,1H),5.02–4.88(m,2H),4.43–4.26(m,2H),4.13–4.00(m,2H),3.88–3.75(m ,1H),3.48–3.38(m,2H),3.25–3.10(m,2H),3.07–2.95(m,2H),2.95–2.65(m,3H),2.50–2.35(m,2H),2.23 –2.06(m,3H).
LCMS m/z＝691.3[M+1]+ LCMS m/z＝691.3[M+1] +
实施例47：化合物47的制备
Example 47: Preparation of Compound 47
第一步：47B的制备Step One: Preparation of 47B
将47A(1.0g，4.81mmol)、二碳酸二叔丁酯(1.16g，5.32mmol)和TEA(0.73g，7.21mmol) 溶于50mL四氢呋喃中，室温反应12h。将反应体系加入到100mL水中，用乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-9:1)，得到47B(1.3g，收率：88％)。47A (1.0g, 4.81mmol), di-tert-butyl dicarbonate (1.16g, 5.32mmol) and TEA (0.73g, 7.21mmol) Dissolve in 50mL tetrahydrofuran and react at room temperature for 12h. Add the reaction system to 100 mL of water, extract with ethyl acetate (50 mL :0-9:1) to obtain 47B (1.3g, yield: 88%).
第二步：47C的制备Step 2: Preparation of 47C
将47B(1.05g，3.4mmol)、1A(0.92g，5.08mmol)、TEA(2.06g，20.36mmol)、CuI(130mg，0.68mmol)和PdCl2(PPh3)2(240mg，0.34mmol)加入到反应瓶中，在氮气保护下加入10mL DMF，50℃反应0.5h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到47C(1.05g，收率：85％)。47B (1.05g, 3.4mmol), 1A (0.92g, 5.08mmol), TEA (2.06g, 20.36mmol), CuI (130mg, 0.68mmol) and PdCl 2 (PPh 3 ) 2 (240mg, 0.34mmol) were added To the reaction bottle, add 10 mL DMF under nitrogen protection and react at 50°C for 0.5 h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 47C (1.05g, yield: 85%).
第三步：47a的制备Step 3: Preparation of 47a
将47C(0.91g，2.52mmol)和碳酸钠(0.53g，5.0mmol)加入到10mL DMF中，加入2mL水，85℃反应12h。将反应液冷却至室温，加入到100mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到47a(0.5g，收率：76％)。Add 47C (0.91g, 2.52mmol) and sodium carbonate (0.53g, 5.0mmol) to 10mL DMF, add 2mL water, and react at 85°C for 12h. The reaction solution was cooled to room temperature, added to 100 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 47a (0.5g, yield: 76%).
LCMS m/z＝262.2[M+1]+ LCMS m/z＝262.2[M+1] +
第四步：47b的制备Step 4: Preparation of 47b
将47a(0.35g，1.34mmol)、1-(2,6-二氯-4-(三氟甲基)苯基)-4-碘-1H-吡唑(0.55g，1.35mmol)(合成方法见J.Org.Chem.,2003,68,8075-8079)、CuI(13mg，0.068mmol)、(1S,2S)-(+)-N,N'-二甲基-1,2-环己二胺(0.095g，0.67mmol)和碳酸钾(0.28g，2.03mmol)加入到反应瓶中，在氮气保护下加入10mL DMF，100℃反应2h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到47b(0.5g，收率：69％)。47a (0.35g, 1.34mmol), 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-iodo-1H-pyrazole (0.55g, 1.35mmol) (Synthesis method See J.Org.Chem., 2003, 68, 8075-8079), CuI (13mg, 0.068mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexane Diamine (0.095g, 0.67mmol) and potassium carbonate (0.28g, 2.03mmol) were added to the reaction bottle, 10mL DMF was added under nitrogen protection, and the reaction was carried out at 100°C for 2 hours. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL /ethyl acetate (v/v)=1:0-1:2) to obtain 47b (0.5g, yield: 69%).
LCMS m/z＝540.1[M+1]+ LCMS m/z＝540.1[M+1] +
第五步：47c的对甲苯磺酸盐的制备Step 5: Preparation of 47c p-toluenesulfonate
将47b(0.2g，0.37mmol)和对甲苯磺酸一水合物(0.21g，1.10mmol)溶于5mL乙腈中，室温反应3h。将反应体系减压浓缩，得到粗品47c的对甲苯磺酸盐(0.16g)。Dissolve 47b (0.2g, 0.37mmol) and p-toluenesulfonic acid monohydrate (0.21g, 1.10mmol) in 5 mL acetonitrile and react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure to obtain crude product 47c p-toluenesulfonate (0.16g).
LCMS m/z＝440.0[M+1]+ LCMS m/z＝440.0[M+1] +
第六步：化合物47的制备Step 6: Preparation of Compound 47
将上述粗品47c的对甲苯磺酸盐(0.16g)、1f(0.12g，0.43mmol)和DIPEA(0.29g，2.24mmol)溶于5mL DMF中，80℃反应5h。将反应体系冷却到室温，加入100mL乙酸乙酯，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物47(0.05g，收率：17％)。Dissolve the p-toluenesulfonate (0.16g), 1f (0.12g, 0.43mmol) and DIPEA (0.29g, 2.24mmol) of the above crude product 47c in 5mL DMF, and react at 80°C for 5h. The reaction system was cooled to room temperature, 100 mL of ethyl acetate was added, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain compound 47 (0.05g, yield: 17%).
1H NMR(400MHz,CDCl3)δ8.01(s,2H),7.87(s,1H),7.80–7.64(m,4H),6.86–6.80(m,1H),6.62–6.53(m,1H),4.99–4.89(m,1H),4.45–4.32(m,2H),4.15–4.03(m,2H),3.95–3.80(m,1H),2.98–2.65(m,3H),2.37(s,3H),2.19–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.01(s,2H),7.87(s,1H),7.80–7.64(m,4H),6.86–6.80(m,1H),6.62–6.53(m,1H ),4.99–4.89(m,1H),4.45–4.32(m,2H),4.15–4.03(m,2H),3.95–3.80(m,1H),2.98–2.65(m,3H),2.37(s ,3H),2.19–2.07(m,1H).
LCMS m/z＝696.0[M+1]+ LCMS m/z＝696.0[M+1] +
实施例48：化合物48三氟乙酸盐的制备
Example 48: Preparation of compound 48 trifluoroacetate salt
第一步：48b的制备Step 1: Preparation of 48b
将48a(0.68g，3mmol)加入到20mL DMF中，0℃加入60％氢化钠(0.096g)，室温反应1h后，加入3-氯-4-氟三氟甲苯(0.6g，3.02mmol)，25℃反应16h。向反应体系中加入100mL乙酸乙酯，有机相用200mL纯化水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝10:1)，得48b(1.1g，收率：90％)。Add 48a (0.68g, 3mmol) to 20mL DMF, add 60% sodium hydride (0.096g) at 0°C, and react at room temperature for 1 hour, then add 3-chloro-4-fluorotrifluorotoluene (0.6g, 3.02mmol). React at 25°C for 16 hours. Add 100 mL of ethyl acetate to the reaction system, wash the organic phase with 200 mL of purified water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 10: 1), 48b (1.1g, yield: 90%) was obtained.
第二步：48c的制备Step 2: Preparation of 48c
将48b(1.1g，2.7mmol)加入到20mL二氯甲烷中，加入5mL三氟乙酸，25℃反应2h。将反应液减压浓缩，加入100mL二氯甲烷，有机相用50mL饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，得48c(0.8g，收率：97％)。Add 48b (1.1g, 2.7mmol) to 20mL dichloromethane, add 5mL trifluoroacetic acid, and react at 25°C for 2h. The reaction solution was concentrated under reduced pressure, 100 mL of methylene chloride was added, the organic phase was washed with 50 mL of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 48c (0.8 g, yield: 97%).
第三步：48d的制备Step 3: Preparation of 48d
将48c(0.8g，2.62mmol)加入到40mL二氯乙烷中，加入4-碘苯甲醛(0.63g，2.72mmol)，室温反应2h后，加入三乙酰氧基硼氢化钠(0.84g，3.96mmol)，25℃反应15h。向反应体系中加入50mL二氯甲烷，有机相用50mL饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝1:1)，得48d(1.0g，收率：73％)。Add 48c (0.8g, 2.62mmol) to 40mL dichloroethane, add 4-iodobenzaldehyde (0.63g, 2.72mmol), react at room temperature for 2 hours, then add sodium triacetoxyborohydride (0.84g, 3.96 mmol), react at 25℃ for 15h. Add 50 mL of methylene chloride to the reaction system, wash the organic phase with 50 mL of saturated sodium bicarbonate aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) =1:1), 48d (1.0g, yield: 73%) was obtained.
LCMS m/z＝522.0[M+1]+ LCMS m/z＝522.0[M+1] +
第四步：化合物48三氟乙酸盐的制备Step 4: Preparation of compound 48 trifluoroacetate salt
将48d(0.26g，0.5mmol)溶于8mL DMF中，依次加入上述粗品中间体1(0.34g)、TEA(0.5g，4.94mmol)、CuI(0.019g，0.1mmol)和PdCl2(PPh3)2(0.07g，0.1mmol)，置换氮气三次，60℃反应1h。将反应液冷却至室温，加入40mL水，过滤，滤饼用20mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:3)，所得粗品过Pre-HPLC(仪器及制备柱：采用Glison GX-281制备液相，制备柱型号是Sunfire C18，5μm，内径×长度＝30mm×150mm)。制备方法：粗品用甲醇和二甲亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％TFA)。梯度洗脱方法：乙腈由5％梯度洗脱60％(洗脱时间15min)，冻干得到化合物48的三氟乙酸盐(90mg)。48d (0.26g, 0.5mmol) was dissolved in 8mL DMF, and the above crude intermediate 1 (0.34g), TEA (0.5g, 4.94mmol), CuI (0.019g, 0.1mmol) and PdCl 2 (PPh 3 ) 2 (0.07g, 0.1mmol), replace nitrogen three times, and react at 60°C for 1 hour. Cool the reaction solution to room temperature, add 40 mL of water, filter, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/acetic acid). Ethyl ester (v/v) = 1:3), and the obtained crude product was passed through Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm ). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 48 (90 mg).
1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.77(d,1H),7.73–6.93(m,7H),6.83–6.76(m,1H),6.59(dd,1H),4.98–4.89(m,1H),4.73–3.77(m,10H),2.95–2.65(m,3H),2.60–1.85(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ8.19(s,1H),7.77(d,1H),7.73–6.93(m,7H),6.83–6.76(m,1H),6.59(dd,1H), 4.98–4.89(m,1H),4.73–3.77(m,10H),2.95–2.65(m,3H),2.60–1.85(m,9H).
LCMS m/z＝731.2[M+1]+ LCMS m/z＝731.2[M+1] +
实施例49：化合物49的制备
Example 49: Preparation of Compound 49
第一步：49b-1和49b-2的制备Step One: Preparation of 49b-1 and 49b-2
将49a(0.8g，5.47mmol)溶于40mL DMF中，加入碳酸铯(3.54g，10.86mmol)，90℃下分四批加入49A(1.50g，5.97mmol)(加料时间6h)，90℃反应16h。将反应体系冷却至室温，加入100mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝3:1)，分别得49b-1(0.6g，收率：36％)和49b-2(0.2g，收率：12％)。Dissolve 49a (0.8g, 5.47mmol) in 40mL DMF, add cesium carbonate (3.54g, 10.86mmol), add 49A (1.50g, 5.97mmol) in four batches at 90°C (addition time 6h), react at 90°C 16h. The reaction system was cooled to room temperature, 100 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v)=3:1), respectively obtained 49b-1 (0.6g, yield: 36%) and 49b-2 (0.2g, yield: 12%).
第二步：49d的制备Step 2: Preparation of 49d
将49c(2.96g，10.0mmol)和环丙基硼酸(5.16g，60.07mmol)溶解于70mL 1,4-二氧六环与15mL水中，加入磷酸钾(12.76g,60.11mmol)，氮气氛围下加入双三环己基膦二氯化钯(2.22g,3.01mmol)，100℃反应16h。将反应体系冷却至室温，加入80mL水，用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝5:1)，得到49d(2.1g，收率：96％)。Dissolve 49c (2.96g, 10.0mmol) and cyclopropylboronic acid (5.16g, 60.07mmol) in 70mL of 1,4-dioxane and 15mL of water. Add potassium phosphate (12.76g, 60.11mmol) under nitrogen atmosphere. Add bistricyclohexylphosphine palladium dichloride (2.22g, 3.01mmol) and react at 100°C for 16h. The reaction system was cooled to room temperature, 80 mL of water was added, extracted with 100 mL of ethyl acetate, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v)=5:1), 49d (2.1 g, yield: 96%) was obtained.
LCMS m/z＝219.2[M+1]+ LCMS m/z＝219.2[M+1] +
第三步：49e的制备Step 3: Preparation of 49e
将49d(0.5g，2.29mmol)溶解于10mL甲醇中，加入0.2g 10％Pd/C，置于氢气球氛围下室温反应4h。将反应体系过滤，将滤液减压浓缩，得到粗品49e(0.4g)。Dissolve 49d (0.5g, 2.29mmol) in 10mL methanol, add 0.2g 10% Pd/C, and react at room temperature for 4 hours under a hydrogen balloon atmosphere. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 49e (0.4g).
第四步：49f的制备Step 4: Preparation of 49f
将上述粗品49e(0.12g)与49b-1(0.10g，0.33mmol)溶解于8mL乙醇与8mL甲苯中，氮气氛围下100℃反应16h。将反应体系冷却至室温，减压浓缩，粗品用硅胶色谱柱分离提纯(石油醚:乙酸乙酯(v/v)＝2:1)，得到49f(0.11g，收率：71％)。The above crude products 49e (0.12g) and 49b-1 (0.10g, 0.33mmol) were dissolved in 8mL ethanol and 8mL toluene, and reacted at 100°C for 16h under nitrogen atmosphere. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=2:1) to obtain 49f (0.11g, yield: 71%).
LCMS m/z＝470.3[M+1]+ LCMS m/z＝470.3[M+1] +
第五步：49g对甲苯磺酸盐的制备Step 5: Preparation of 49g p-toluenesulfonate
将49f(0.1g，0.21mmol)溶解于10mL乙腈中，加入对甲苯磺酸一水合物(0.24g，1.26mmol)，35℃反应4h。将反应体系冷却至室温，减压浓缩，得到粗品49g的对甲苯磺酸盐(0.33g)。Dissolve 49f (0.1g, 0.21mmol) in 10 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.24g, 1.26mmol), and react at 35°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to obtain 49 g of crude p-toluenesulfonate (0.33 g).
LCMS m/z＝370.3[M+1]+ LCMS m/z＝370.3[M+1] +
第六步：化合物49的制备Step 6: Preparation of Compound 49
将上述粗品49g的对甲苯磺酸盐(0.33g)溶解于5mL DMSO中，加入DIPEA(0.21g，1.62mmol)和1f(83mg，0.30mmol)，80℃反应3h。将反应体系冷却至室温，加入35mL水，抽滤，将滤饼用10mL水洗涤，将滤饼用100mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶 柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝15:1)，得到化合物49(40mg，收率：21％)。Dissolve 49g of the above crude product p-toluenesulfonate (0.33g) in 5mL DMSO, add DIPEA (0.21g, 1.62mmol) and 1f (83mg, 0.30mmol), and react at 80°C for 3 hours. Cool the reaction system to room temperature, add 35 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel for the crude product Column chromatography separated and purified (dichloromethane/methanol (v/v) = 15:1) to obtain compound 49 (40 mg, yield: 21%).
1H NMR(400MHz,DMSO-d6)δ12.9–12.4(m,1H),11.07(s,1H),8.74–8.20(m,3H),7.94–7.84(m,1H),7.72(d,1H),7.15–6.90(m,2H),6.87–6.77(m,1H),6.51–6.42(m,1H),6.08–5.92(m,1H),5.15–5.02(m,1H),4.75–4.60(m,2H),4.57–4.42(m,2H),3.00–2.80(m,1H),2.70–2.45(m,3H),2.14–1.90(m,2H),1.12–0.75(m,6H),0.73–0.60(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.9–12.4(m,1H),11.07(s,1H),8.74–8.20(m,3H),7.94–7.84(m,1H),7.72(d ,1H),7.15–6.90(m,2H),6.87–6.77(m,1H),6.51–6.42(m,1H),6.08–5.92(m,1H),5.15–5.02(m,1H),4.75 –4.60(m,2H),4.57–4.42(m,2H),3.00–2.80(m,1H),2.70–2.45(m,3H),2.14–1.90(m,2H),1.12–0.75(m, 6H),0.73–0.60(m,2H).
LCMS m/z＝626.4[M+1]+ LCMS m/z＝626.4[M+1] +
实施例50：化合物50的制备
Example 50: Preparation of Compound 50
化合物50以化合物49e和49b-2为原料，参照实施例49的合成方法的得到。Compound 50 was obtained by referring to the synthesis method of Example 49 using compounds 49e and 49b-2 as raw materials.
1H NMR(400MHz,DMSO-d6)δ12.66–12.40(m,1H),11.07(s,1H),8.78(s,1H),8.72–8.44(m,1H),8.24–8.04(m,1H),7.78(d,1H),7.73(d,1H),7.15–6.93(m,2H),6.83(dd,1H),6.50–6.43(m,1H),5.88–5.76(m,1H),5.14–5.03(m,1H),4.75–4.62(m,2H),4.60–4.50(m,2H),2.99–2.80(m,1H),2.67–2.50(m,3H),2.14–1.86(m,2H),1.14–0.75(m,6H),0.71–0.60(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.66–12.40(m,1H),11.07(s,1H),8.78(s,1H),8.72–8.44(m,1H),8.24–8.04(m ,1H),7.78(d,1H),7.73(d,1H),7.15–6.93(m,2H),6.83(dd,1H),6.50–6.43(m,1H),5.88–5.76(m,1H ),5.14–5.03(m,1H),4.75–4.62(m,2H),4.60–4.50(m,2H),2.99–2.80(m,1H),2.67–2.50(m,3H),2.14–1.86 (m,2H),1.14–0.75(m,6H),0.71–0.60(m,2H).
实施例51：化合物51的制备
Example 51: Preparation of Compound 51
第一步：51b的制备Step One: Preparation of 51b
将51a(2.2g，9.88mmol)溶于20mL甲醇中，0℃下加入硼氢化钠(0.37g，9.78mmol)，室温反应0.5h。向反应液中加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到51b(2.05g，收率：92％)。Dissolve 51a (2.2g, 9.88mmol) in 20mL methanol, add sodium borohydride (0.37g, 9.78mmol) at 0°C, and react at room temperature for 0.5h. Add 50 mL of ethyl acetate and 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1- 1:1), obtaining 51b (2.05g, yield: 92%).
第二步：51c的制备Step 2: Preparation of 51c
将51b(0.15g，0.67mmol)溶于5mL THF溶剂中，加入三苯基膦(0.26g，0.99mmol)和3-氟-5-碘苯酚(0.16g，0.67mmol)，0℃下加入DEAD(0.21g，1.21mmol)，室温反应19h。向反应液中加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到51c(0.13g，收率：44％)。Dissolve 51b (0.15g, 0.67mmol) in 5mL THF solvent, add triphenylphosphine (0.26g, 0.99mmol) and 3-fluoro-5-iodophenol (0.16g, 0.67mmol), add DEAD at 0°C (0.21g, 1.21mmol), reacted at room temperature for 19h. Add 50 mL of ethyl acetate and 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1- 1:1), obtaining 51c (0.13g, yield: 44%).
第三步：化合物51的制备Step 3: Preparation of Compound 51
化合物51以化合物51c为原料，参照实施例48的合成方法得到。Compound 51 was obtained by referring to the synthesis method of Example 48 using compound 51c as raw material.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.71–7.62(m,2H),7.61–7.54(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.74–6.63(m,2H),6.56(dd,1H),6.51–6.43(m,1H),5.66(q,1H),4.98–4.89(m,1H),4.42–4.32(m,2H),4.13–4.02(m,2H),3.88–3.76(m,1H),2.95–2.66(m,3H), 2.18–2.07(m,1H),1.62(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.71–7.62(m,2H),7.61–7.54(m,1H),7.53–7.46(m,1H),6.84–6.78(m ,1H),6.74–6.63(m,2H),6.56(dd,1H),6.51–6.43(m,1H),5.66(q,1H),4.98–4.89(m,1H),4.42–4.32(m ,2H),4.13–4.02(m,2H),3.88–3.76(m,1H),2.95–2.66(m,3H), 2.18–2.07(m,1H),1.62(d,3H).
实施例52：化合物52的制备
Example 52: Preparation of Compound 52
第一步：52b的制备Step One: Preparation of 52b
氮气氛围下将52a(0.5g，2.54mmol)、52A(1.01g，3.81mmol)和三苯基膦(1.33g，5.07mmol)加入到10mL四氢呋喃中，0℃下滴加DIAD(1.54g，7.62mmol)，室温反应3h。将反应体系加入到50mL水中，用乙酸乙酯萃取(50mL×3)，有机相用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:0-1:1)，得到52b(0.5g，收率：44％)。52a (0.5g, 2.54mmol), 52A (1.01g, 3.81mmol) and triphenylphosphine (1.33g, 5.07mmol) were added to 10mL tetrahydrofuran under nitrogen atmosphere, and DIAD (1.54g, 7.62mmol) was added dropwise at 0°C. mmol), react at room temperature for 3 hours. The reaction system was added to 50 mL of water, extracted with ethyl acetate (50 mL : Ethyl acetate (v/v) = 1:0-1:1) to obtain 52b (0.5g, yield: 44%).
第二步：化合物52的制备Step 2: Preparation of Compound 52
化合物52以化合物52b为原料，参照实施例51的合成方法得到。Compound 52 was obtained by referring to the synthesis method of Example 51 using compound 52b as raw material.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.74–7.66(m,1H),7.66–7.58(m,1H),7.48–7.39(m,1H),7.34–7.27(m,1H),7.15(dd,1H),6.99–6.90(m,1H),6.88–6.80(m,1H),6.71(d,1H),6.59(dd,1H),5.75(q,1H),4.98–4.90(m,1H),4.47–4.37(m,2H),4.17–4.05(m,2H),3.98–3.85(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.71(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.74–7.66(m,1H),7.66–7.58(m,1H),7.48–7.39(m,1H),7.34–7.27(m ,1H),7.15(dd,1H),6.99–6.90(m,1H),6.88–6.80(m,1H),6.71(d,1H),6.59(dd,1H),5.75(q,1H), 4.98–4.90(m,1H),4.47–4.37(m,2H),4.17–4.05(m,2H),3.98–3.85(m,1H),2.96–2.65(m,3H),2.18–2.08(m ,1H),1.71(d,3H).
实施例53：化合物53的制备
Example 53: Preparation of Compound 53
第一步：53b的制备Step One: Preparation of 53b
将53a(0.24g，1.01mmol)溶于10mL DMF中，加入碳酸钾(0.28g，2.03mmol)和53A(0.24g，1.21mmol)，90℃反应12h。将反应体系冷却至室温，加入30mL乙酸乙酯和50mL纯化水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝4:1)，得53b(0.4g，收率：95％)。Dissolve 53a (0.24g, 1.01mmol) in 10mL DMF, add potassium carbonate (0.28g, 2.03mmol) and 53A (0.24g, 1.21mmol), and react at 90°C for 12h. The reaction system was cooled to room temperature, 30 mL of ethyl acetate and 50 mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 4:1), 53b (0.4g, yield: 95%) was obtained.
第三步：化合物53的制备Step 3: Preparation of Compound 53
化合物53以化合物53b为原料，参照实施例52的合成方法得到。Compound 53 was obtained by referring to the synthesis method of Example 52 using compound 53b as raw material.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.73–7.65(m,1H),7.65–7.55(m,1H),7.49–7.40(m,1H),7.07–6.97(m,1H),6.92–6.81(m,1H),6.78–6.68(m,2H),6.68–6.58(m,1H),6.48(dd,1H),4.92–4.82(m,1H),4.35–4.23(m,2H),4.07–3.95(m,2H),3.82–3.67(m,1H),2.90–2.55(m,3H),2.14–1.97(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.18(s,1H),7.73–7.65(m,1H),7.65–7.55(m,1H),7.49–7.40(m,1H),7.07–6.97(m ,1H),6.92–6.81(m,1H),6.78–6.68(m,2H),6.68–6.58(m,1H),6.48(dd,1H),4.92–4.82(m,1H),4.35–4.23 (m,2H),4.07–3.95(m,2H),3.82–3.67(m,1H),2.90–2.55(m,3H),2.14–1.97(m,1H).
实施例54：化合物54的制备
Example 54: Preparation of Compound 54
第一步：54b的制备Step One: Preparation of 54b
将54a(3g，13.48mmol)溶于45mL氯仿中，0℃加入溴素(2.1g，13.14mmol)，室温反应16h。向反应体系中加入60mL二氯甲烷，有机相用100mL饱和碳酸氢钠水溶液和50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝87:13)，得54b(1.5g，收率：37％)。Dissolve 54a (3g, 13.48mmol) in 45mL chloroform, add bromine (2.1g, 13.14mmol) at 0°C, and react at room temperature for 16h. Add 60 mL of methylene chloride to the reaction system, wash the organic phase with 100 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: acetic acid). Ethyl ester (v/v)=87:13), to obtain 54b (1.5g, yield: 37%).
LCMS m/z＝301.1[M+1]+ LCMS m/z＝301.1[M+1] +
第二步：54c的制备Step 2: Preparation of 54c
将29b(2.30g,7.18mmol)溶于THF(20mL)中，加入4mL水和一水合氢氧化锂(0.6g,14.3mmol)，室温反应30min。向反应液中滴加1mol/L盐酸调pH至6，加入50mL乙酸乙酯，分液，有机相用20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得粗品1(2.0g)。将粗品1(1.74g)加入到100mL单口瓶中，加入干燥二氯甲烷(20mL)，加入DIPEA(1.54g，11.91mmol)，0℃下缓慢滴加54b(1.2g，4.0mmol)，室温反应16h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝73:27)，得粗品(1.0g)。将上述粗品(1g)溶于30mL甲苯中，加入醋酸铵(1.5g，19.46mmol)，90℃反应16h。将反应体系冷却至室温，减压浓缩，加入二氯甲烷(100mL)和100mL纯化水，有机相用50mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝7:3)，所得粗品用Prep-HPLC制备(仪器:waters 2767制备液相；色谱柱:SunFire@PrepC18(19×250nm)；流动相A：乙腈；流动相B：水(含5mmol/L乙酸铵)；梯度洗脱：流动相A含量从60-90％；流速：12mL/min；柱温：室温；检测波长：210nm；样品用DMF溶解，用0.45um滤头过滤，制成样品液；洗脱时间：18min)，得54c(45mg，收率：2％)。Dissolve 29b (2.30g, 7.18mmol) in THF (20mL), add 4mL of water and lithium hydroxide monohydrate (0.6g, 14.3mmol), and react at room temperature for 30min. Add 1 mol/L hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL of ethyl acetate, separate the layers, wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1 (2.0 g). Add crude product 1 (1.74g) to a 100mL single-neck bottle, add dry dichloromethane (20mL), add DIPEA (1.54g, 11.91mmol), slowly add 54b (1.2g, 4.0mmol) at 0°C, and react at room temperature. 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=73:27) to obtain a crude product (1.0g). Dissolve the above crude product (1g) in 30mL toluene, add ammonium acetate (1.5g, 19.46mmol), and react at 90°C for 16h. The reaction system was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (100 mL) and 100 mL of purified water were added. The organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated on a silica gel chromatography column. Purification (petroleum ether: ethyl acetate (v/v) = 7:3), the crude product obtained is prepared by Prep-HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: SunFire@PrepC18 (19×250nm); mobile phase A : acetonitrile; mobile phase B: water (containing 5mmol/L ammonium acetate); gradient elution: mobile phase A content from 60-90%; flow rate: 12mL/min; column temperature: room temperature; detection wavelength: 210nm; use DMF for samples Dissolve and filter with a 0.45um filter head to prepare a sample solution; elution time: 18min) to obtain 54c (45mg, yield: 2%).
LCMS m/z＝493.2[M+1]+ LCMS m/z＝493.2[M+1] +
第三步；化合物54的制备Step 3: Preparation of compound 54
将54c(45mg，0.091mmol)加入到50mL单口瓶中，加入干燥DMF(8mL)，加入上述粗品中间体1(47mg)、TEA(28mg，0.277mmol)，氮气氛围下加入PdCl2(PPh3)2(12mg，0.017mmol)和CuI(7mg，0.037mmol)，50℃反应2h。将反应体系冷却至室温，缓慢加入饱和氯化铵水溶液(80mL)，用乙酸乙酯萃取(50mL×3)，有机相用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝27:73)，得化合物54(20mg，收率：31％)。Add 54c (45 mg, 0.091 mmol) into a 50 mL single-neck bottle, add dry DMF (8 mL), add the above crude intermediate 1 (47 mg), TEA (28 mg, 0.277 mmol), and add PdCl 2 (PPh 3 ) under nitrogen atmosphere 2 (12 mg, 0.017 mmol) and CuI (7 mg, 0.037 mmol), reacted at 50°C for 2 hours. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (80mL), extract with ethyl acetate (50mL×3), wash the organic phase with saturated aqueous sodium chloride solution (60mL×2), and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v)=27:73) to obtain compound 54 (20 mg, yield: 31%).
1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.48–8.30(m,1H),8.17–8.02(m,1H),7.85–7.40(m,6H),6.84–6.75(m,1H),6.54(dd,1H),4.99–4.88(m,1H),4.40–4.29(m,2H),4.11–4.00(m,2H),3.88–3.72(m,1H),3.24–3.08(m,2H),2.98–2.65(m,5H),2.35–2.00(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.62(s,1H),8.48–8.30(m,1H),8.17–8.02(m,1H),7.85–7.40(m,6H),6.84–6.75(m ,1H),6.54(dd,1H),4.99–4.88(m,1H),4.40–4.29(m,2H),4.11–4.00(m,2H),3.88–3.72(m,1H),3.24–3.08 (m,2H),2.98–2.65(m,5H),2.35–2.00(m,3H).
LCMS m/z＝702.2[M+1]+ LCMS m/z＝702.2[M+1] +
实施例55：化合物55的制备
Example 55: Preparation of Compound 55
第一步：55b的制备Step One: Preparation of 55b
向反应瓶中加入55a(0.5g，2.11mmol)(合成方法见WO2021262596)、55A(0.97g，3.17mmol)、四(三苯基膦)钯(0.24g，0.21mmol)和碳酸钾(0.58g，4.2mmol)溶于20mL 1,4-二氧六环和4mL水中，100℃反应12h。将反应液冷却至室温，加入到50mL乙酸乙酯中，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:0-1:2)，得到55b(0.5g，收率：82％)。Add 55a (0.5g, 2.11mmol) (for synthesis methods, see WO2021262596), 55A (0.97g, 3.17mmol), tetrakis(triphenylphosphine)palladium (0.24g, 0.21mmol) and potassium carbonate (0.58g) into the reaction flask. , 4.2mmol) was dissolved in 20mL 1,4-dioxane and 4mL water, and reacted at 100°C for 12h. The reaction solution was cooled to room temperature, added to 50 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL : Ethyl acetate (v/v) = 1:0-1:2) to obtain 55b (0.5g, yield: 82%).
LCMS m/z＝290.1[M+1]+ LCMS m/z＝290.1[M+1] +
第二步：55c的制备Step 2: Preparation of 55c
将55b(0.5g，1.73mmol)、CuI(0.49g，2.57mmol)和KI(0.43g，2.59mmol)和亚硝酸异戊酯(0.36g，3.07mmol)溶于70mL乙腈中，70℃反应2h。将反应体系减压浓缩，加入到50mL乙酸乙酯和50mL水中，过滤，水相用50mL乙酸乙酯萃取，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(v/v)＝1:0-1:2)，得到55c(0.2g，收率：29％)。Dissolve 55b (0.5g, 1.73mmol), CuI (0.49g, 2.57mmol), KI (0.43g, 2.59mmol) and isoamyl nitrite (0.36g, 3.07mmol) in 70mL acetonitrile, react at 70°C for 2h . Concentrate the reaction system under reduced pressure, add it to 50 mL of ethyl acetate and 50 mL of water, filter, extract the aqueous phase with 50 mL of ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column After separation and purification (petroleum ether:ethyl acetate (v/v)=1:0-1:2), 55c (0.2g, yield: 29%) was obtained.
第三步：化合物55的制备Step 3: Preparation of Compound 55
将55c(0.044g，0.11mmol)、上述粗品中间体1(0.056g)、TEA(0.067g，0.66mmol)、CuI(4.2mg，0.022mmol)和PdCl2(PPh3)2(7.7mg，0.011mmol)加入到反应瓶中，氮气氛围下加入2mL DMF，55℃反应2h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用10mL水洗涤，将滤饼用20mL DCM溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚:二氯甲烷:乙酸乙酯(v/v)＝1:1:2)，得化合物55(0.025g，收率：37％)。55c (0.044g, 0.11mmol), the above crude intermediate 1 (0.056g), TEA (0.067g, 0.66mmol), CuI (4.2mg, 0.022mmol) and PdCl 2 (PPh 3 ) 2 (7.7mg, 0.011 mmol) into the reaction bottle, add 2 mL DMF under nitrogen atmosphere, and react at 55°C for 2 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, suction filtered, the filter cake was washed with 10 mL of water, the filter cake was dissolved in 20 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: Dichloromethane:ethyl acetate (v/v)=1:1:2) to obtain compound 55 (0.025g, yield: 37%).
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.75(s,1H)7.68(d,1H),7.63–7.55(m,1H),7.48–7.40(m,1H),7.32–7.24(m,1H),7.23–7.08(m,2H),6.86–6.79(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.45–4.32(m,2H),4.18–4.05(m,2H),3.94–3.80(m,1H),2.97–2.62(m,3H),2.22–2.07(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.01(s,1H),7.75(s,1H)7.68(d,1H),7.63–7.55(m,1H),7.48–7.40(m,1H),7.32 –7.24(m,1H),7.23–7.08(m,2H),6.86–6.79(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.45–4.32(m,2H) ,4.18–4.05(m,2H),3.94–3.80(m,1H),2.97–2.62(m,3H),2.22–2.07(m,1H).
LCMS m/z＝610.0[M+1]+ LCMS m/z＝610.0[M+1] +
实施例56：化合物56的制备
Example 56: Preparation of Compound 56
化合物56以化合物34a和56a为原料，参照实施例34的合成方法得到。Compound 56 was obtained by referring to the synthesis method of Example 34 using compounds 34a and 56a as raw materials.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.75–7.65(m,3H),7.57–7.49(m,2H),7.23–7.11(m,2H),6.82(d,1H),6.57(dd,1H),6.45(t,1H),5.13(s,2H),4.98–4.89(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.76(m,1H),2.95–2.65(m,3H),2.37(s,3H),2.19(s,3H),2.17–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.75–7.65(m,3H),7.57–7.49(m,2H),7.23–7.11(m,2H),6.82(d,1H ),6.57(dd,1H),6.45(t,1H),5.13(s,2H),4.98–4.89(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H), 3.92–3.76(m,1H),2.95–2.65(m,3H),2.37(s,3H),2.19(s,3H),2.17–2.08(m,1H).
实施例57：化合物57的制备
Example 57: Preparation of Compound 57
化合物57以化合物34a和57a为原料，参照实施例34的合成方法得到。Compound 57 was obtained by referring to the synthesis method of Example 34 using compounds 34a and 57a as raw materials.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.76–7.64(m,3H),7.56–7.49(m,2H),7.41(t,1H),6.82(d,1H),6.73–6.61(m,2H),6.57(dd,1H),5.09(s,2H),4.98–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H),3.95–3.82(m,1H),2.95–2.65(m,3H),2.36(s,3H),2.19(s,3H),2.17–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.94(s,1H),7.76–7.64(m,3H),7.56–7.49(m,2H),7.41(t,1H),6.82(d,1H), 6.73–6.61(m,2H),6.57(dd,1H),5.09(s,2H),4.98–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H), 3.95–3.82(m,1H),2.95–2.65(m,3H),2.36(s,3H),2.19(s,3H),2.17–2.08(m,1H).
实施例58：化合物58的制备
Example 58: Preparation of Compound 58
第一步：58b的制备Step One: Preparation of 58b
将58A(2.40g，7.83mmol)溶于20mL 1,4-二氧六环和2mL水的混合溶剂中，加入58a(2.05g，7.82mmol)、Pd(dppf)Cl2·DCM(0.64g，0.79mmol)和磷酸钾(3.32g，15.64mmol)，置换氮气三次，80℃反应19h。将反应体系冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到58b(2.1g，收率：85％)。Dissolve 58A (2.40g, 7.83mmol) in a mixed solvent of 20mL 1,4-dioxane and 2mL water, add 58a (2.05g, 7.82mmol), Pd(dppf)Cl 2 ·DCM (0.64g, 0.79mmol) and potassium phosphate (3.32g, 15.64mmol), replaced with nitrogen three times, and reacted at 80°C for 19h. The reaction system was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 58b (2.1g, yield: 85%).
LCMS m/z＝315.2[M+1]+ LCMS m/z＝315.2[M+1] +
第二步：58c的制备Step 2: Preparation of 58c
将15mL甲基溴化镁(3mol/L四氢呋喃溶液)加入到5mL超干四氢呋喃中，冷却到0℃，滴加58b(1.18g，3.76mmol)的超干四氢呋喃(10mL)溶液，0℃反应3h。0℃下向反应液中滴加50mL饱和氯化铵水溶液，用150mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-5:1)，得粗品58c(1.21g)。Add 15 mL of methylmagnesium bromide (3 mol/L tetrahydrofuran solution) to 5 mL of ultra-dry tetrahydrofuran, cool to 0°C, add dropwise the ultra-dry tetrahydrofuran (10 mL) solution of 58b (1.18g, 3.76 mmol), and react at 0°C for 3 hours. . Add 50 mL of saturated aqueous ammonium chloride solution dropwise to the reaction solution at 0°C, and extract with 150 mL of ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). (v/v)=10:1-5:1), and the crude product 58c (1.21g) was obtained.
第三步：58d的制备Step 3: Preparation of 58d
将4-碘吡唑(0.55g，2.84mmol)溶于5mL THF溶剂中，加入三苯基膦(1.13g，4.31mmol)和上述粗品58c(0.91g)，0℃下加入DEAD(0.87g，5.0mmol)，60℃反应19h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到58d(0.11g，收率：8％)。Dissolve 4-iodopyrazole (0.55g, 2.84mmol) in 5mL THF solvent, add triphenylphosphine (1.13g, 4.31mmol) and the above crude product 58c (0.91g), add DEAD (0.87g, 5.0mmol), reacted at 60℃ for 19h. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 58d (0.11g, yield: 8%).
第四步：化合物58的制备Step 4: Preparation of Compound 58
将58d(135mg，0.275mmol)、上述粗品中间体1(0.094g)、TEA(85mg，0.84mmol)、CuI(11mg，0.0578mmol)和PdCl2(PPh3)2(39mg，0.056mmol)加入到反应瓶中，氮气保护下加入8mL DMF，55℃反应3h。将反应液冷却至室温，加入20mL水，抽滤，滤饼用5mL水洗涤，将滤饼用40mL DCM/MeOH(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色 谱柱分离纯化(二氯甲烷/甲醇(v/v)＝10:1-5:1)，得化合物58(36mg，收率：19％)。58d (135 mg, 0.275 mmol), the above crude intermediate 1 (0.094 g), TEA (85 mg, 0.84 mmol), CuI (11 mg, 0.0578 mmol) and PdCl 2 (PPh 3 ) 2 (39 mg, 0.056 mmol) were added to In the reaction bottle, add 8 mL DMF under nitrogen protection and react at 55°C for 3 hours. Cool the reaction solution to room temperature, add 20 mL of water, filter with suction, wash the filter cake with 5 mL of water, dissolve the filter cake with 40 mL of a mixed solvent of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and reduce Concentrate by pressure, and color the crude product with silica gel. Column separation and purification (dichloromethane/methanol (v/v) = 10:1-5:1) was performed to obtain compound 58 (36 mg, yield: 19%).
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.75–7.71(m,1H),7.69–7.64(m,3H),7.60–7.52(m,1H),7.45–7.34(m,3H),7.16–7.09(m,2H),6.80(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.99–2.64(m,3H),2.18–2.08(m,1H),2.00(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.92(s,1H),7.75–7.71(m,1H),7.69–7.64(m,3H),7.60–7.52(m,1H),7.45–7.34(m ,3H),7.16–7.09(m,2H),6.80(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m ,2H),3.88–3.75(m,1H),2.99–2.64(m,3H),2.18–2.08(m,1H),2.00(s,6H).
实施例59：化合物59的制备
Example 59: Preparation of Compound 59
第一步：59b的制备Step One: Preparation of 59b
将59A(0.6g，1.96mmol)溶于10mL 1,4-二氧六环和1mL水中，加入59a(2.05g，7.76mmol)、Pd(dppf)Cl2·DCM(0.64g，0.79mmol)和磷酸钾(3.32g，15.64mmol)，氮气氛围下80℃反应19h。将反应液冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到59b(0.58g，收率：93％)。Dissolve 59A (0.6g, 1.96mmol) in 10mL 1,4-dioxane and 1mL water, add 59a (2.05g, 7.76mmol), Pd(dppf)Cl 2 ·DCM (0.64g, 0.79mmol) and Potassium phosphate (3.32g, 15.64mmol), reacted at 80°C for 19h under nitrogen atmosphere. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 59b (0.58g, yield: 93%).
第二步：59c的制备Step 2: Preparation of 59c
将59b(0.37g，1.17mmol)溶于5mL甲醇中，0℃加入硼氢化钠(0.045g，1.19mmol)，室温反应0.5h。加入25mL乙酸乙酯和35mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到59c(0.17g，收率：46％)。Dissolve 59b (0.37g, 1.17mmol) in 5mL methanol, add sodium borohydride (0.045g, 1.19mmol) at 0°C, and react at room temperature for 0.5h. Add 25 mL of ethyl acetate and 35 mL of water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1) , 59c (0.17g, yield: 46%) was obtained.
第三步：59d的制备Step 3: Preparation of 59d
将4-碘吡唑(0.10g，0.52mmol)溶于10mL THF中，加入三苯基膦(0.21g，0.8mmol)和59c(0.17g，0.53mmol)，0℃加入DEAD(0.16g，0.92mmol)，40℃反应19h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到59d(0.19g，收率：74％)。Dissolve 4-iodopyrazole (0.10g, 0.52mmol) in 10mL THF, add triphenylphosphine (0.21g, 0.8mmol) and 59c (0.17g, 0.53mmol), add DEAD (0.16g, 0.92mmol) at 0°C mmol), react at 40°C for 19 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1), obtained 59d (0.19g, yield: 74%).
第四步：化合物59的制备Step 4: Preparation of Compound 59
将59d(190mg，0.38mmol)、上述粗品中间体1(0.13g)、TEA(120mg，1.19mmol)、CuI(14mg，0.074mmol)和PdCl2(PPh3)2(53mg，0.076mmol)加入到反应瓶中，氮气保护下加入15mL DMF，55℃反应3h。将反应液冷却至室温，加入20mL水，抽滤，滤饼用5mL水洗涤，将滤饼用40mL DCM/MeOH(v/v)＝5:1的混合溶剂溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝10:1-5:1)，得化合物59(66mg，收率：25％)。59d (190 mg, 0.38 mmol), the above crude intermediate 1 (0.13 g), TEA (120 mg, 1.19 mmol), CuI (14 mg, 0.074 mmol) and PdCl 2 (PPh 3 ) 2 (53 mg, 0.076 mmol) were added to In the reaction bottle, add 15 mL DMF under nitrogen protection and react at 55°C for 3 hours. Cool the reaction solution to room temperature, add 20 mL of water, filter with suction, wash the filter cake with 5 mL of water, dissolve the filter cake with 40 mL of a mixed solvent of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and reduce The mixture was concentrated under pressure, and the crude product was separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1-5:1) to obtain compound 59 (66 mg, yield: 25%).
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.79–7.72(m,1H),7.70–7.54(m,4H),7.45–7.38(m,1H),7.31–7.23(m,1H),7.05(dd,1H),6.98(dd,1H),6.80(d,1H),6.55(dd,1H),5.54(q,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.93(s,1H),7.79–7.72(m,1H),7.70–7.54(m,4H),7.45–7.38(m,1H),7.31–7.23(m ,1H),7.05(dd,1H),6.98(dd,1H),6.80(d,1H),6.55(dd,1H),5.54(q,1H),4.98–4.88(m,1H),4.40– 4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93(d,3H).
实施例60：化合物60的制备
Example 60: Preparation of Compound 60
第一步：60b的制备Step One: Preparation of 60b
将60A(1.01g，3.3mmol)溶于10mL 1,4-二氧六环和1mL水中，加入60a(0.97g，3.3mmol)、Pd(dppf)Cl2·DCM(0.27g，0.33mmol)和磷酸钾(2.10g，9.89mmol)，氮气氛围下80℃反应19h。将反应体系冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到60b(0.95g，收率：83％)。Dissolve 60A (1.01g, 3.3mmol) in 10mL 1,4-dioxane and 1mL water, add 60a (0.97g, 3.3mmol), Pd(dppf)Cl2·DCM (0.27g, 0.33mmol) and phosphoric acid Potassium (2.10g, 9.89mmol), reacted at 80°C for 19h under nitrogen atmosphere. The reaction system was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 60b (0.95g, yield: 83%).
第二步：60c的制备Step 2: Preparation of 60c
将60b(0.5g，1.44mmol)溶于5mL四氢呋喃/甲醇(v/v)＝10:1的混合溶剂中，0℃加入硼氢化钠(0.13g，3.44mmol)，60℃反应1.5h。将反应液冷却至室温，加入40mL乙酸乙酯和35mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到60c(0.412g，收率：94％)。Dissolve 60b (0.5g, 1.44mmol) in 5mL of a mixed solvent of tetrahydrofuran/methanol (v/v) = 10:1, add sodium borohydride (0.13g, 3.44mmol) at 0°C, and react at 60°C for 1.5h. The reaction solution was cooled to room temperature, 40 mL of ethyl acetate and 35 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 60c (0.412g, yield: 94%).
第三步：60d的制备Step 3: Preparation of 60d
将4-碘吡唑(0.25g，1.29mmol)溶于10mL THF中，加入三苯基膦(0.51g，1.94mmol)和60c(0.412g，1.35mmol)，0℃加入DEAD(CAS:1972-28-7)(0.39g，2.24mmol)，室温反应19h。向反应液中加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到60d(0.21g，收率：34％)。Dissolve 4-iodopyrazole (0.25g, 1.29mmol) in 10mL THF, add triphenylphosphine (0.51g, 1.94mmol) and 60c (0.412g, 1.35mmol), add DEAD (CAS: 1972- 28-7) (0.39g, 2.24mmol), reacted at room temperature for 19h. Add 50 mL of ethyl acetate and 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1- 1:1), 60d (0.21g, yield: 34%) was obtained.
第四步：化合物60的制备Step 4: Preparation of Compound 60
将60d(210mg，0.44mmol)、上述粗品中间体1(0.15g)、TEA(130mg，1.28mmol)、CuI(17mg，0.089mmol)和PdCl2(PPh3)2(62mg，0.088mmol)加入到反应瓶中，氮气氛围下加入10mL DMF，55℃反应3.5h。将反应液冷却至室温，加入50mL水，抽滤，滤饼用5mL水洗涤，将滤饼用40mL DCM/MeOH(v/v)＝5:1溶解，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝10:1-5:1)，得化合物60(54mg，收率：18％)。60d (210 mg, 0.44 mmol), the above crude intermediate 1 (0.15 g), TEA (130 mg, 1.28 mmol), CuI (17 mg, 0.089 mmol) and PdCl 2 (PPh 3 ) 2 (62 mg, 0.088 mmol) were added to In the reaction bottle, add 10 mL DMF under nitrogen atmosphere and react at 55°C for 3.5 hours. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 5 mL of water, dissolve the filter cake with 40 mL of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1-5:1) to obtain compound 60 (54 mg, yield: 18%).
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.79–7.73(m,1H),7.70–7.62(m,2H),7.61–7.55(m,2H),7.45–7.39(m,1H),7.32–7.26(m,1H),7.07(dd,1H),6.99(dd,1H),6.80(d,1H),6.55(dd,1H),5.34(s,2H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.12–4.03(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.20–2.08(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.98(s,1H),7.79–7.73(m,1H),7.70–7.62(m,2H),7.61–7.55(m,2H),7.45–7.39(m ,1H),7.32–7.26(m,1H),7.07(dd,1H),6.99(dd,1H),6.80(d,1H),6.55(dd,1H),5.34(s,2H),4.98– 4.88(m,1H),4.40–4.30(m,2H),4.12–4.03(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.20–2.08(m,1H ).
实施例61：化合物61的制备
Example 61: Preparation of Compound 61
第一步：61b的制备 Step One: Preparation of 61b
将18mL甲基溴化镁(3mol/L四氢呋喃溶液)加入到5mL超干四氢呋喃中，0℃滴加61a(3.01g，11.49mmol)的超干四氢呋喃(30mL)溶液，0℃反应3h。0℃向反应液中滴加100mL饱和氯化铵水溶液，用250mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-5:1)，得61b(1.65g，收率：55％)。Add 18 mL of methylmagnesium bromide (3 mol/L tetrahydrofuran solution) to 5 mL of ultra-dry tetrahydrofuran, add dropwise the ultra-dry tetrahydrofuran (30 mL) solution of 61a (3.01 g, 11.49 mmol) at 0 ° C, and react at 0 ° C for 3 hours. Add 100 mL saturated aqueous ammonium chloride solution dropwise to the reaction solution at 0°C, extract with 250 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v)=10:1-5:1), 61b (1.65g, yield: 55%) was obtained.
第二步：61c的制备Step 2: Preparation of 61c
将61b(0.3g，1.14mmol)和苯酚(0.13g，1.38mmol)溶于5mL四氯化碳中，0℃加入三氟化硼乙醚(0.32g，2.25mmol)，室温反应2h。向反应液中加入50mL水，用40mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到61c(0.32g，收率：83％)。Dissolve 61b (0.3g, 1.14mmol) and phenol (0.13g, 1.38mmol) in 5 mL carbon tetrachloride, add boron trifluoride ether (0.32g, 2.25mmol) at 0°C, and react at room temperature for 2 hours. Add 50 mL of water to the reaction solution, extract with 40 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10: 1-1:1), 61c (0.32g, yield: 83%) was obtained.
第三步：61d的制备Step 3: Preparation of 61d
将61c(320mg，0.95mmol)、1A(170mg，0.94mmol)、TEA(291mg，2.88mmol)、CuI(36mg，0.19mmol)和PdCl2(PPh3)2(135mg，0.19mmol)加入到反应瓶中，氮气氛围下加入5mL DMF，55℃反应3.5h。将反应液冷却至室温，加入50mL水，用100mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(二氯甲烷/甲醇(v/v)＝10:1-5:1)，得61d(172mg，收率：47％)。Add 61c (320mg, 0.95mmol), 1A (170mg, 0.94mmol), TEA (291mg, 2.88mmol), CuI (36mg, 0.19mmol) and PdCl 2 (PPh 3 ) 2 (135mg, 0.19mmol) into the reaction flask. , add 5mL DMF under nitrogen atmosphere, and react at 55°C for 3.5h. The reaction solution was cooled to room temperature, 50 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1-5:1), 61d (172 mg, yield: 47%) was obtained.
第四步：61e的制备Step 4: Preparation of 61e
将61d(0.3g，0.77mmol)溶于10mL二氯甲烷中，加入2-[N,正双(三氟甲烷烷磺酰)氨基]吡啶(0.33g，0.92mmol)、DMAP(9mg，0.074mmol)和TEA(0.12g，1.19mmol)，室温反应1h。将反应体系减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到61e(0.15g，收率：37％)。Dissolve 61d (0.3g, 0.77mmol) in 10mL dichloromethane, add 2-[N, n-bis(trifluoromethanesulfonyl)amino]pyridine (0.33g, 0.92mmol), DMAP (9mg, 0.074mmol) ) and TEA (0.12g, 1.19mmol), reacted at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1) to obtain 61e (0.15g, yield: 37%).
第五步：61f的制备Step 5: Preparation of 61f
将61e(0.15g，0.286mmol)溶于10mL 1,4-二氧六环和1mL水的混合溶剂中，加入2-氯-4-(三氟甲基)苯硼酸频那醇酯(0.08g，0.26mmol)、磷酸钾(0.17g，0.8mmol)和Pd(dppf)Cl2·DCM(0.021g，0.026mmol)，氮气氛围下80℃反应19h。将反应液冷却至室温，加入100mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到61f(0.14g，收率：97％)。Dissolve 61e (0.15g, 0.286mmol) in a mixed solvent of 10mL 1,4-dioxane and 1mL water, and add 2-chloro-4-(trifluoromethyl)phenylboronic acid pinacol ester (0.08g , 0.26mmol), potassium phosphate (0.17g, 0.8mmol) and Pd(dppf)Cl2·DCM (0.021g, 0.026mmol), reacted at 80°C for 19h under nitrogen atmosphere. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 61f (0.14g, yield: 97%).
化合物61以化合物61f为原料，参照实施例41的合成方法得到。Compound 61 was obtained by referring to the synthesis method of Example 41 using compound 61f as a raw material.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.75–7.70(m,1H),7.67(d,1H),7.59–7.51(m,1H),7.49–7.40(m,1H),7.39–7.31(m,4H),7.30–7.25(m,2H),7.25–7.20(m,2H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.43–4.32(m,2H),4.14–4.04(m,2H),3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.71(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.92(s,1H),7.75–7.70(m,1H),7.67(d,1H),7.59–7.51(m,1H),7.49–7.40(m,1H) ),7.39–7.31(m,4H),7.30–7.25(m,2H),7.25–7.20(m,2H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H ),4.43–4.32(m,2H),4.14–4.04(m,2H),3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.71(s ,6H).
实施例62：化合物62的制备
Example 62: Preparation of Compound 62
第一步：62B的制备Step One: Preparation of 62B
将62A(10.00g，34.96mmol)(合成方法见WO2022032026)与3-碘氮杂环丁-1-甲酸叔丁酯(11.88g，41.96mmol)溶于100mL DMA中，加入锌粉(13.72g，211.08mmol)，氮气氛围下加入2-脒基吡啶盐酸盐(CAS:51285-26-8)(1.10g，6.98mmol)与氯化镍乙二醇二甲醚络合物(CAS:29046-78-4)(1.54g，7.01mmol)，氮气氛围下100℃反应16h。将反应体系冷却至室温，加入300mL水和200mL乙酸乙酯，过滤，将滤液分液，水相用200mL乙酸乙酯萃取，有机相用100mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝4:1)，得到62B(2.9g，收率：23％)。Dissolve 62A (10.00g, 34.96mmol) (for synthesis method, see WO2022032026) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (11.88g, 41.96mmol) in 100mL DMA, add zinc powder (13.72g, 211.08mmol), add 2-amidinopyridine hydrochloride (CAS: 51285-26-8) (1.10g, 6.98mmol) and nickel chloride ethylene glycol dimethyl ether complex (CAS: 29046- 78-4) (1.54g, 7.01mmol), reacted at 100°C for 16h under nitrogen atmosphere. Cool the reaction system to room temperature, add 300 mL water and 200 mL ethyl acetate, filter, separate the filtrate, extract the aqueous phase with 200 mL ethyl acetate, wash the organic phase with 100 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product. Separate and purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 62B (2.9 g, yield: 23%).
第二步：62C的制备Step 2: Preparation of 62C
将62B(2.9g，8.0mmol)溶解于40mL甲醇中，加入碳酸钾(6.63g，48mmol)与碳酸铯(5.21g，15.99mmol)，60℃反应16h。将反应体系冷却至室温，加入100mL DCM，过滤，将滤液减压浓缩，粗品用硅胶柱色谱纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到62C(1.8g，收率：84％)。Dissolve 62B (2.9g, 8.0mmol) in 40mL methanol, add potassium carbonate (6.63g, 48mmol) and cesium carbonate (5.21g, 15.99mmol), and react at 60°C for 16h. The reaction system was cooled to room temperature, 100 mL DCM was added, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1) to obtain 62C (1.8 g, collected rate: 84%).
第三步：62a-1的制备Step 3: Preparation of 62a-1
将62C(1.8g，6.76mmol)溶解于30mL乙腈中，加入KI(1.68g，10.12mmol)与CuI(1.93g，10.13mmol)，缓慢滴加亚硝酸异戊酯(1.43g，12.21mmol)，50℃反应16h。将反应体系冷却至室温，加入100mL饱和硫代硫酸钠水溶液，过滤，将滤液用100mL乙酸乙酯萃取，有机相用50mL水洗涤，无水硫酸钠干燥，减压浓缩，粗品用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝3:1)，得到62a-1(1.4g，收率：55％)。Dissolve 62C (1.8g, 6.76mmol) in 30mL acetonitrile, add KI (1.68g, 10.12mmol) and CuI (1.93g, 10.13mmol), slowly add isoamyl nitrite (1.43g, 12.21mmol) dropwise, React at 50°C for 16 hours. Cool the reaction system to room temperature, add 100 mL of saturated sodium thiosulfate aqueous solution, filter, extract the filtrate with 100 mL of ethyl acetate, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography. After purification (petroleum ether/ethyl acetate (v/v)=3:1), 62a-1 (1.4 g, yield: 55%) was obtained.
第四步：62b的制备Step 4: Preparation of 62b
将62a-1(0.58g，1.54mmol)溶于15mL 1,4-二氧六环和1mL水中，加入62a(0.45g，1.61mmol)、Pd(dppf)Cl2·DCM(0.13g，0.16mmol)和磷酸钾(0.98g，4.62mmol)，置换氮气三次，80℃反应19h。将反应体系冷却至室温，加入80mL乙酸乙酯和100mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到62b(0.46g，收率：74％)。Dissolve 62a-1 (0.58g, 1.54mmol) in 15mL 1,4-dioxane and 1mL water, add 62a (0.45g, 1.61mmol), Pd(dppf)Cl2·DCM (0.13g, 0.16mmol) and potassium phosphate (0.98g, 4.62mmol), replaced with nitrogen three times, and reacted at 80°C for 19 hours. The reaction system was cooled to room temperature, 80 mL of ethyl acetate and 100 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 62b (0.46g, yield: 74%).
第五步：62c的制备Step 5: Preparation of 62c
将62b(0.46g，1.14mmol)溶于10mL四氢呋喃/甲醇(v/v)＝10:1中，0℃加入硼氢化锂(0.097g，4.45mmol)，60℃反应2h。将反应液冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯 (v/v)＝10:1-1:1)，得到62c(0.41g，收率：96％)。Dissolve 62b (0.46g, 1.14mmol) in 10 mL tetrahydrofuran/methanol (v/v) = 10:1, add lithium borohydride (0.097g, 4.45mmol) at 0°C, and react at 60°C for 2 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). (v/v)=10:1-1:1), 62c (0.41g, yield: 96%) was obtained.
第六步：62d的制备Step Six: Preparation of 62d
将62c(0.200g，0.53mmol)溶于5mL二氯甲烷中，0℃加入吡啶(0.13g，1.64mmol)和MsCl(0.073g，0.64mmol)，室温反应2h。加入20mL二氯甲烷和20mL水，有机相用无水硫酸钠干燥，减压浓缩，得粗品1。将上述粗品1溶于5mL乙腈中，加入碳酸铯(0.52g，1.60mmol)和34a(0.18g，0.81mmol)，60℃反应19h。将反应体系冷却至室温，加入50mL乙酸乙酯和50mL水，有机相用无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-1:1)，得到62d(0.13g，收率：42％)。Dissolve 62c (0.200g, 0.53mmol) in 5mL dichloromethane, add pyridine (0.13g, 1.64mmol) and MsCl (0.073g, 0.64mmol) at 0°C, and react at room temperature for 2h. Add 20 mL dichloromethane and 20 mL water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1. Dissolve the above crude product 1 in 5 mL acetonitrile, add cesium carbonate (0.52g, 1.60mmol) and 34a (0.18g, 0.81mmol), and react at 60°C for 19h. The reaction system was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10 :1-1:1) to obtain 62d (0.13g, yield: 42%).
第七步：化合物62的制备Step 7: Preparation of Compound 62
将62d(0.13g，0.22mmol)和对甲苯磺酸(0.15g，0.87mmol)溶于5mL乙腈中，室温反应12h。将反应液减压浓缩，得粗品2。将上述粗品2、碳酸氢钠(0.074g，0.88mmol)、1f(0.073g，0.26mmol)和DIPEA(0.11g，0.85mmol)溶于5mL DMSO中，80℃反应3h。将反应液冷却到室温，加入100mL乙酸乙酯，有机相用饱和氯化钠水溶液洗涤(50mL×3)，无水硫酸钠干燥，减压浓缩，粗品用硅胶色谱柱分离纯化(石油醚/乙酸乙酯(v/v)＝1:0-1:2)，得到化合物62(0.05g，收率：31％)。Dissolve 62d (0.13g, 0.22mmol) and p-toluenesulfonic acid (0.15g, 0.87mmol) in 5mL acetonitrile and react at room temperature for 12h. The reaction solution was concentrated under reduced pressure to obtain crude product 2. Dissolve the above crude product 2, sodium bicarbonate (0.074g, 0.88mmol), 1f (0.073g, 0.26mmol) and DIPEA (0.11g, 0.85mmol) in 5mL DMSO, and react at 80°C for 3h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate was added, the organic phase was washed with saturated sodium chloride aqueous solution (50 mL Ethyl ester (v/v)=1:0-1:2) to obtain compound 62 (0.05g, yield: 31%).
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.76–7.66(m,3H),7.58–7.51(m,2H),7.51–7.42(m,1H),7.40–7.22(m,4H),6.87(d,1H),6.65–6.55(m,2H),5.18(s,2H),4.99–4.89(m,1H),4.58–4.46(m,2H),4.39–4.26(m,1H),4.20–4.10(m,2H),2.98–2.65(m,3H),2.41(s,3H),2.24(s,3H),2.19–2.09(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.95(s,1H),7.76–7.66(m,3H),7.58–7.51(m,2H),7.51–7.42(m,1H),7.40–7.22(m ,4H),6.87(d,1H),6.65–6.55(m,2H),5.18(s,2H),4.99–4.89(m,1H),4.58–4.46(m,2H),4.39–4.26(m ,1H),4.20–4.10(m,2H),2.98–2.65(m,3H),2.41(s,3H),2.24(s,3H),2.19–2.09(m,1H).
LCMS m/z＝733.4[M-1]- LCMS m/z＝733.4[M-1] -
生物测试例Biological test examples
1.抑制22RV1细胞增殖实验1. Inhibition of 22RV1 cell proliferation experiment
前列腺癌细胞22RV1购置于ATCC，细胞培养基为RPMI 1640+10％FBS，培养于37℃,5％CO2孵箱中。第一天收集处于指数生长期的细胞，用1％css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板，使细胞为2000个/孔，孵育过夜。第二天加入不同浓度的化合物，置于孵箱中培养继续孵育7天。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7573)操作说明，每孔加入50μL预先融化并平衡到室温的CellTiter-Glo试剂，用微孔板震荡器混匀2分钟，于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。结果按照式(1)处理，计算出化合物各个浓度的抑制率，并使用origin9.2软件，采用DoseResp函数计算化合物抑制率为50％的IC50值。其中RLUcompound为药物处理组的读数，RLUcontrol为DMSO溶剂对照组的平均值。
Inhibition％＝[1-RLUcompound/RLUcontrol]×100％  式(1)Prostate cancer cell 22RV1 was purchased from ATCC. The cell culture medium was RPMI 1640+10% FBS and cultured in a 37°C, 5% CO 2 incubator. Collect the cells in the exponential growth phase on the first day, use 1% css-FBS phenol red-free medium to adjust the cell suspension to the corresponding concentration and plate it to 2000 cells/well, and incubate overnight. The next day, compounds of different concentrations were added, placed in an incubator, and incubated for another 7 days. After the incubation, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 μL of CellTiter-Glo reagent that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 minutes. The fluorescence signal value was then measured using a microplate reader (PHERAstar FSX). The results are processed according to formula (1), the inhibition rate of each concentration of the compound is calculated, and the IC 50 value of the compound's inhibition rate of 50% is calculated using the origin9.2 software and the DoseResp function. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the DMSO solvent control group.
Inhibition%=[1-RLU compound /RLU control ]×100% Formula (1)
抑制22RV1细胞增殖的IC50值结果见表1。The IC 50 value results for inhibiting 22RV1 cell proliferation are shown in Table 1.
表1本发明化合物抑制22RV1细胞的IC50值

Table 1 IC 50 value of compounds of the present invention inhibiting 22RV1 cells

结论：本发明化合物，例如实施例化合物对前列腺细胞22RV1具有抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, have inhibitory effects on prostate cells 22RV1.
2. 22RV1细胞中AR剪切突变体7(AR-V7)的降解实验2. Degradation experiment of AR splicing mutant 7 (AR-V7) in 22RV1 cells
前列腺癌细胞22RV1购置于ATCC，细胞培养基为1640+10％FBS，培养于37℃，5％CO2孵箱中。第一天收集处于指数生长期的细胞，用1％css-FBS无酚红培养基将细胞悬液调整为相应浓度铺板，6孔板每孔1mL，细胞数量为300000个/孔。次日加入含待测化合物的1％css-FBS无酚红培养基，其中一个孔加入0.2％DMSO的1％css-FBS无酚红培养基作为DMSO溶媒对照，6孔板培养于37℃,5％CO2孵箱中。24或48小时后，胰酶消化，收集细胞于1.5mL离心管，向每孔加入15μL RIPA裂解液(含1X蛋白酶抑制剂混合物(Protease Inhibitor cocktail))，于冰上裂解15分钟后，12000g，4℃，离心10分钟。收集上清蛋白样品，用BCA法进行蛋白定量。使用全自动蛋白质表达定量分析检测AR-V7，实验过程如下，将待测蛋白浓度稀释至2mg/mL。取4μL稀释后的蛋白样品加入1μL 5×Master Mix(试剂盒提供)，将配制好的样品放在95℃变性5分钟，放在冰上待用。使用Antibody Diluent II(试剂盒提供)稀释一抗，一抗为AR V7(CST,19672S)与β-actin(CST,3700)，稀释比例分别为1:10和1:500。二抗为1:1混合羊抗小鼠和羊抗兔二抗，显色液为1:1混合的Lumino-S和Peroxide。按照试剂盒说明书将配制好的试剂依次加入检测板内，上机检测。Western条带处理使用全自动蛋白质表达定量分析软件“Compass for SW”根据信号值自动模拟western条带。根据式(2)计算不同药物浓度下，AR-V7(2)相对 于溶媒对照的降解率。其中AR-V7compound为给药组AR-V7相对峰面积，AR-V7solvent为溶媒对照组AR-V7相对峰面积。
AR-V7％＝(1-AR-V7compound/AR-V7solvent)×100％  式(2)Prostate cancer cell 22RV1 was purchased from ATCC, the cell culture medium was 1640+10% FBS, and cultured in a 37°C, 5% CO2 incubator. Cells in the exponential growth phase were collected on the first day, and the cell suspension was adjusted to the corresponding concentration using 1% css-FBS phenol red-free medium and plated, with 1 mL per well of a 6-well plate, and the number of cells was 300,000 cells/well. The next day, 1% css-FBS phenol red-free medium containing the compound to be tested was added, and 0.2% DMSO of 1% css-FBS phenol red-free medium was added to one well as a DMSO solvent control. The 6-well plate was cultured at 37°C. 5% CO 2 incubator. After 24 or 48 hours, trypsinize, collect the cells in a 1.5mL centrifuge tube, add 15μL RIPA lysis solution (containing 1X protease inhibitor cocktail (Protease Inhibitor cocktail)) to each well, lyse on ice for 15 minutes, 12000g, Centrifuge at 4°C for 10 minutes. Supernatant protein samples were collected and protein quantified using BCA method. Use fully automated protein expression quantitative analysis to detect AR-V7. The experimental process is as follows. Dilute the protein concentration to be tested to 2 mg/mL. Take 4 μL of the diluted protein sample and add 1 μL of 5×Master Mix (provided by the kit). Denature the prepared sample at 95°C for 5 minutes and put it on ice until use. Use Antibody Diluent II (provided in the kit) to dilute the primary antibodies. The primary antibodies are AR V7 (CST, 19672S) and β-actin (CST, 3700). The dilution ratios are 1:10 and 1:500 respectively. The secondary antibody was a 1:1 mixture of goat anti-mouse and goat anti-rabbit secondary antibodies, and the chromogenic solution was a 1:1 mixture of Lumino-S and Peroxide. According to the instructions of the kit, add the prepared reagents to the detection plate in sequence, and run the test on the machine. Western band processing uses the fully automatic protein expression quantitative analysis software "Compass for SW" to automatically simulate western bands based on signal values. Calculate according to formula (2), under different drug concentrations, the relative Degradation rate compared to solvent control. Among them, AR-V7 compound is the relative peak area of AR-V7 in the administration group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group.
AR-V7%=(1-AR-V7 compound /AR-V7 solvent )×100% Formula (2)
DC50计算：按照式(2)处理，使用Graphpad软件计算并采用log(inhibitor)vs.response–Variable slope(four parameters)函数分析AR-V7降解率为50％时的化合物浓度DC50值。DC 50 calculation: According to formula (2), use Graphpad software to calculate and use the log (inhibitor) vs. response–Variable slope (four parameters) function to analyze the DC 50 value of the compound concentration when the AR-V7 degradation rate is 50%.
降解AR-V7蛋白的DC50值结果见表2。The results of DC 50 value for degrading AR-V7 protein are shown in Table 2.
表2本发明化合物48小时降解22RV1细胞AR-V7蛋白的DC50值
Table 2 DC 50 value of compounds of the present invention degrading AR-V7 protein in 22RV1 cells in 48 hours
结论：本发明化合物，例如实施例化合物对前列腺细胞22RV1中AR-V7具有良好的降解作用。Conclusion: The compounds of the present invention, such as the example compounds, have a good degradation effect on AR-V7 in prostate cells 22RV1.
3.大鼠药代动力学测试3. Rat pharmacokinetic test
实验目的：本试验通过单剂量静脉和灌胃给予受试物于SD大鼠，测定大鼠血浆中受试物的浓度，评价受试物在大鼠体内药代特征。Purpose of the experiment: In this experiment, the test substance was administered to SD rats through a single dose intravenously and intragastrically, to measure the concentration of the test substance in rat plasma, and to evaluate the pharmacokinetic characteristics of the test substance in rats.
试验动物：雄性SD大鼠，200～250g，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。Test animals: male SD rats, 200-250g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验方法：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Test method: On the day of the test, 6 SD rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表3
table 3
*剂量以游离碱计。*Dosage is based on free base.
取样：于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。Sampling: Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
IV&PO组采集血浆时间点：0,5min,15min,30min,1,2,4,6,8,24h。The plasma collection time points in the IV&PO group were: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, and 24h.
分析检测前，所有样品存于-60℃。用LC-MS/MS对样品进行定量分析。Before analysis and detection, all samples were stored at -60°C. Samples were quantitatively analyzed using LC-MS/MS.
表4本发明化合物在大鼠血浆中药代动力学参数

Table 4 Pharmacokinetic parameters of the compounds of the present invention in rat plasma

*注：i.g.(灌胃)给予化合物-表示未测：*Note: Compounds administered i.g. (gavage) - indicates not tested:
结论：运用本发明化合物，例如实施例化合物在大鼠体内具有较好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in rats.
4.小鼠药代动力学测试4. Mouse pharmacokinetic test
4.1试验动物：雄性ICR小鼠，25～30g，6只/化合物。购于成都达硕实验动物有限公司。4.1 Test animals: male ICR mice, 25-30g, 6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
4.2试验设计：试验当天，6只ICR小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。4.2 Experimental design: On the day of the experiment, 6 ICR mice were randomly divided into groups according to body weight. No food or water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表5.给药信息
Table 5. Dosing information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,7,24h。分析检测前，所有样品存于-60℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and detection, all samples were stored at -60°C and quantitatively analyzed using LC-MS/MS.
表6本发明化合物在小鼠血浆中药代动力学参数
Table 6 Pharmacokinetic parameters of the compounds of the present invention in mouse plasma
*注：i.g.(灌胃)给予化合物；*Note: Compounds are administered i.g. (gavage);
结论：运用本发明化合物，例如实施例化合物在小鼠体内具有较好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in mice.
5.比格犬药代动力学测试5. Beagle dog pharmacokinetics test
试验动物：雄性比格犬，8～10kg左右，6只/化合物，购于北京玛斯生物技术有限公司。Experimental animals: male beagles, about 8-10kg, 6/compound, purchased from Beijing Mas Biotechnology Co., Ltd.
试验方法：试验当天，6只比格犬按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Test method: On the day of the test, 6 beagle dogs were randomly divided into groups according to body weight. No food and water for 14 to 18 hours one day before administration, and food 4 hours after administration.
表7.给药信息
Table 7. Dosing information
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline； Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后通过颈静脉或四肢静脉取血1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24,48h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 mL of blood was taken from the jugular vein or limb veins and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24, 48h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.
结论：运用本发明化合物，例如实施例化合物在犬体内具有较好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in dogs.
6.猴药代动力学测试6. Monkey pharmacokinetic test
试验动物：雄性食蟹猴，3～5kg，3～6年龄，4只/化合物。购于苏州西山生物技术有限公司。Test animals: male cynomolgus monkeys, 3 to 5 kg, 3 to 6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
试验方法：试验当天，4只猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Test method: On the day of the test, 4 monkeys were randomly divided into groups according to body weight. No food and water for 14 to 18 hours one day before administration, and food 4 hours after administration.
表8.给药信息
Table 8. Dosing Information
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
口服(灌胃)给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1.0 mL of blood was taken from the veins of the limbs and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, and 24h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.
结论：运用本发明化合物，例如实施例化合物在猴体内具有较好的口服吸收。Conclusion: The compounds of the present invention, such as the compounds in the examples, have better oral absorption in monkeys.
7.hERG钾离子通道作用测试7.hERG potassium ion channel function test
实验平台：电生理手动膜片钳系统Experimental platform: electrophysiology manual patch clamp system
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after infusion of the electrode liquid is about 2-5MΩ. The glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamp voltage and data recording were controlled and recorded via computer using pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz. After obtaining the whole-cell recording, the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ≥ 2).
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1–(I/Io)]×100％ Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50mV) at different compound concentrations was calculated using the following formula:
Inhibition%＝[1–(I/Io)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。Among them, Inhibition% represents the inhibition percentage of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。Among them, X is the Log value of the detected concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively.
结论：本发明化合物，例如实施例化合物对hERG钾通道电流没有明显的抑制作用。Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on hERG potassium channel current.
8.肝微粒体稳定性测试8. Liver Microsome Stability Test
本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。This experiment uses five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and the liver intrinsic clearance rate CL int(Liver) .
结论：本发明化合物，例如实施例化合物具有良好的肝微粒体稳定性。Conclusion: The compounds of the present invention, such as the example compounds, have good liver microsome stability.
9.CYP450酶抑制测试9.CYP450 enzyme inhibition test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC 50 value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms.
结论：本发明化合物，例如实施例化合物对人肝微粒体细胞色素P450的5种同工酶没有明显的抑制作用。Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on the five isoenzymes of human liver microsomal cytochrome P450.
10.Caco2渗透性测试10.Caco2 Penetration Test
试验使用单层Caco-2细胞，在96孔Transwell板中采用三平行孵育。将含有本发明化合物(2μM)或对照化合物地高辛(10μM)、纳多洛尔(2μM)和美托洛尔(2μM)的转运缓冲溶液(HBSS，10mM HEPES，pH 7.4±0.05)加入顶端侧或基底侧的给药端孔中。对应接收端孔中加入含DMSO的转运缓冲溶液。在37±1℃条件下孵育2小时后，取出细胞板并从顶端和底端各取出适量样品至新的96孔板中。随后加入含内标的乙腈沉淀蛋白。使用LC MS/MS分析样品并测定本发明化合物和对照化合物的浓度。浓度数据用于计算从单层细胞顶端侧向基底侧、以及基底侧向顶端转运的表观渗透系数，从而计算外排率。用荧光黄的渗漏评价孵育2小时后单层细胞的完整性。The assay uses a monolayer of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the invention (2μM) or the control compounds digoxin (10μM), nadolol (2μM) and metoprolol (2μM) was added to the apical side Or in the administration port hole on the basal side. Add DMSO-containing transport buffer solution to the corresponding receiving port hole. After incubating for 2 hours at 37±1°C, remove the cell plate and take appropriate amounts of samples from the top and bottom ends into a new 96-well plate. Acetonitrile containing internal standard was then added to precipitate the protein. Samples were analyzed using LC MS/MS and the concentrations of compounds of the invention and control compounds were determined. Concentration data were used to calculate apparent permeability coefficients for transport from the apical side to the basal side, and from the basal side to the apical side of the cell monolayer, and thus the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.
结论：本发明化合物，例如实施例化合物具有一定的Caco2渗透性。Conclusion: The compounds of the present invention, such as the example compounds, have certain Caco2 permeability.
11.本发明化合物对小鼠22RV1皮下移植瘤模型生长的抑制实验11. Experiment on the inhibition of the growth of the 22RV1 subcutaneous transplanted tumor model in mice by the compounds of the present invention
细胞培养：22RV1细胞(来源于ATCC)体外培养，培养条件为添加10％胎牛血清以及含10μg/mL重组胰岛素的培养基，37℃，5％CO2。一周常规传代2次。当细胞维持在指数增长期时，收取细胞，计数，接种。Cell culture: 22RV1 cells (derived from ATCC) were cultured in vitro. The culture conditions were medium supplemented with 10% fetal calf serum and 10 μg/mL recombinant insulin at 37°C and 5% CO 2 . Passaging was performed twice a week. When the cells are maintained in the exponential growth phase, cells are harvested, counted, and seeded.
动物：BALB/c nude小鼠，雄性，4-6周龄，体重14-20克。由北京维通利华实验动物技术 有限公司提供。Animals: BALB/c nude mice, male, 4-6 weeks old, weighing 14-20 grams. by Beijing Vitong Lever Experimental Animal Technology Ltd. provided.
肿瘤接种：实验小鼠于右侧背部皮下接种5×106 22RV1细胞，细胞重悬在PBS与基质胶(1:1)中，定期观察肿瘤生长情况，待肿瘤生长至平均体积为80mm3时进行去势：用异氟烷麻醉小鼠，手术阉割通过阴囊中线切口进行，允许双侧进入，暴露每个睾丸后，用5-0vicryl缝线结扎精索，然后切除睾丸，然后分别用5-0Vicyryl缝合阴囊和皮肤，术后需继续观察动物至完全苏醒。去势后，肿瘤可能缩小(肿瘤退化)，当平均肿瘤体积重新生长到100mm3左右时开始分组和治疗，分组当天为Day 0。Tumor inoculation: Experimental mice were subcutaneously inoculated with 5×10 6 22RV1 cells on the right back. The cells were resuspended in PBS and Matrigel (1:1). Tumor growth was observed regularly until the tumor grew to an average volume of 80 mm 3 Perform castration: Anesthetize mice with isoflurane, and surgical castration is performed through a midline incision in the scrotum, allowing bilateral access. After exposing each testicle, the spermatic cord is ligated with 5-0 vicryl sutures, and then the testicles are removed, and then each testicle is ligated with 5-0 vicryl sutures. 0Vicyryl sutures the scrotum and skin, and the animal needs to continue to be observed after surgery until it fully wakes up. After castration, the tumors may shrink (tumor regression). Grouping and treatment will begin when the average tumor volume re-grows to about 100 mm. The day of grouping is Day 0.
给药：本发明化合物按照一定给药剂量，口服给药(PO)，每天一次给药(QD)，每组10只小鼠，所有组持续给药28天。Administration: The compound of the present invention was administered orally (PO) and once a day (QD) according to a certain dosage. There were 10 mice in each group, and all groups were administered continuously for 28 days.
实验观察和结束：每周3次测量小鼠体重以及肿瘤测量。给药28天后结束实验，安乐死所有小鼠。肿瘤体积计算公式：肿瘤体积(mm3)＝1/2×(a×b2)(其中a表示长径，b表示短径)，原始数据由天平和游标卡尺测量。Experimental observation and conclusion: The mouse body weight and tumor measurement were measured three times a week. The experiment was terminated 28 days after administration, and all mice were euthanized. Tumor volume calculation formula: tumor volume (mm 3 ) = 1/2 × (a × b 2 ) (where a represents the long diameter and b represents the short diameter), and the original data were measured by a balance and a vernier caliper.
结论：本发明化合物，例如实施例化合物对小鼠22RV1皮下移植瘤模型生长有一定的抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, have a certain inhibitory effect on the growth of the mouse 22RV1 subcutaneous transplanted tumor model.
12. 1.HEK293细胞增殖实验12. 1.HEK293 cell proliferation experiment
人胚肾293细胞HEK293购置于ATCC，完全培养基为EMEM+10％FBS，培养于37℃,5％CO2孵箱中。收集处于指数生长期的细胞，用完全培养基将细胞悬液调整为相应浓度并铺板，使细胞为1000个/孔，体积为每孔180μL。次日加入20μL不同浓度的化合物，置于孵箱中继续孵育培养7天。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7573)操作说明，每孔加入50μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。化学发光读数使用Graphpad Prim 8.0软件，采用使用四参数非线性回归模型绘制S型浓度曲线并计算IC50值。结果按照式(3)处理，计算出化合物各个浓度的增殖率Growth％，并使用Graphpad Prim 8.0软件，计算增殖率为50％时化合物的浓度IC50值。其中RLUcompound为药物处理组的读数，RLUcontrol为溶剂对照组的平均值。
Growth％＝RLUcompound/RLUcontrol×100％   式(3)Human embryonic kidney 293 cells HEK293 were purchased from ATCC. The complete culture medium was EMEM+10% FBS and cultured in a 37°C, 5% CO 2 incubator. Collect cells in the exponential growth phase, adjust the cell suspension to the corresponding concentration with complete culture medium and plate it so that the number of cells is 1000/well and the volume is 180 μL per well. The next day, 20 μL of compounds of different concentrations were added and placed in an incubator to continue incubation for 7 days. After the culture, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 μL of CTG solution that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 minutes before using. The fluorescence signal value was measured with a microplate reader (PHERAstar FSX). Chemiluminescence readings were performed using Graphpad Prim 8.0 software, using a four-parameter nonlinear regression model to draw a S-shaped concentration curve and calculate the IC 50 value. The results were processed according to formula (3), the growth rate of each concentration of the compound was calculated, and the IC 50 value of the concentration of the compound when the growth rate was 50% was calculated using Graphpad Prim 8.0 software. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group.
Growth%=RLU compound /RLU control ×100% Formula (3)
结论：本发明化合物，例如实施例化合物对人胚肾293细胞HEK293具有较弱的抑制作用。 Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak inhibitory effects on human embryonic kidney 293 cells HEK293.

Claims (15)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物，
    B-L-K  (I)；    A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
    BLK(I);
    L选自键或-C1-50烃基-，所述烃基中有1至20个亚甲基单元任选被-Ak-、-Cy-替换；L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;
    每个-Ak-各自独立地选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自卤素、OH、CN、NH2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基的取代基所取代；Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S -(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -NR L ( CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH＝CH-, -Si(R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(＝O )(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- optionally substituted by 1 to 2 selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl Substituted with substituents of C 1-6 alkyl and cyano-substituted C 1-6 alkyl;
    q各自独立的选自0、1、2、3、4、5或6；q is independently selected from 0, 1, 2, 3, 4, 5 or 6;
    RL各自独立的选自H、C1-6烷基、3-7元杂环基、3-7元环烷基、苯基或5-6元杂芳基，所述的杂环基或杂芳基含有1至4个选自O、S、N的杂原子；R L are each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
    每个-Cy-各自独立地选自键或者或者任选取代的如下基团之一：4-8元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Each -Cy- is independently selected from one of the bonded or optionally substituted groups: 4-8 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospirocyclyl, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4- 6- carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl , heteroaryl, heteromonocyclyl, heterocyclyl, heterospirocyclyl or heterobridged cyclyl containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optional Replaced by 1 or 2 =O;
    RL2各自独立地选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-4亚烷基-O-C1-4烷基、-O-C1-4亚烷基-O-C3-10碳环基、-C1-4亚烷基-O-C1-4亚烷基-O-C1-4烷基、-C1-4亚烷基-O-C1-4亚烷基-O-C3-10碳环基、-O-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl Base, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene-OC 1-4 alkyl, -OC 1-4 alkylene -OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3 -10 carbocyclyl, -OC 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to a 10-membered heterocyclyl group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclyl group or heterocyclyl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I , OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, and halogen-substituted C 1-4 alkoxy, the heterocyclic group contains 1 to 4 selected from O, S, N of heteroatoms;
    B选自 B is selected from
    B1选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb1所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle. The carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
    B2选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb2所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle. The carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b2 . The heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
    B3选自C3-20碳环基或4-20元杂环，所述碳环基或杂环任选被1至4个Rb3所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from C 3-20 carbocyclyl or 4-20 membered heterocycle. The carbocyclyl or heterocycle is optionally substituted by 1 to 4 R b3 . The heterocyclyl contains 1 to 4 Heteroatom selected from O, S, N;
    或者B3选自键； Or B 3 select from key;
    L1选自键或 L 1 selected from key or
    L2选自键或 L 2 selected from key or
    Y1、Y2、Y3、Y4各自独立地选自键、O、S、NRb5a；Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from bonds, O, S, NR b5a ;
    Q1、Q2、Q3、Q4各自独立地选自 Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from
    v1、v2、v3、v4各自独立地选自0、1、2、3或4；v 1 , v 2 , v 3 and v 4 are each independently selected from 0, 1, 2, 3 or 4;
    Rb1、Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、NH2、NHC1-4烷基、N(C1-4烷基)2、-C(＝O)NH2、-C(＝O)NHC1-4烷基、-C(＝O)N(C1-4烷基)2、-C(＝O)OC1-4烷基、-S(＝O)2NH2、-S(＝O)2N(C1-4烷基)2、-S(＝O)2NHC1-4烷基、-ORb22、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-NHC(＝O)Rb22、-N(C1-4烷基)C(＝O)Rb22、-NHS(＝O)2Rb22、-N(C1-4烷基)S(＝O)2Rb22、-O-C3-12碳环基、-NH-C3-12碳环基、-S-C3-12碳环基、C3-12碳环基、C6-10芳基、5至12元杂芳基、4至12元杂环基、-C1-4亚烷基-Rb22、-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-Rb22、-C1-4亚烷基-O-C1-4亚烷基-ORb22，所述的亚烷基、烷基、烯基、炔基、烷氧基、烷硫基、碳环基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、-O-C3-10碳环基、C3-10碳环基或4至10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b1 and R b2 are each independently selected from H, F, Cl, Br, I, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -C(=O) NH 2 , -C(=O)NHC 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -C(=O)OC 1-4 alkyl, -S(=O ) 2 NH 2 , -S(=O) 2 N(C 1-4 alkyl) 2 , -S(=O) 2 NHC 1-4 alkyl, -OR b22 , -C(=O)R b22 , -S(=O) 2 R b22 , -P(=O)(R b22 ) 2 , -NHC(=O)R b22 , -N(C 1-4 alkyl)C(=O)R b22 , - NHS(=O) 2 R b22 , -N(C 1-4 alkyl)S(=O) 2 R b22 , -OC 3-12 carbocyclyl, -NH-C 3-12 carbocyclyl, -SC 3-12 carbocyclyl, C 3-12 carbocyclyl, C 6-10 aryl, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, -C 1-4 alkylene -R b22 , -OC 1-4 alkylene- R b22 , -C 1-4 alkylene-OC 1-4 alkylene-R b22 , -C 1-4 alkylene-OC 1-4 alkylene-OR b22 , the alkylene group, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, carbocyclyl group, heterocyclyl group, aryl group or heteroaryl group is optionally selected from 1 to 4 F , Cl, Br, I, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, C 1-4 alkyl, halogen substituted C 1- 4 alkyl, cyano-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -OC 3 -10 carbocyclyl, C 3-10 carbocyclyl or 4 to 10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;
    Rb3各自独立的选自卤素、＝O、＝S、OH、CN、NO2、COOH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-(CH2)n-Rb22、-O-Rb22、-S-Rb22、-NH-Rb22、-(CH2)m1-X-(CH2)m2-Rb24、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自卤素、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、C2-4炔基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b3 is each independently selected from halogen, =O, =S, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -SR b22 , -NH-R b22 , -(CH 2 ) m1 -X-(CH 2 ) m2 - R b24 , -N(R b21 ) 2 , -C(＝O)N(R b21 ) 2 , -C(＝O)OR b21 , -C(＝O)R b22 , -S(＝O) 2 R b22 , -P(＝O)(R b22 ) 2 , -S(＝O) 2 N(R b21 ) 2 , -NR b21 C(＝O)R b22 , -NR b21 S(＝O) 2 R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkyl Oxygen, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted by 1 to 4 selected from halogen, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, Substituted with a substituent of a 5-10-membered heteroaryl group or a 4-10-membered heterocyclyl group, the heteroaryl group or heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;
    n各自独立的选自0、1、2、3或4；n is independently selected from 0, 1, 2, 3 or 4;
    Rb21各自独立的选自H或C1-4烷基，所述的烷基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH, C 1- Substituted with substituents of 4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;
    Rb22各自独立的选自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NH-C1-4烷基、C3-6环烷基，所述的烷基、烷氧基、环烷基、烯基、炔基任选被1至4个选自卤素、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、C3-6环烷基、C1-4烷氧基的取代基所取代；R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -NH-C 1-4 alkyl, C 3 -6 cycloalkyl group, the alkyl group, alkoxy group, cycloalkyl group, alkenyl group, and alkynyl group are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, CF 3 , COOH , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents;
    或Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环基，所述的碳环基或者杂环基任选被1至4个选自卤素、OH、NH2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基或C1-4烷氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；Or any one of R b1 and R b3 , R b2 and R b3 are directly connected to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 A substituent selected from halogen, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl or C 1-4 alkoxy Substituted, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、 COOH、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C3-12环烷基、C6-10芳基、5-10元杂芳基或3-12元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C2-6炔基、C3-8环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl , the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1 -6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl Contains 1 to 4 heteroatoms selected from O, S, and N;
    或任意Rb4、Rb5和与其相连接的碳原子共同形成C3-8环烷基或3至8元杂单环基，所述的环烷基或杂单环基任选被1至4个选自F、Cl、Br、I、OH、NH2、-N(Rb21)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基、5-6元杂芳基或3至8杂环基的取代基所取代，所述的杂单环基、杂芳基或杂环基含有1至4个选自O、S、N的杂原子；Or any R b4 , R b5 and the carbon atom connected thereto together form a C 3-8 cycloalkyl group or a 3 to 8-membered heteromonocyclic group, and the cycloalkyl or heteromonocyclic group is optionally replaced by 1 to 4 Each one is selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1- 4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substituents, the Heteromonocyclyl, heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N;
    Rb5a选自H、C1-4烷基、-(CH2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6环烷基、C6-10芳基、5-10元杂芳基或4-10元杂环基，所述的-CH2-、烷基、环烷基、杂环基、芳基或杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-10元杂芳基或4-10元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3-6 ring Alkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl The group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    X各自独立的选自NH、O或S；X is each independently selected from NH, O or S;
    m1各自独立的选自0、1、2或3；m1 is each independently selected from 0, 1, 2 or 3;
    m2各自独立的选自0、1、2或3；m2 is independently selected from 0, 1, 2 or 3;
    Rb23各自独立的选自C2-4烯基、C2-4炔基、C3-10碳环基或4-10元杂环基，所述的碳环基、烯基、炔基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, the carbocyclyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
    Rb24各自独立的选自C1-4烷氧基、NH-C1-4烷基、NH-C3-6环烷基、C3-6环烷基氧基、C3-10碳环基或4-10元杂环基，所述的烷氧基、碳环基、环烷基、环烷基氧基、杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、CF3、COOH、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R b24 is each independently selected from C 1-4 alkoxy, NH-C 1-4 alkyl, NH-C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-10 carbocycle group or 4-10 membered heterocyclic group, the alkoxy group, carbocyclyl group, cycloalkyl group, cycloalkyloxy group, heterocyclic group is optionally substituted by 1 to 4 selected from F, Cl, Br, I , OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    K选自K1、K2、K3、K4；K is selected from K1, K2, K3, K4;
    K1选自 K1 is selected from
    K2选自 K2 is selected from
    K3选自 K3 is selected from
    K4选自 K4 is selected from
    Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或3-12元杂环基，所述的杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O) NR q - or 3-12 membered heterocyclic group, the heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , Substituted with a substituent of C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    Rq选自H或C1-6烷基；R q is selected from H or C 1-6 alkyl;
    A选自C3-10碳环基、C6-10芳基、3-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；A is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, and the heterocyclyl or heteroaryl contains 1 to 4 selected from Heteroatom of O, S or N;
    F各自独立地选自C3-20碳环基、C6-20芳基、3-20元杂环基或5-20元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；Each F is independently selected from C 3-20 carbocyclyl, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, the heterocyclyl or heteroaryl containing 1 to 4 A heteroatom selected from O, S or N;
    Rk2各自独立地选自键、-C(＝O)-、-S(＝O)2-、-S(＝O)-或-C(Rk3)2-；R k2 is each independently selected from the group consisting of bonds, -C(=O)-, -S(=O) 2 -, -S(=O)-, or -C(R k3 ) 2 -;
    Rk1各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、Rk7a，所述的烷基、烷氧基或环烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, Rk7a , the alkyl, alkoxy or cycloalkyl is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted by CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
    Rk7a选自H、C1-4烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
    Rk3各自独立地选自H、F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-6烷基、C1-6烷氧基、C3-8环烷基或3-8元杂环基，所述的烷基、烷氧基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, = Substituted with O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S or N heteroatoms;
    或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或 环骨架共同形成C3-8碳环基或3-8元杂环基，所述碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom directly connected to the two or The ring skeleton together forms a C 3-8 carbocyclyl or 3-8 membered heterocyclyl, which is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O , NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heterocyclic groups selected from O, S or N atom;
    Rk4各自独立地选自H、OH、NH2、CN、CONH2、C1-6烷基、C3-8环烷基或3-8元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl The base or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    M1选自键、-CH2-C(＝O)NH-或-C(＝O)CH2NH-；M 1 is selected from the group consisting of bonds, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;
    M2选自-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6环烷基或4-10元杂环基，所述的烷基、环烷基或杂环基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl Or the heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, so The heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    M3选自-NH-或-O-；M 3 is selected from -NH- or -O-;
    Rk10选自C1-6烷基，所述的烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、C1-6烷基或C3-6环烷基的取代基所取代；R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 ring Substituted by alkyl substituents;
    Rk11各自独立的选自H、F、Cl、Br、I、＝O、OH、SH、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-O-C(＝O)-C1-6烷基，所述的烷基、烷氧基或烷硫基任选被1至4个选自F、Cl、Br、I、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
    Rk12、Rk13各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自F、Cl、Br、I、＝O、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents substituted;
    Rk14选自5-6元杂芳基，所述的杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；R k14 is selected from 5-6 membered heteroaryl groups, and the heteroaryl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkane Substituted by a substituent of a halogen-substituted C 1-4 alkyl group, a hydroxyl-substituted C 1-4 alkyl group, a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
    G选自C6-10芳基或5-10元杂芳基，所述的芳基或者杂芳基任选被1至4个选自F、Cl、Br、I、OH、＝O、CF3、CN、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代，所述杂芳基含有1至4个选自N、O或S的杂原子；G is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3. Substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;
    n1、n2、n3各自独立的选自0、1、2或3；n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;
    p1或p2各自独立的选自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    B选自 B is selected from
    或者B选自V选自键或L1；Or B is selected from V is selected from key or L 1 ;
    L1、L2不为键；L 1 and L 2 are not keys;
    B1选自6-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C6-8单碳环基、C6-14并环烷基、C6-12螺环烷基、C5-12桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B1任选被1至4个 Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 1 is selected from 6-7-membered heteromonocyclic group, 5-14-membered heterocyclic group, 5-12-membered heterospirocyclic group, 7-10-membered heterocyclic group, C 6-8 monocarbocyclic group, C 6-14 paracycloalkyl, C 6-12 spirocycloalkyl, C 5-12 bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered heterocyclyl, C 12-18 Tricyclic ring group, 12- to 18-membered heterotricyclyl group, 5-10-membered heteroaryl group or 6-14-membered aryl group, the B 1 is optionally substituted by 1 to 4 R b2 substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    B3选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12元螺环烷基、C5-12元桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B3任选被1至4个Rb3取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 3 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14- membered cycloalkyl, C 6-12 -membered spirocycloalkyl, C 5-12 -membered bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered heterocyclyl, C 12 -18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, the B 3 is optionally substituted by 1 to 4 R b3 , the hetero The aryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    B2选自4-7元杂单环基、5-14元杂并环基、5-12元杂螺环基、7-10元杂桥环基、C3-8单碳环基、C6-14并环烷基、C6-12元螺环烷基、C5-12元桥环烷基、苯并C3-10碳环基、苯并3至10元杂环基、C12-18三并环基、12至18元杂三环基、5-10元杂芳基或6-14元芳基，所述B2任选被1至4个Rb2取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；B 2 is selected from 4-7 membered heteromonocyclic group, 5-14 membered heterocyclic group, 5-12 membered heterospirocyclic group, 7-10 membered heterocyclic group, C 3-8 monocarbocyclic group, C 6-14- membered cycloalkyl, C 6-12 -membered spirocycloalkyl, C 5-12 -membered bridged cycloalkyl, benzo C 3-10 carbocyclyl, benzo 3 to 10 membered heterocyclyl, C 12 -18 tricyclic group, 12 to 18 membered heterotricyclic group, 5-10 membered heteroaryl group or 6-14 membered aryl group, the B 2 is optionally substituted by 1 to 4 R b2 , the hetero The aryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    Rb4、Rb5各自独立的选自H、F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、COOH、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、C3-8环烷基、C6-10芳基、O-C3-8环烷基、NH-C3-8环烷基、5-6元杂芳基或3-8元杂环基，所述的烷基、烯基、炔基、烷氧基、烷硫基、环烷基、芳基、杂芳基或杂环基任选被1至4个选自F、Cl、Br、I、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、CN、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C2-4炔基、C3-6环烷基或3至8杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子；R b4 and R b5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, COOH, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 3-8 cycloalkyl, C 6-10 aryl base, OC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy The base, alkylthio group, cycloalkyl group, aryl group, heteroaryl group or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , NHC 1-4 alkyl, N (C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2 -4 alkynyl, C 3-6 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N ;
    Rb5a选自H、C1-4烷基、-(CH2)n-Rb22，所述的-CH2-、烷基任选被1至4个选自F、Cl、Br、I、OH、＝O、-N(Rb21)2、CN、COOH、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C3-6环烷基、5-6元杂芳基或4-8元杂环基的取代基所取代，所述的杂芳基或杂环基含有1至4个选自O、S、N的杂原子。R b5a is selected from H, C 1-4 alkyl, -(CH 2 ) n -R b22 , and the -CH 2 -, alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 Alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、 -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3 -Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1 -Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
    Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S -, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(=O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -(C ≡C) q - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkane Substituted with substituents such as C 1-4 alkoxy group, halogen-substituted C 1-4 alkyl group, hydroxyl-substituted C 1-4 alkyl group, and cyano-substituted C 1-4 alkyl group;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立地选自键或任选取代的如下基团之一：4-7元杂单环基、4-10元杂并环基、5-12元杂螺环基、7-10元杂桥环基、3-7元单环烷基、4-10元并环烷基、5-12元螺环烷基、5-10元桥环烷基、苯并C4-6碳环基、苯并4至6元杂环基、5-10元杂芳基或6-10元芳基，当被取代时，被1至4个RL2取代，所述的杂环基、杂芳基、杂单环基、杂并环基、杂螺环基或杂桥环基含有1至4个选自O、S、N的杂原子，当杂原子选自S时，任选被1或2个＝O取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the optionally substituted following groups: 4-7 membered heteromonocyclyl, 4-10 membered heterocyclyl, 5-12 membered heterospiro Cyclic group, 7-10 membered hetero-bridged cyclic group, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 5-10-membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the Heterocyclyl, heteroaryl, heteromonocyclyl, heterocyclocyclyl, heterospirocyclyl or heterobridged cyclyl contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatom is selected from S , optionally replaced by 1 or 2 =O;
    q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
    RL各自独立的选自H或C1-6烷基。Each R L is independently selected from H or C 1-6 alkyl.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    K2选自 K2 is selected from
    K3选自 K3 is selected from
    A选自C3-8碳环基、苯基、4-7元杂环基，或5-6元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子； A is selected from C 3-8 carbocyclyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl. The heterocyclyl or heteroaryl contains 1 to 4 selected from O, S or heteroatoms of N;
    F各自独立地选自C3-7单环碳环基、C4-10并环碳环基、C5-12螺环碳环基、C5-10桥环碳环基、4-7元杂单环基、4-10元杂并环基、8-15元三环杂并环基、12-17元四环杂并环基、5-17元杂螺环基、C6-14芳基、5-10元杂芳基、所述杂单环基、杂并环基、杂螺环基、杂桥环基或杂芳基含有1至4个选自O、S或N的杂原子；F is each independently selected from C 3-7 monocyclic carbocyclyl, C 4-10 paracyclic carbocyclyl, C 5-12 spirocyclic carbocyclyl, C 5-10 bridged carbocyclyl, 4-7 membered Heteromonocyclic group, 4-10 membered heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-17 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, C 6-14 aromatic base, 5-10 membered heteroaryl group, The heteromonocyclic group, heteroacyclic group, heterospirocyclic group, heterobridged cyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;
    表示环选自芳香环或非芳香环； Indicates that the ring is selected from aromatic rings or non-aromatic rings;
    E各自独立地选自C3-10碳环基、苯基、4-12元杂环基、5-12元杂芳基，所述杂环基或杂芳基含有1至4个选自O、S或N的杂原子；Each E is independently selected from C 3-10 carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 selected from O , S or N heteroatoms;
    Q各自独立地选自键、-O-、-S-、-CH2-、-NRq-、-C(＝O)-、-NRqC(＝O)-、-C(＝O)NRq-或4-7元杂环基，所述的杂环基任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Q is each independently selected from the group consisting of bonds, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O) NR q - or 4-7 membered heterocyclyl, the heterocyclyl is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , Substituted with a substituent of C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    Rq选自H或C1-4烷基；R q is selected from H or C 1-4 alkyl;
    Rk1、Rk3各自独立的选自H、F、Cl、Br、I、OH、＝O、NH2、CF3、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基，所述烷基或烷氧基任选被1至4个选自F、Cl、Br、I、OH或NH2的取代基所取代；R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkyl Oxygen group, the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ;
    或者两个Rk3和与二者直接相连的碳原子或环骨架、两个Rk1和与二者直接相连的碳原子或环骨架共同形成C3-6碳环基或3-7元杂环基，所述碳环基或杂环基，任选被1至4个选自F、Cl、Br、I、OH、＝O、NH2、CN、COOH、CONH2、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环基含有1至4个选自O、S或N的杂原子；Or two R k3 and the carbon atom or ring skeleton directly connected to the two, two R k1 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclyl or 3-7 membered heterocycle. The carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , and C 1-4 alkyl Or substituted by a C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;
    Rk4各自独立的选自H、OH、NH2、CF3、CN或C1-4烷基；R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;
    Rk5各自独立地选自C(CH3)2、C(＝O)、CH2、CH2CH2、S(＝O)2、 R k5 are each independently selected from C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 , S(=O) 2 ,
    Rk6各自独立地选自C(＝O)、CH、S(＝O)、S(＝O)2、CH2或N；R k6 is each independently selected from C(=O), CH, S(=O), S(=O) 2 , CH 2 or N;
    Rk7各自独立地选自C(CH3)2、C(＝O)、CH、N、CH2、O、S、NRk7a；R k7 are each independently selected from C(CH 3 ) 2 , C(=O), CH, N, CH 2 , O, S, NR k7a ;
    Rk8各自独立地选自C、N或CH； Rk8 is each independently selected from C, N or CH;
    Rk9各自独立地选自键、C(CH3)2、C(＝O)、CH2、CH2CH2或S(＝O)2；R k9 are each independently selected from keys, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ;
    Rka选自O、S或NH；R ka is selected from O, S or NH;
    Rk7a选自H、C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-6元杂环烷基，所述烷基、环烷基、杂环烷基任选被1至4个选自F、Cl、Br、I、OH、NH2、CN、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C Substituted with substituents of 2-4 alkenyl, C 2-4 alkynyl, and C 3-6 cycloalkyl;
    Rk14选自 R k14 selected from
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    B选自 B is selected from
    V选自键、O、S、NRb5a、NRb5a-(Q2)v2-、-(Q2)v2-NRb5a、-O-(Q2)v2-、-(Q2)v2-O-、-(Q2)v2-；V is selected from bonds, O, S, NR b5a , NR b5a -(Q 2 ) v2 -, -(Q 2 ) v2 -NR b5a , -O-(Q 2 ) v2 -, -(Q 2 ) v2 -O -, -(Q 2 ) v2 -;
    v2、v4各自独立地选自1、2、3或4；v 2 and v 4 are each independently selected from 1, 2, 3 or 4;
    Y1、Y3各自独立地选自键、O、S、NRb5a；Y 1 and Y 3 are each independently selected from bond, O, S, NR b5a ;
    Y2、Y4各自独立地选自O、S、NRb5a；Y 2 and Y 4 are each independently selected from O, S, NR b5a ;
    Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-S-、-S-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-C≡C-或者键，所述的-CH2-、-CH＝CH-任选被1至2个选自F、Cl、Br、I、OH、CN、NH2、CF3、羟甲基、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S -, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(＝O)-, -(CH 2 ) q -C(＝O)NR L -, -C(＝O)-, -C(＝O)-(CH 2 ) q -NR L -, -CH＝CH-, -C≡ C- or bond, the -CH 2 -, -CH=CH- is optionally replaced by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , CF 3 , hydroxymethyl, methane Substituted with a substituent of base, ethyl, methoxy or ethoxy;
    q各自独立的选自0、1、2或3；q is independently selected from 0, 1, 2 or 3;
    RL各自独立的选自H或C1-4烷基；R L are each independently selected from H or C 1-4 alkyl;
    K1选自 K1 is selected from
    K4选自 K4 is selected from
    Q选自键、C(＝O)；Q is selected from bond, C(=O);
    Qa选自键、CH2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3)、 Qa is selected from bonds, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ),
    Qb选自键、CH2、O、S、C(＝O)、NHC(＝O)、N(CH3)C(＝O)；Qb is selected from bond, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);
    E、A各自独立地选自苯环基、吡啶环基、哒嗪环基、吡嗪环基、嘧啶环基、吡咯环基、吡唑环基、咪唑环基、噻唑环基、呋喃环基、噻吩环基或噁唑环基；E and A are each independently selected from benzene ring group, pyridine ring group, pyridazine ring group, pyrazine ring group, pyrimidine ring group, pyrrole ring group, pyrazole ring group, imidazole ring group, thiazole ring group, furan ring group , thiophene ring group or oxazole ring group;
    F各自独立地选自环丁基、环戊基、环己基、双环[1.1.1]戊烷基、6,7-二氢-5H-环戊[c]吡啶基、2,3-二氢-1H-茚基、苯基、萘基、蒽基、菲基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮、苯并噁唑基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并吡啶基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基、苯并三嗪基、吡咯并吡咯基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并嘧啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡唑、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基、吲哚并吡啶基、吲哚并噻吩基、吲哚并呋喃基、 其左侧与L直接连接； F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridimidazolyl, benzimidazole base, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazole Pyridazinyl, pyrazopyridinyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimido Pyrimidinyl, pyridopyridyl, pyridopyrazole, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyridazinyl, pyrazinopyrazinyl, indolopyridine base, indolothienyl, indolofuranyl, Its left side is directly connected to L;
    Rka选自O、S或NH；R ka is selected from O, S or NH;
    Rk7各自独立地选自C(CH3)2、CH2、O、N(CH3)、N(CH2CH3)、N(环丙基)或NH；R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;
    Rk7a选自H、甲基、乙基、丙基、异丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个选自F、Cl、Br、I、OH、CN、CF3、C1-4烷基、C1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C3-6环烷基的取代基所取代； Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl Substituted with substituents of C 3-6 cycloalkyl group;
    p1或p2各自独立的选自0、1、2或3。p1 or p2 are each independently selected from 0, 1, 2 or 3.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    RL选自H、甲基或乙基；R L is selected from H, methyl or ethyl;
    q各自独立的选自0、1或2；q is independently selected from 0, 1 or 2;
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一：环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、氮杂环己烯基、哌啶基、吗啉基、哌嗪基、1,4-二氮杂庚烷基、吡啶基、苯基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基螺环丙基、环丙基螺环丁基、环丙基螺环戊基、环丙基螺环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、氮杂环丁基并氮杂环丁基、氮杂环丁基并吡咯烷基、氮杂环丁基并哌啶基、吡咯烷基并氮杂环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、哌啶基并氮杂环丁基、哌啶基并吡咯烷基、哌啶基并哌啶基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、氮杂环丁基螺氮杂环丁基、氮杂环丁基螺吡咯烷基、氮杂环丁基螺哌啶基、吡咯烷基螺氮杂环丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮杂环丁基、哌啶基螺哌啶基、 当被取代时，被1至4个RL2取代；Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, pyridyl, phenyl, cyclopropylcyclopropyl, cyclopropyl cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl and cyclopentyl , cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocycle Butyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclohexyl Propylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl , cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl base, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidine Azetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, Cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, nitrogen Heterocyclidylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrole Alkylspiropiperidinyl, piperidylspiroazetidinyl, piperidinylspiropiperidinyl, When substituted, by 1 to 4 R L2 ;
    RL2各自独立地选自F、Cl、Br、I、OH、NH2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-O-C1-2亚烷基-O-C1-2烷基、-O-C1-2亚烷基-O-C3-6碳环基、-C1-2亚烷基-O-C1-2亚烷基-O-C1-2烷基、-C1-2亚烷基-O-C1-2亚烷基-O-C3-6碳环基、-O-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、烯基、炔基、烷氧基、亚烷基、碳环基或杂环基任选被1至4个选自F、Cl、Br、I、OH、COOH、CN、NH2、NHC1-4烷基、N(C1-4烷基)2、＝O、C1-4烷基、卤素取代的C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子；R L2 is each independently selected from F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene -OC 1-2 alkyl, -OC 1-2 alkylene -OC 3-6 carbocyclyl, - C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl, so The above-mentioned alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic or heterocyclic groups are optionally selected from 1 to 4 F, Cl, Br, I, OH, COOH, CN, NH 2. NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, Substituted with C 1-4 alkoxy or halogen-substituted C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;
    B1选自取代或未取代的如下基团之一：苯基、萘基、噻吩、呋喃、吡咯、吡唑、咪唑、吡啶、2-吡啶酮、嘧啶、吡嗪、哒嗪、喹啉、异喹啉、喹唑啉、3,4-二氢-1H-苯并吡喃、1,2,3,4-四氢喹啉、苯并呋喃、苯并噻吩、苯并吡咯、苯并噁唑、苯并噻唑、苯并咪唑、苯并吡唑、吗啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、咔唑，当被取代时，被1至4个Rb1取代；B 1 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, thiophene, furan, pyrrole, pyrazole, imidazole, pyridine, 2-pyridone, pyrimidine, pyrazine, pyridazine, quinoline, Isoquinoline, quinazoline, 3,4-dihydro-1H-benzopyran, 1,2,3,4-tetrahydroquinoline, benzofuran, benzothiophene, benzopyrrole, benzox Azole, benzothiazole, benzimidazole, benzopyrazole, morpholine, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidine Base, carbazole, when substituted, is substituted by 1 to 4 R b1 ;
    或者B1选自任选取代的如下结构之一： 当被取代时，被1至4个Rb1取代；Or B 1 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b1 ;
    或者B1选自B1A；or B 1 is selected from B 1A ;
    B2选自取代或未取代的如下基团之一：苯环基、萘基、喹啉、吡唑、吡啶、咪唑、三氮唑、噻唑、噁唑、异噁唑、噻吩、苯并吡咯、吲哚、苯并咪唑、苯并吡唑、苯并噻吩、苯并噻唑、吡唑并四氢吡咯、3-哒嗪酮、2-吡啶酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基，当被取代时，被1至4个Rb2取代； B 2 is selected from one of the following substituted or unsubstituted groups: phenyl ring, naphthyl, quinoline, pyrazole, pyridine, imidazole, triazole, thiazole, oxazole, isoxazole, thiophene, benzopyrrole , indole, benzimidazole, benzopyrazole, benzothiophene, benzothiazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 2-pyridone, 1,2,3,4-tetrahydroquin Phenoline, 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, When substituted, by 1 to 4 R b2 ;
    或者B2选自任选取代的如下结构之一： 当被取代时，被1至4个Rb2取代；Or B 2 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b2 ;
    或者B2选自B2A；or B 2 is selected from B 2A ;
    B1A、B2A各自独立地选自任选取代的如下结构之一： 当被取代时，B1A被1至4个Rb1取代，B2A被1至4个Rb2取代；B 1A and B 2A are each independently selected from one of the optionally substituted following structures: When substituted, B 1A is replaced by 1 to 4 R b1 and B 2A is replaced by 1 to 4 R b2 ;
    B3选自取代或未取代的如下基团之一：氧杂环丁基、环丁基、环戊基、环己基、氮杂环丁基、四氢呋喃基、苯基、吡啶、萘基、吡唑、吡咯、吡咯烷基、哌啶、哌嗪、氮杂环己烯基、四氢吡喃基、咪唑、噻吩、噻唑、噁唑、异噁唑、三氮唑、2-吡啶酮、苯并吡咯、苯并吡咯烷、苯并噻吩、苯并噻唑、苯并吡唑、苯并咪唑、吡唑并四氢吡咯、3-哒嗪酮、1,2,3,4-四氢喹啉、1,2,3,4-四氢异喹啉、环丁基螺环丁基、环丁基螺氮杂环丁基、环戊基并环戊基、环戊基并吡咯烷基、环丁基螺哌啶基，当被取代时，被1至4个Rb3取代；B 3 is selected from one of the following substituted or unsubstituted groups: oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, phenyl, pyridine, naphthyl, pyridyl Azole, pyrrole, pyrrolidinyl, piperidine, piperazine, azepine, tetrahydropyranyl, imidazole, thiophene, thiazole, oxazole, isoxazole, triazole, 2-pyridone, benzene Pyrrole, benzopyrrolidine, benzothiophene, benzothiazole, benzopyrazole, benzimidazole, pyrazolotetrahydropyrrole, 3-pyridazinone, 1,2,3,4-tetrahydroquinoline , 1,2,3,4-tetrahydroisoquinoline, cyclobutylspirocyclobutyl, cyclobutylspiroazetidinyl, cyclopentylcyclopentyl, cyclopentylpyrrolidinyl, cyclobutylspiroazetidinyl Butylspiropiperidinyl, when substituted, is substituted by 1 to 4 R b3 ;
    或者B3选自任选取代的如下结构之一： 当被取代时，被1至4个Rb3取代； Or B 3 is selected from one of the optionally substituted following structures: When substituted, by 1 to 4 R b3 ;
    V选自键、O、S、NRb5a、NRb5a-C1-4亚烷基、C1-4亚烷基-NRb5a、O-C1-4亚烷基、C1-4亚烷基-O、C1-4亚烷基，所述的亚烷基任选被1至4个Rb4或Rb5所取代；V is selected from bond, O, S, NR b5a , NR b5a -C 1-4 alkylene, C 1-4 alkylene-NR b5a , OC 1-4 alkylene, C 1-4 alkylene- O. C 1-4 alkylene group, the alkylene group is optionally substituted by 1 to 4 R b4 or R b5 ;
    Rb1各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-NH-环丙基、-NH-环丁基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b1 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , - C(＝O)NH-CH 3 , -C(＝O)N(CH 3 ) 2 , -S(＝O) 2 NH 2 , -P(＝O) 2 (CH 3 ) 2 , -S(＝ O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclo Propyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxolanyl, oxetanyl, morpholine, pyrrolidinyl Cyclopentyl, azetidinylspirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
    Rb3各自独立的选自F、Cl、Br、I、＝O、＝S、OH、NH2、N(CH3)2、NHCH3、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-S-环丙基、-S-环丁基、-CH2-环丙基、-CH2-环丁基、-O-CH2-环丙基、-O-CH2-环丁基、-O-CH2CH2-甲氧基、-O-CH2CH2-O-环丙基、-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-甲氧基、-CH2-O-CH2CH2-O-环丙基、-CH2-O-CH2CH2-O-环丁基、-CH2-O-CH2CH2-NH-甲基、-CH2-甲氧基、-CH2-乙氧基、甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、吡咯、吡唑、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、苯基任选被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CF3、NH2、N(CH3)2、甲基、甲氧基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基的取代基所取代；R b3 is each independently selected from F, Cl, Br, I, =O, =S, OH, NH 2 , N(CH 3 ) 2 , NHCH 3 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 , -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, -S-cyclopropyl , -S-cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -O-CH 2 -cyclopropyl, -O- CH 2 -cyclobutyl , -O-CH 2 CH 2 -methoxy, -O-CH 2 CH 2 -O-cyclopropyl, -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -methoxy, - CH 2 -O-CH 2 CH 2 -O-cyclopropyl, -CH 2 -O-CH 2 CH 2 -O-cyclobutyl, -CH 2 -O-CH 2 CH 2 -NH-methyl, - CH 2 -methoxy, -CH 2 -ethoxy, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, pyrrole, pyrazole, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinyl And cyclopentyl, azetidinyl spirocyclohexyl, Phenyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, pyrrole , pyrazole, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl base spirocyclohexyl, The phenyl group is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , N(CH 3 ) 2 , methyl, methoxy, ethynyl, propyl Substituted by alkynyl, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl substituents;
    Rb2各自独立的选自H、F、Cl、Br、I、＝O、＝S、OH、NH2、NHCH3、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3或者任选取代的如下基团之一：甲基、乙基、丙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮杂环丁基、吡咯烷基、哌啶基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉、吡咯烷基并环戊基、氮杂环丁基螺环己基、环丙基螺环丁基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环己基、-CH2-环丙基、-CH2-环丁基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-O-环丁基、-NH-环丙基、-NH-环丁基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基、-CH2OCH2CH2-NH-甲基、当被取代时，被1至4个选自F、Cl、Br、I、OH、CN、CHF2、CH2F、CF3、NH2、NHCH3、N(CH3)2、 CH2OH、甲基、乙基、异丙基、甲氧基、乙氧基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、吡咯烷基、哌啶基、吡唑基、吗啉基的取代基所取代；R b2 is each independently selected from H, F, Cl, Br, I, =O, =S, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3. -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O )(CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, Propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, nitrogen Heterocyclylbutyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, Cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, -CH 2 -cyclopropyl, -CH 2 - Cyclobutyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, -NH-cyclopropyl, -NH- Cyclobutyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O- Cyclopropyl, -CH 2 OCH 2 CH 2 -NH-methyl, When substituted, 1 to 4 are selected from F, Cl, Br, I, OH, CN, CHF 2 , CH 2 F, CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 OH, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidyl, pyrazole Substituted by substituents of base and morpholinyl;
    作为选择，Rb1与Rb3、Rb2与Rb3任其一直接连接形成C5-7碳环基、5至7元杂环基，所述的碳环基或者杂环基任选被1至4个选自F、Cl、Br、I、OH、-NH2、CN、CH2F、CHF2、CF3、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子；Alternatively, any one of R b1 and R b3 or R b2 and R b3 is directly connected to form a C 5-7 carbocyclic group or a 5- to 7-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally replaced by 1 Substituted with 4 substituents selected from F, Cl, Br, I, OH, -NH 2 , CN, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, methoxy or ethoxy, The heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    K选自表K-1所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-1.
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 6 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    Cy1、Cy2、Cy3、Cy4或Cy5各自独立的选自键或取代的或者未取代的如下基团之一： 当被取代时，被1至4个RL2取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: When substituted, by 1 to 4 R L2 ;
    RL2各自独立地选自F、Cl、Br、＝O、COOH、CN、NHCH3、N(CH3)2、OH、NH2或任选取代的如下基团之一：甲基、乙基、异丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、异丙基氧基、环丙基、环丁基、环戊基、环己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、吗啉、-CH2-环丙基、-CH2-吗啉、-CH2-吡唑、-OCH2-环丙基、-O-环丙基、-OCH2CH2-O-甲基、-OCH2CH2-O-环丙基、-CH2OCH2CH2-O-甲基、-CH2OCH2CH2-O-环丙基，当被取代时，被1至4个选自F、CHF2、CF3、OCHF2、OCF3、甲基、甲氧基、＝O、CH2OH、COOH、CN、NHCH3、N(CH3)2、OH、NH2的取代基所取代；R L2 is each independently selected from F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl , isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -Cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, by 1 to 4 selected from F, CHF 2 , CF 3 , OCHF 2 , OCF 3 , methyl, methoxy, =O, CH 2 Substituted with OH, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituents;
    B选自表B-1、表B-2或表B-3所示的结构片段之一，其右侧与L连接，b1、b2各自独立地选自0、1或2；B is selected from one of the structural fragments shown in Table B-1, Table B-2 or Table B-3, its right side is connected to L, and b1 and b2 are each independently selected from 0, 1 or 2;
    K选自表K-2所示的结构片段之一。K is selected from one of the structural fragments shown in Table K-2.
  8. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2- Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3- Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3- Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, - Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4- , -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1- Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4- , -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3- Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5- , -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
    Ak1、Ak2、Ak3、Ak4、Ak5各自独立的选自-O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH-或-NHC(＝O)-；Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH=CH-, -CH＝C(CN)-, -CH＝C(F)-, -C(CN)＝CH-, -C(F)＝CH-, -C≡C-, -C(CH 3 ) 2 - , -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH- , -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;
    V选自键、NH、NHC(CH3)2CH2、NHCH2C(CH3)2、CH2CH2、C(CH3)2CH2、CH2C(CH3)2、NHCH2CH2、NHCH2、OCH2、CH2NH、CH2O、NHC(CH3)2、OC(CH3)2、C(CH3)2NH、C(CH3)2O、N(CH3)CH2、N(CH3)C(CH3)2、C(CH3)2N(CH3)、CH2N(CH3)、N(CH3)、O、S。V is selected from bonds, NH, NHC(CH 3 ) 2 CH 2 , NHCH 2 C(CH 3 ) 2 , CH 2 CH 2 , C(CH 3 ) 2 CH 2 , CH 2 C(CH 3 ) 2 , NHCH 2 CH 2 , NHCH 2 , OCH 2 , CH 2 NH, CH 2 O, NHC(CH 3 ) 2 , OC(CH 3 ) 2 , C(CH 3 ) 2 NH, C(CH 3 ) 2 O, N(CH 3 )CH 2 , N(CH 3 )C(CH 3 ) 2 , C(CH 3 ) 2 N(CH 3 ), CH 2 N(CH 3 ), N(CH 3 ), O, S.
  9. 根据权利要求8所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 8 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    L选自键或表L-1、L-2或L-3所示的结构片段之一，其中基团左侧与B连接。 L is selected from a bond or one of the structural fragments shown in Table L-1, L-2 or L-3, in which the left side of the group is connected to B.
  10. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
  11. 一种药物组合物，包括权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical composition. an acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound of any one of claims 1-10 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics.
  12. 根据权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者权利要求10所述的药物组合物在用于制备治疗与AR或AR剪切突变体活性或表达量相关疾病的药物中的应用。The compound according to any one of claims 1 to 10 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the pharmaceutical combination according to claim 10 The application of the substance in the preparation of drugs for the treatment of diseases related to the activity or expression of AR or AR splicing mutants.
  13. 根据权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者权利要求10所述的药物组合物在用于制备治疗与抑制或降解AR或AR剪切突变体相关疾病的药物中的应用。The compound according to any one of claims 1 to 10 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the pharmaceutical combination according to claim 10 The use of substances in the preparation of drugs for the treatment of diseases associated with inhibition or degradation of AR or AR splicing mutants.
  14. 根据权利要求12或13所述的应用，其特征在于，所述的疾病选自前列腺癌。The application according to claim 12 or 13, characterized in that the disease is selected from prostate cancer.
  15. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选AR或AR剪切突变体活性或表达量相关疾病。 A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-10 or its stereoisomers, deuterated products, solvates, or precursors. Drugs, metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably a disease related to the activity or expression of AR or AR splicing mutants.
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