WO2024012570A1 - Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci - Google Patents

Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci Download PDF

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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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English (en)
Chinese (zh)
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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/fr

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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

L'invention concerne un composé tel que représenté par la formule générale (I), ou un stéréoisomère, une forme deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un co-cristal de celui-ci ; et des intermédiaires de ceux-ci, et leur utilisation dans des maladies liées au RA telles que des cancers. B-L-K (I)
PCT/CN2023/107465 2022-07-15 2023-07-14 Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci WO2024012570A1 (fr)

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