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WO2024175024A1 - New fused heterocyclic compound as cdks inhibitor and use thereof - Google Patents

New fused heterocyclic compound as cdks inhibitor and use thereof Download PDF

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Publication number
WO2024175024A1
WO2024175024A1 PCT/CN2024/077920 CN2024077920W WO2024175024A1 WO 2024175024 A1 WO2024175024 A1 WO 2024175024A1 CN 2024077920 W CN2024077920 W CN 2024077920W WO 2024175024 A1 WO2024175024 A1 WO 2024175024A1
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Prior art keywords
ring
alkyl
cycloalkyl
halogen
heterocyclyl
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PCT/CN2024/077920
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French (fr)
Chinese (zh)
Inventor
张龙
牛张明
Original Assignee
杭州德睿智药科技有限公司
德睿智药(苏州)新药研发有限公司
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Publication of WO2024175024A1 publication Critical patent/WO2024175024A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically discloses novel heterocyclic compounds with CDKs target inhibitory activity, compositions containing such compounds, and methods for applying such compounds to prepare drugs for treating or preventing diseases associated with CDKs targets.
  • CDKs Cyclin-dependent kinases
  • 21 CDKs have been discovered so far, and most of them must bind to cyclins to form active heterodimer complexes for activation. This active dimeric complex can phosphorylate the corresponding substrates, thereby driving various processes of the cell cycle and regulating cell growth and proliferation.
  • CDK1/2/4/6 mainly function by regulating the cell cycle, while CDK7/8/9/10/11 can also participate in cell cycle and transcriptional regulation to exert biological functions.
  • CDK7 mainly forms a CDK-activated kinase complex (CAK) with cyclin H and MAT1.
  • CAK CDK-activated kinase complex
  • the CAK complex can phosphorylate other cell cycle kinases to promote the normal progress of the cell cycle.
  • CAK complex can phosphorylate RNA polymerase II to participate in the transcriptional regulation of related genes.
  • CDK7 is overexpressed in many malignant tumors such as liver cancer, gastric cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, neuroblastoma, prostate cancer, non-small cell lung cancer and acute myeloid leukemia, and is correlated with aggressive clinical pathology and poor prognosis. Since the members of the entire CDK family have a high degree of homology and their mechanisms in different types of tumors are also different, non-selective CDK7 inhibitors have certain adverse reactions caused by off-target effects in clinical trials. At present, there are no selective CDK7 inhibitors on the market. A large number of preclinical and clinical trials have shown that highly selective CDK7 inhibitors have great potential therapeutic value in a variety of refractory tumors.
  • novel heterocyclic compounds of the formula (I) of the present invention not only have significant CDK7 inhibitory activity, but also have higher activity, better selectivity, pharmacokinetics and bioavailability than the clinical reference compounds THZ2, Samuraciclib, CYC-202, etc. with known structures. It is expected that they will have better human PK properties and efficacy, and are more suitable for development as candidate drugs for the prevention or treatment of diseases related to CDKs targets or signal pathways.
  • the object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof.
  • X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Rings A and B are arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R 3 can be directly connected to Y; when ring A is absent, L 1 and L 2 can be directly connected;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , or C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1A),
  • X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R d can be directly connected to Y;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 0 1 1 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalky
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alky
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1B):
  • X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1C):
  • X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1D):
  • X is independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alky
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer of 0, 1 or 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1E):
  • X is independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C
  • R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R R 2 and the carbon atoms connected to it on the ring form a 3
  • Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 and any two of R d1 and R d2 are optionally substituted by one or more groups selected from hydrogen,
  • the halogen is arbitrarily and independently selected from F, Cl, Br , I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer of 0, 1 or 2.
  • Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R1 can be directly connected to Y; preferably, it is absent or a monocyclic structure; most preferably, it is absent, a benzene ring, a pyridine ring, a thiazole ring, a pyrazole ring, an azetidine, an azocyclopentane
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2):
  • X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2C):
  • X is arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18
  • R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy , C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl , C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2D):
  • X is arbitrarily and independently selected from N, CR;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 member
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2E):
  • X is arbitrarily and independently selected from N, CR;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkane R2 is a C1-10 alkyl, a C2-10 alkenyl, a C2-10 alkynyl or a C1-10 alkoxyl group, a C2-10 heteroalkyl, a C3-10 saturated or partially saturated cycloalkyl, an aryl, a heteroaryl, a C3-10 saturated or partially saturated heterocyclic group, a C1-10 alkyl substituted with a C3-10 cycloalkyl or C3-10 heterocyclic alkyl, a C2-10 heteroalkyl substituted with a C3-10 cycloalkyl , a C3-10 heterocyclic group, a C1-10 alkyl substituted with a C3-10 alkyl, or a carboxyl or carboxyl substitute; or any two R
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2F):
  • X is arbitrarily and independently selected from N, CR;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 1-10 alkyl substituted with C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted with carboxyl or carboxyl substitute; or any two R 2 together with the atoms connected to them on the ring form a 3-18 member
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-4A),
  • X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl , C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R2 together with the atoms connected to them on the ring form a 3-18 membered
  • Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-4B):
  • X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
  • Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
  • Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 member
  • R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cyclo Alkyl acyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • ring A is selected from 3-10 membered heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl;
  • ring A is selected from
  • ring B is absent or selected from 4-6 membered heterocyclyl, C 6-10 aryl; for example azetidinyl, tetrahydropyrrolyl, piperidinyl, phenyl;
  • ring B is absent or selected from
  • X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are selected from N, C, CR;
  • R is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, such as ethyl, isopropyl, cyclopropyl.
  • Y is absent or selected from O, C(O), CH 2 —O which is unsubstituted or optionally substituted by one or two C 1-6 alkyl groups.
  • L 1 is selected from NH, CH 2 —NH.
  • L 2 is absent or selected from C(O), NH, N(C 1-6 alkyl), N-C 1-6 alkylene.
  • YL 2 is selected from the following groups: OC(O), unsubstituted or optionally substituted with one or two C 1-6 alkyl groups: NH, CH 2 —OC(O), C(O)NH, O—CH 2 —C(O).
  • R 0 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, -L 3 R 01 .
  • L 3 is absent or selected from O, NH, N-C 1-6 alkylene (eg NH—CH 2 , NH—CH(CH 3 )).
  • R 0 is selected from methyl, isopropyl, cyclopropyl, trifluoromethyl,
  • R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy.
  • R 3 is selected from H, C 2-6 alkenyl-C(O), C 2-6 alkenyl-C(O)NH, halogenated C 2-6 alkenyl-C(O), (C 1-6 alkyl) 2 NC 2-6 alkenyl-C(O), 3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 1-6 alkoxy-3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 2-6 alkynyl-C(O);
  • R3 is selected from H
  • m is selected from 0, 1, 2, 3 or 4.
  • n is selected from 0, 1, 2, 3, 4 or 5.
  • the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution is selected from the compounds with structures disclosed in the embodiments, such as compounds 1 to 113, compounds C1-1 to C1-582, compounds C2-77 to C2-335, compounds C3-77 to C3-362, and compounds C4-77 to C4-258.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution.
  • the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
  • the pharmaceutical composition is preferably administered orally.
  • the oral dosage form is not particularly limited, and any oral dosage form known in the art may be used, preferably tablets, capsules, suspensions or oral solutions, etc.
  • the dosage standard used is, for example, 1-1500 mg/day.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • a pharmaceutically acceptable excipient which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • excipients including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the use of the above-mentioned compounds in the preparation of drugs for preventing and/or treating diseases related to CDKs signaling pathways including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and the like.
  • diseases related to CDKs signaling pathways including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and the like.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, and the use of the pharmaceutical composition in preventing and/or treating diseases related to CDKs signaling pathway.
  • formula (I) its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution
  • the present invention also provides a method for preventing and/or treating diseases related to the CDKs signaling pathway, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, or administering to a patient a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition.
  • the diseases related to the CDKs signaling pathway have the definitions described above.
  • the patient is a mammal, preferably a human.
  • C1-10 is selected from the group consisting of C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
  • C2-10 is selected from the group consisting of C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 and C10 ;
  • C3-10 is selected from the group consisting of C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
  • alkyl is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1 to 20 carbon atoms, also noted as “C 1-20 alkyl”.
  • C 1-10 alkyl means straight and branched alkyl radicals having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • C 1-8 alkyl means straight and branched alkyl radicals having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C 1-6 alkyl means straight and branched alkyl radicals having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.
  • alkylene refers to a straight or branched chain divalent hydrocarbon group of the formula -(CH 2 ) n -
  • Non-limiting examples include ethylene and propylene.
  • the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.
  • aliphatic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group
  • the carbocycle can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl or can optionally contain one, two or more double bonds and/or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl.
  • non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6).
  • the heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt).
  • the heterocyclic group can include fused or bridged rings and/or spirocyclic rings.
  • the non-limiting examples of monocyclic heterocyclic radical include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic radical includes the heterocyclic radical of spirocycle, condensed ring and bridge ring, and can also be the heterocyclic radical of benzo condensation such as dihydroisoquinolinyl.
  • the heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.
  • the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl or "aromatic ring” means: it should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl”.
  • C 6-14 aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl or biphenyl, or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be mono-
  • spirocyclic ring refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • paracyclic refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • heteroaryl/heteroaromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan.
  • heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
  • the heteroaryl/heteroaromatic ring may be optionally substituted or unsubstituted.
  • the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridin-2-yl may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene;
  • thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts are derivatives of the compounds of the present invention, wherein the parent compound is modified by salification with an acid or alkali.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts such as Na salts, potassium salts, amine salts, quaternary ammonium salts of parent compounds, and the like.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene
  • the inorganic base and organic base described in the following examples are selected from sodium, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • compounds provided by the present invention also exist in prodrug form.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.
  • solvate refers to an association formed by one or more solvent molecules and the compounds of the present invention.
  • Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. Therefore, the term “hydrate” refers to an association formed by a solvent molecule that is water.
  • Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds.
  • the racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to technicians in the field of cosmetics or topical drugs. For additional information about carriers, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents When a substituent's bond can cross-link to two atoms on a ring, such substituent can be bonded to any atom on the ring.
  • substituent When a substituent is listed without indicating the atom through which it is bonded to a compound included in the chemical structure but not specifically mentioned, such substituent can be bonded through any atom thereof. Combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention is now further described by examples.
  • the examples given below are for illustrative purposes only and are not intended to limit the scope of this invention.
  • the compounds of the present invention can be prepared using many known methods in the field of organic synthesis.
  • the embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based thereon.
  • Preferred methods include, but are not limited to, the following description methods.
  • aq represents water
  • DCM dichloromethane
  • PE represents petroleum ether
  • DMF represents N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOAc represents ethyl acetate
  • EtOH represents ethanol
  • MeOH represents methanol
  • Cbz represents benzyloxycarbonyl, an amine protecting group
  • Boc represents tert-butyloxycarbonyl, an amine protecting group
  • HOAc represents acetic acid
  • NaBH(OAc) 3 represents sodium triacetoxyborohydride
  • rt represents room temperature
  • THF represents tetrahydrofuran
  • Boc 2 O represents di-tert-butyl dicarbonate
  • TFA represents trifluoroacetic acid
  • DIPEA represents diisopropylethylamine
  • Pd(dppf)Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II
  • Example 1-1 Synthesis of 2,2,2-trifluoroacetate of 3-acrylamide-N-(3-((2-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)phenyl)benzamide (Compound C1-1):
  • Trifluoroacetic acid (1 mL) was added dropwise to a solution of (3R,4R)-tert-butyl 4-((4-((3-(3-acrylamidobenzamide)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 0.09 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature for 2 hours.
  • Trifluoroacetic acid (0.3 mL) was added dropwise to a solution of (3R,4R)-tert-butyl 4-((4-((3-(3-acrylamidobenzamide)phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 0.089 mmol) in dichloromethane (1.5 mL), and the mixture was reacted at room temperature for 1 hour.
  • the reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3-(3-acrylamidobenzamido)benzyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.039 mmol, yield: 78%).
  • LC-MS: m/z 783[M+H] + .
  • Trifluoroacetic acid (1 mL) was added dropwise to a dichloromethane solution (3 mL) containing tert-butyl (3R,4R)-4-((7-((3-(3-acrylamidobenzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (30 mg, 0.039 mmol), and the mixture was reacted at room temperature for 2 hours.
  • reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol, yield: 23%).
  • LC-MS: m/z 740[M+H] + .
  • Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.054 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour.
  • the obtained mixed reaction liquid was diluted with water (50 mL) and extracted with dichloromethane (3 ⁇ 50 mL). The combined organic phase was washed with saturated brine (1 ⁇ 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • N 7 -(3-azabicyclo[3.2.1]octan-8-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (322 mg, 0.84 mmol) was added to the above reaction liquid, and the obtained mixed reaction liquid was heated at 40°C and stirred for 17 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (ethyl acetate).
  • Triethylamine (0.22 g, 2.01 mmol) and triphosgene (99 mg, 0.33 mmol) were added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.15 g, 0.80 mmol) in dichloromethane (3 ml) at 0°C.
  • the resulting mixed reaction solution was stirred at 0°C for 30 minutes.
  • Triethylamine (1.1 g, 10.8 mmol) and bis(trichloromethyl)carbonate (440 mg, 1.485 mmol) were added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (514 mg, 2.97 mmol) in dichloromethane (2 mL) at 0°C, and stirred at 0°C for 0.5 hours.
  • the reaction was completed by LCMS.
  • the mixed reaction solution was purified by preparative HPLC to obtain 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (5 mg, yield: 4.3%), LC-MS m/z: 542 [M+H] + ;
  • the resulting mixed reaction mixture was heated at 110° C. and stirred for 16 hours under nitrogen protection.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 30 mL).
  • the combined organic phase was washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • di-tert-butyl dicarbonate (3.47 g, 86.82 mmol) was added in portions to a solution of 4-((tert-butoxycarbonyl)(5-(((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (0.4 g, 0.55 mmol), 4-dimethylaminopyridine (6.7 mg, 0.06 mmol) and triethylamine (0.17 g, 1.65 mmol) in tetrahydrofuran (4 mL).
  • the resulting mixed reaction solution was stirred at room temperature for 1 hour. At 0°C, the mixed reaction solution was quenched with water and extracted with ethyl acetate (1 ⁇ 30 mL). The combined organic phase was washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phase was washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction vessel was sealed and heated in a microwave at 110°C for 2 hours.
  • the resulting mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 20 mL).
  • the combined organic phases were washed with brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phase was washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N,N-diisopropylethylamine (900 mg, 6.98 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (500 mg, 2.33 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (560 mg, 2.79 mmol) in isopropanol (7 mL).
  • the resulting mixed reaction solution was heated at 70°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 200 mL).
  • triphosgene (186 mg, 0.63 mmol) was added in batches to a solution of 3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (333 mg, 1.51 mmol) and triethylamine (380 mg, 3.76 mmol) in tetrahydrofuran (2 mL).
  • the resulting mixed reaction solution was stirred at 0°C for 30 minutes.
  • 5-chloro-3-ethyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (350 mg, 1.25 mmol) was added to the above mixed reaction solution system.
  • the resulting mixed reaction solution was stirred at room temperature overnight.
  • Tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (42 mg, 0.076 mmol) were added to a deoxygenated and pre-stirred toluene solution (2 mL) of 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (200 mg, 0.380 mmol), (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (92 mg, 0.46 mmol) and cesium carbonate (371 mg, 1.14 mmol).
  • the microwave tube was sealed and heated at 140° C. under microwave conditions for 2 hours.
  • the resulting mixed reaction solution was diluted with brine/water (10 mL, 1:1) and extracted with ether (3 ⁇ 50 mL).
  • the combined organic phase was washed with brine/water (4 ⁇ 10 mL, 1:1), dried, and concentrated under reduced pressure.
  • the resulting mixed reaction liquid was stirred at room temperature for 2 hours.
  • the mixed reaction liquid was diluted with water and extracted with ethyl acetate (3 ⁇ 80 mL).
  • the combined organic phase was washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic phase was washed with saturated brine (1 ⁇ 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phase was washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated under reduced pressure.
  • tert-butyl 3-hydroxyazetidine-1-carboxylate (469 mg, 2.71 mmol) and potassium tert-butoxide (3 mL, 1 M tetrahydrofuran solution) were added to the above mixed reaction solution, heated at 50° C. and stirred for 16 hours. The obtained mixed reaction solution was concentrated under reduced pressure.
  • N 7 -(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine 500 mg, 1.30 mmol was added to the above mixed reaction solution.
  • the obtained mixed reaction solution was concentrated under reduced pressure.
  • BIOT-002-9043 (Compound 18A): Peak: 1.667 min; (38 mg, yield: 30.8%), LC-MS m/z: 595 [M+H] + ;
  • BIOT-002-90912 Peak: 1.725 min; (1R, 3r, 5S)-3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester (20 mg, yield: 16.2%), LC-MS m/z: 595 [M+H] + ;
  • BIOT-002-9046 (Compound 19A) (15 mg, yield: 4%): Peak 1: 1.030; LC-MS m/z: 609 [M+H] + ;
  • BIOT-002-90216 (Compound 19B) (15 mg, yield: 4%): Peak 2: 1.066; LC-MS m/z: 609 [M+H] + ;
  • BIOT-002-9047 (Compound 20A) (20 mg, yield: 17.4%): Peak 1: 1.682 min; LC-MS m/z: 556 [M+H] + ;
  • BIOT-002-90193 (Compound 20B) (20 mg, yield: 17.4%): Peak 2: 1.747 min; LC-MS m/z: 556 [M+H] + ;
  • Triphosgene (240 mg, 0.81 mmol) was added dropwise to dichloromethane (4 mL) containing tert-butyl 3-hydroxyazetidine-1-carboxylate (419 mg, 2.42 mmol) and triethylamine (489 mg, 4.84 mmol) at 0°C.
  • the resulting mixed reaction liquid was stirred at 0°C for 1 hour.
  • 3-isopropyl-N 7 -(piperidin-4-ylmethyl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine 600 mg, 1.61 mmol was added at 0°C.
  • 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of 1-(tert-butyloxycarbonyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (185 mg, 0.32 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction liquid was stirred at room temperature for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure.
  • Triethylamine (0.22 g, 2.01 mmol) and triphosgene (99 mg, 0.33 mmol) were added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.15 g, 0.80 mmol) in dichloromethane (3 ml) at 0°C.
  • the resulting mixed reaction solution was stirred at 0°C for 30 minutes.
  • Triphosgene (73 mg, 0.25 mmol) was added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (111 mg, 0.59 mmol) and triethylamine (149 mg, 1.48 mmol) in tetrahydrofuran (2 mL) at 0°C.
  • the resulting mixed reaction solution was stirred at 0°C for 30 minutes.
  • the resulting mixed reaction solution was stirred at room temperature for 2 hours.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 80 mL).
  • the combined organic phase was washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Triphosgene 160 mg, 0.54 mmol was added dropwise to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (302 mg, 1.61 mmol) and triethylamine (326 mg, 3.23 mmol) in dichloromethane (4 mL) at 0°C.
  • the resulting mixed reaction solution was stirred at 0°C for 1 hour.
  • 3-isopropyl-N 7 -(piperidin-4-ylmethyl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine 400 mg, 1.08 mmol was added to the above mixed reaction solution.
  • 2,2,2-Trifluoroacetic acid (0.4 mL) was added dropwise to a solution of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (182 mg, 0.31 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure.
  • Triphosgene (21 mg, 0.070 mmol) was added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (39 mg, 0.21 mmol) and triethylamine (42.5 mg, 0.42 mmol) in tetrahydrofuran (1 mL) at 0°C. The resulting mixed reaction solution was stirred at room temperature for 1 hour.
  • the resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic phase was washed with saturated brine (1 ⁇ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Triphosgene (111 mg, 0.37 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (243 mg, 1.40 mmol) and triethylamine (283 mg, 2.81 mmol) in dichloromethane (4 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 1 hour.
  • N 4 -((1R, 3s, 5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine 360 mg, 0.94 mmol was added to the above mixed reaction solution. After the addition, the resulting mixed reaction solution was stirred at 0°C for 12 hours. The resulting mixed reaction solution was concentrated under reduced pressure.
  • BIOT-002-9067 Compound 29A (10 mg, yield: 6%): LC-MS m/z: 571 [M+H] + ;
  • BIOT-002-90208 (Compound 29B) (10 mg, yield: 6%) (10 mg, yield: 6%): LC-MS m/z: 571 [M+H] + ;
  • tert-butyl 3-hydroxypyrrolidine-1-carboxylate 507 mg, 2.71 mmol
  • potassium tert-butoxide 2 mL, 1 M tetrahydrofuran solution
  • the resulting mixed reaction solution was stirred at room temperature for 3 hours. LCMS detected that the reaction was complete.
  • the resulting mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic phase was washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the reactor was sealed and microwaved at 140°C for 1 hour.
  • the mixed reaction solution was diluted with brine (10 mL) and water (10 mL) and extracted with ether (3 ⁇ 20 mL).
  • tert-butyl (R)-3-((7-((tert-butyloxycarbonyl)(piperidin-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate 400 mg, 0.70 mmol was added at 0°C.
  • the resulting mixed reaction solution was stirred at room temperature overnight.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 50 mL).
  • the combined organic phase was washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N, N, N', N'-tetramethylchloroformamidine hexafluorophosphorus 104 mg, 0.37 mmol
  • 1-methyl-1H-imidazole 76 mg, 0.93 mmol
  • (R)-3-((7-(((1-((azetidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester 125 mg, 0.19 mmol
  • 2-fluoroacrylic acid 25 mg, 0.28 mmol
  • the resulting mixed reaction solution was stirred at room temperature for 5 hours.
  • the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 ⁇ 50 mL).
  • the combined organic phase was washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was diluted with water and ethyl acetate ( 3 ⁇ 30mL). The combined organic phases were washed with saturated brine (1 ⁇ 10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • tert-butyl (R)-3-((7-((tert-butyloxycarbonyl)(piperidin-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (71 mg, 0.15 mmol) was added to the mixed reaction solution, and the mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure.
  • 2,2,2-Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.2 g, 2.54 mmol) in dichloromethane (9 mL).
  • the resulting mixed reaction liquid was stirred at room temperature for 1 hour.
  • the resulting mixed reaction liquid was concentrated under reduced pressure.
  • methylmagnesium bromide (2.3 mL, 3M solution in tetrahydrofuran) was added dropwise to a solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (500 mg, 1.14 mmol) in tetrahydrofuran (5 mL). The resulting mixed reaction solution was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction at 0°C, and extracted with dichloromethane (3 ⁇ 50 mL).
  • Triphosgene (245 mg, 0.83 mmol) was added to a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.24 mmol) and triethylamine (250 mg, 2.48 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (227 mg, 0.83 mmol) was added to the above mixed reaction solution at room temperature. The resulting mixed reaction solution was stirred at room temperature overnight.

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Abstract

Disclosed in the present invention is a new fused heterocyclic compound having an inhibitory activity on a CDKs target. Specifically disclosed is a compound having a structure as shown in formula (I) as a CDKs target inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, isotope substitute or isomer thereof.

Description

作为CDKs抑制剂的新型并杂环类新化合物及其应用Novel heterocyclic compounds as CDKs inhibitors and their applications
本申请要求享有申请人：This application requires the applicant to:
于2023年21日向中国国家知识产权局提交的，专利申请号为202310145396.8，名称为“作为CDKs抑制剂的新型并杂环类新化合物及其应用”的在先申请的优先权权益；The priority benefit of the prior application with patent application number 202310145396.8, entitled “Novel heterocyclic compounds as CDKs inhibitors and their applications”, filed with the State Intellectual Property Office of China on 21 December 2023;
于2023年5月24日向中国国家知识产权局提交的，专利申请号为202310593060.8，名称为“作为CDKs抑制剂的新型并杂环类新化合物及其应用”的在先申请的优先权权益；The priority benefit of the prior application, patent application number 202310593060.8, filed with the State Intellectual Property Office of China on May 24, 2023, entitled “Novel heterocyclic compounds as CDKs inhibitors and their applications”;
于2023年7月10日向中国国家知识产权局提交的，专利申请号为202310840097.6，名称为“作为CDKs抑制剂的新型并杂环类新化合物及其应用”的在先申请的优先权权益；The priority benefit of the prior application, patent application number 202310840097.6, entitled “Novel heterocyclic compounds as CDKs inhibitors and their applications”, filed with the State Intellectual Property Office of China on July 10, 2023;
于2023年8月24日向中国国家知识产权局提交的，专利申请号为202311074460.4，名称为“作为CDKs抑制剂的新型并杂环类新化合物及其应用”的在先申请的优先权权益；The priority benefit of the prior application, patent application number 202311074460.4, entitled “Novel heterocyclic compounds as CDKs inhibitors and their applications”, filed with the State Intellectual Property Office of China on August 24, 2023;
该在先申请的全文通过引用的方式结合于本申请中。The entire content of this prior application is incorporated into this application by reference.
技术领域Technical Field
本发明属于医药化学领域，具体包括公开了具有CDKs靶点抑制活性的新型并杂环类化合物，包含该类化合物的组合物及以及将该类化合物应用于制备治疗或预防与CDKs靶点相关的疾病的药物的方法。The present invention belongs to the field of pharmaceutical chemistry, and specifically discloses novel heterocyclic compounds with CDKs target inhibitory activity, compositions containing such compounds, and methods for applying such compounds to prepare drugs for treating or preventing diseases associated with CDKs targets.
背景技术Background Art
细胞周期蛋白依赖性激酶(cyclin-dependent kinases，CDKs)属于丝氨酸/苏氨酸蛋白激酶家族。目前已发现21种CDK，大部分的CDK的激活都必须与细胞周期蛋白(cyclin)结合从而形成具有活性的异源二聚体复合物。这种具有活性的二聚体复合物能够将相应的底物进行磷酸化，进而驱动细胞周期的各个过程，从而调控细胞的生长与增殖。在所有的CDK中，其中CDK1/2/4/6主要通过调控细胞周期发挥功能，而CDK7/8/9/10/11则同时能够参与细胞周期以及转录调控从而发挥生物学功能。Cyclin-dependent kinases (CDKs) belong to the serine/threonine protein kinase family. 21 CDKs have been discovered so far, and most of them must bind to cyclins to form active heterodimer complexes for activation. This active dimeric complex can phosphorylate the corresponding substrates, thereby driving various processes of the cell cycle and regulating cell growth and proliferation. Among all CDKs, CDK1/2/4/6 mainly function by regulating the cell cycle, while CDK7/8/9/10/11 can also participate in cell cycle and transcriptional regulation to exert biological functions.
研究表明，许多恶性肿瘤的发生与发展与细胞周期失调相关，其中CDK的过度活化是其中最重要的原因之一。CDK在肿瘤细胞的增殖与凋亡中都有着重要功能，因此，通过选择性抑制CDK对肿瘤的治疗能起到积极的治疗作用。目前已有靶向CDK4/6的抑制剂帕博西尼、瑞博西尼、阿贝西利以及达尔西利上市，并且在乳腺癌的治疗中显示出了优异的疗效。CDK7作为CDK家族中重要的一员，主要通过与细胞周期蛋白H(cyclinH)和MAT1组成CDK激活激酶复合物(CAK)。CAK复合物一方面可以磷酸化其它的细胞周期激酶，推动细胞周期的正常进行。另外一方面，CAK复合物能够磷酸化RNA聚合酶II参与相关基因的转录调控。Studies have shown that the occurrence and development of many malignant tumors are related to cell cycle disorders, among which the overactivation of CDK is one of the most important reasons. CDK plays an important role in the proliferation and apoptosis of tumor cells. Therefore, selective inhibition of CDK can play a positive therapeutic role in the treatment of tumors. At present, inhibitors targeting CDK4/6, such as palbociclib, ribociclib, abemaciclib and darcillib, are on the market and have shown excellent efficacy in the treatment of breast cancer. As an important member of the CDK family, CDK7 mainly forms a CDK-activated kinase complex (CAK) with cyclin H and MAT1. On the one hand, the CAK complex can phosphorylate other cell cycle kinases to promote the normal progress of the cell cycle. On the other hand, the CAK complex can phosphorylate RNA polymerase II to participate in the transcriptional regulation of related genes.
研究表明，CDK7在肝癌、胃癌、宫颈癌、乳腺癌、胰腺癌、结直肠癌、神经母细胞瘤、前列腺癌、非小细胞肺癌及急性髓性白血病等许多种恶性肿瘤中都存在过表达现象，并且与侵袭性临床病理和不良预后都具有一定的相关性。由于整个CDK家族的成员同源性较高，而且在不同类型的肿瘤类型中的机制也有着一定的差异，因此非选择性的CDK7抑制剂在临床试验中存在着一定的由于脱靶效应引起的不良反应。目前尚无有选择性的CDK7抑制剂上市，大量的临床前以及临床试验都显示高选择性的CDK7抑制剂在多种难治的肿瘤中都有着巨大的潜在治疗价值。Studies have shown that CDK7 is overexpressed in many malignant tumors such as liver cancer, gastric cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, neuroblastoma, prostate cancer, non-small cell lung cancer and acute myeloid leukemia, and is correlated with aggressive clinical pathology and poor prognosis. Since the members of the entire CDK family have a high degree of homology and their mechanisms in different types of tumors are also different, non-selective CDK7 inhibitors have certain adverse reactions caused by off-target effects in clinical trials. At present, there are no selective CDK7 inhibitors on the market. A large number of preclinical and clinical trials have shown that highly selective CDK7 inhibitors have great potential therapeutic value in a variety of refractory tumors.
技术效果Technical Effects
本发明人意外地发现部分本发明的式(I)结构新型并杂环类新化合物不仅具有显著的CDK7抑制活性，而且相比于结构已知的临床参照化合物THZ2、Samuraciclib、CYC-202等还具有更高的活性、更好的选择性、药代及生物利用度等特性，预期将会有更优的人体PK特性及药效，以及更适合作为候选药物开发用于预防或治疗与CDKs靶点或信号通路相关的疾病。The inventors unexpectedly discovered that some of the novel heterocyclic compounds of the formula (I) of the present invention not only have significant CDK7 inhibitory activity, but also have higher activity, better selectivity, pharmacokinetics and bioavailability than the clinical reference compounds THZ2, Samuraciclib, CYC-202, etc. with known structures. It is expected that they will have better human PK properties and efficacy, and are more suitable for development as candidate drugs for the prevention or treatment of diseases related to CDKs targets or signal pathways.
发明内容Summary of the invention
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，
Figure PCTCN2024077920-ftappb-I100001
The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof.
Figure PCTCN2024077920-ftappb-I100001
其中，in,
Figure PCTCN2024077920-ftappb-I100002
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100002
Any independently selected from a single bond or a double bond;
X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环A和B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；当A环为不存在时，L1和L2可以直接相连；Rings A and B are arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R 3 can be directly connected to Y; when ring A is absent, L 1 and L 2 can be directly connected;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , or C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代； Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1A)结构，
Figure PCTCN2024077920-ftappb-I100003
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1A),
Figure PCTCN2024077920-ftappb-I100003
其中，in,
Figure PCTCN2024077920-ftappb-I100004
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100004
Any independently selected from a single bond or a double bond;
X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，Rd可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R d can be directly connected to Y;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、 -C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 ) -, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C (＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or -C(R d1 )(R d2 )S(＝O) 2 -;
Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R011；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 0 1 1 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl, or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代， 且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个RdRd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups; or any two R d R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which they are attached, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 and OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1B)结构，
Figure PCTCN2024077920-ftappb-I100005
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1B):
Figure PCTCN2024077920-ftappb-I100005
其中，in,
Figure PCTCN2024077920-ftappb-I100006
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100006
Any independently selected from a single bond or a double bond;
X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(RdRd2)-、-C(RdRd1)＝C(RdRd2)-、炔键、-OC(RdRd1)(Rd2)-、-C(RdRd1)(RdRd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(RdRd1)(RdRd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(RdRd2)C(Rd1)(RdRd2)-、-OC(RdRd1)(Rd2)C(Rd1)(RdRd2)-、-C(RdRd1)(Rd2)C(RdRd1)(Rd2)O-、-C(RdRd1)(Rd2)C(＝O)N(Rd3)-、-C(RdRd1)(Rd2)C(RdRd1)(RdRd2)N(Rd3)-、-C(Rd1)(RdRd2)C(＝NRd3)-、-C(RdRd1)(RdRd2)N(RdRd3)C(RdRd1)(Rd2)-、-C(RdRd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(RdRd1)(Rd2)-、-OC(RdRd1)(Rd2)-、-SC(RdRd1)(Rd2)-、-C(RdRd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(RdRd2)C(＝O)-、-C(RdRd1)(RdRd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(RdRd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( RdRd2 )-, -C(RdRd1)=C(RdRd2)-, an acetylenic bond, -OC(RdRd1)(Rd2 ) - , -C ( RdRd1 ) ( RdRd2 ) O- , -C( = O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( RdRd1 )( RdRd2 )N ( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 ) - )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d R d2 )C(R d1 )(R d R d2 )-, -OC(R d R d1 )(R d2 )C(R d1 )(R d R d2 )-,- C(R d R d1 )(R d2 )C(R d R d1 )(R d2 )O-, -C(R d R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d R d1 )(R d2 )C(R d R d1 )(R d R d2 )N(R d3 )-, -C(R d1 )(R d R d2 )C(＝NR d3 )-, -C(R d R d1 )(R d R d2 )N(R d R d3 )C(R d R d1 )(R d2 )-, -C(R d R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d R d1 )(R d2 )-, -OC(R d R d1 )(R d2 )-, -SC(R d R d1 )(R d2 )-, -C(R d R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d R d2 )C(=O)-, -C(R d R d1 )(R d R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d R d1 )(R d2 )S(=O) 2 -;
Y独立地选自为不存在、单键、-C(RdRd1)(Rd2)-、-C(RdRd1)＝C(Rd2)-、炔键、-OC(RdRd1)(Rd2)-、-C(RdRd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(RdRd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(RdRd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(RdRd1)(RdRd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(RdRd1)(Rd2)C(Rd1)(RdRd2)O-、-C(RdRd1)(RdRd2)C(＝O)N(RdRd3)-、-C(RdRd1)(RdRd2)C(RdRd1)(RdRd2)N(RdRd3)-、-C(Rd1)(RdRd2)C(＝NRdRd3)-、-C(Rd1)(RdRd2)N(RdRd3)C(RdRd1)(Rd2)-、-C(RdRd1)(RdRd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(RdRd2)-、-OC(RdRd1)(RdRd2)-、-SC(RdRd1)(RdRd2)-、-C(RdRd1)(RdRd2)C(＝O)O-、-OC(＝O)C(RdRd1)(RdRd2)-、-C(RdRd1)(RdRd2)C(＝O)-、-C(RdRd1)(RdRd2)C(＝S)-、-S(＝O)C(RdRd1)(RdRd2)-或-C(RdRd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( RdRd1 )( Rd2 )-, -C( RdRd1 ) =C( Rd2 )-, an acetylenic bond, -OC( RdRd1 ) ( Rd2 )-, -C( RdRd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( RdRd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( RdRd3 ) - )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d R d1 )(R d R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d R d1 )(R d2 )C(R d1 )(R d R d2 )O-, -C(R d R d1 )(R d R d2 )C(＝O)N(R d R d3 )-, -C(R d R d1 )(R d R d2 )C(R d R d1 )(R d R d2 )N(R d R d3 )-, -C(R d1 )(R d R d2 )C(＝NR d R d3 )-, -C(R d1 )(R d R d2 )N(R d R d3 )C(R d R d1 )(R d2 )-, -C(R d R d1 )(R d R d2 )S(＝O) 2 N(R d3 )-, -N(R d 3 )C(R d1 )(R d R d2 )-, -OC(R d R d1 )(R d R d2 )-, -SC(R d R d1 )(R d R d2 )-, -C(R d R d1 )(R d R d2 )C(＝O)O-, -OC(＝O)C(R d R d1 )(R d R d2 )-, -C(R d R d1 )(R d R d2 )C(＝O)-, -C(R d R d1 )(R d R d2 )C(＝S)-, -S(＝O)C(R d R d1 )(R d R d2 )- or -C(R d R d1 )(R d2 )S(＝O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(RdRd2)-、-C(Rd1)＝C(RdRd2)-、炔键、-OC(RdRd1)(RdRd2)-、-C(RdRd1)(RdRd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRdRd3)-、-C(RdRd1)(RdRd2)N(RdRd3)-、-S(＝O)2N(RdRd3)-、-N(RdRd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(RdRd1)(RdRd2)-、-OC(Rd1)(Rd2)C(Rd1)(RdRd2)-、-C(RdRd1)(Rd2)C(Rd1)(RdRd2)O-、-C(RdRd1)(RdRd2)C(＝O)N(RdRd3)-、-C(RdRd1)(RdRd2)C(RdRd1)(RdRd2)N(RdRd3)-、-C(Rd1)(RdRd2)C(＝NRdRd3)-、-C(Rd1)(RdRd2)N(RdRd3)C(RdRd1)(Rd2)-、 -C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( RdRd2 ) -, -C( Rd1 )=C( RdRd2 )-, an acetylenic bond, -OC(RdRd1 ) ( RdRd2 ) -, -C( RdRd1 )( RdRd2 )O-, -C(= O )N( Rd3 ) -, -N(Rd3)-, -C(=NRdRd3)-, -C(RdRd1 ) ( RdRd2 ) N ( RdRd3 )-, -S(=O) 2N ( RdRd3 )-, -N ( RdRd3 ) - )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d R d1 )(R d R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d R d2 )-, -C(R d R d1 )(R d2 )C(R d1 )(R d R d2 )O-, -C(R d R d1 )(R d R d2 )C(＝O)N(R d R d3 ) -, -C(R d R d1 )(R d R d2 )C(R d R d1 )(R d R d2 )N(R d R d3 )-, -C(R d1 )(R d R d2 )C(＝NR d R d3 )-, -C(R d1 )(R d R d2 )N(R d R d3 )C(R d R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R0上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1C)结构，
Figure PCTCN2024077920-ftappb-I100007
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1C):
Figure PCTCN2024077920-ftappb-I100007
其中，in,
Figure PCTCN2024077920-ftappb-I100008
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100008
Any independently selected from a single bond or a double bond;
X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代； Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1D)结构，
Figure PCTCN2024077920-ftappb-I100009
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1D):
Figure PCTCN2024077920-ftappb-I100009
其中，in,
X独立地选自N、CR；X is independently selected from N, CR;
Figure PCTCN2024077920-ftappb-I100010
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100010
Any independently selected from a single bond or a double bond;
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连； Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、 C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two of R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1或2中的整数。t is arbitrarily selected from an integer of 0, 1 or 2.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1E)结构，
Figure PCTCN2024077920-ftappb-I100011
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1E):
Figure PCTCN2024077920-ftappb-I100011
其中，in,
X独立地选自N、CR；X is independently selected from N, CR;
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、 -C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )- , -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构；R2也可以与Rd3连接起来一起形成3-18元单环或多环结构；所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R R 2 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure; R 2 can also be connected with R d3 to form a 3-18 membered monocyclic or polycyclic structure; the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1和Rd2也可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 and any two of R d1 and R d2 are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, and saturated or partially saturated C 3-6 cycloalkyl; and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen , deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two of R d1 and R d2 can also form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br , I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1或2中的整数。t is arbitrarily selected from an integer of 0, 1 or 2.
在某些实施例中，L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或 -C(Rd1)(Rd2)S(＝O)2-；优先选自-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-或-C(Rd1)(Rd2)N(Rd3)-。In certain embodiments, L1 is independently selected from absent, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )-or -C( Rd1 )( Rd2 )S(=O) 2- ; preferably selected from -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )- or -C( Rd1 )( Rd2 )N( Rd3 )-.
环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R1可以和Y直接相连；优选为不存在或单环结构；最优选不存在、苯环、吡啶环、噻唑环、吡唑环、氮杂环丁烷、氮杂环戊烷、氮杂环己烷。Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R1 can be directly connected to Y; preferably, it is absent or a monocyclic structure; most preferably, it is absent, a benzene ring, a pyridine ring, a thiazole ring, a pyrazole ring, an azetidine, an azocyclopentane, and an azohexane.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-2)结构，
Figure PCTCN2024077920-ftappb-I100012
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2):
Figure PCTCN2024077920-ftappb-I100012
其中，in,
Figure PCTCN2024077920-ftappb-I100013
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100013
Any independently selected from a single bond or a double bond;
X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂 环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, The aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-2C)结构，
Figure PCTCN2024077920-ftappb-I100014
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2C):
Figure PCTCN2024077920-ftappb-I100014
其中， in,
X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
L、L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L, L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、 C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy , C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl , C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more than one selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C R d1 , R d2 or R d3 , wherein the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen , deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups ; or any two of R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1、2、3和4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-2D)结构，
Figure PCTCN2024077920-ftappb-I100015
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2D):
Figure PCTCN2024077920-ftappb-I100015
其中，in,
X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
X7任意独立地选自-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；且X7上的氢最佳任选地被1至多个R3取代；X7 is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 ) )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 ) N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C( Rd1 )( Rd2 )-, -OC( Rd1)(Rd2 ) -, -SC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )C(＝O)O-, -OC(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )C(＝O)-, -C( Rd1 )( Rd2 )C(＝S)-, -S(＝O)C( Rd1 )( Rd2 )-, or -C( Rd1 )( Rd2 )S(＝O) 2- ; and the hydrogen on X7 is optionally substituted by 1 to more R3 ;
L、L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L, L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、 -C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(＝O)N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The heteroatom is independently selected from any atom or group of O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1、2、3和4中的整数。 t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-2E)结构，
Figure PCTCN2024077920-ftappb-I100016
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2E):
Figure PCTCN2024077920-ftappb-I100016
其中，in,
X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
L和L1各自独立地选自为-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L and L1 are each independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷 基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkane R2 is a C1-10 alkyl, a C2-10 alkenyl, a C2-10 alkynyl or a C1-10 alkoxyl group, a C2-10 heteroalkyl, a C3-10 saturated or partially saturated cycloalkyl, an aryl, a heteroaryl, a C3-10 saturated or partially saturated heterocyclic group, a C1-10 alkyl substituted with a C3-10 cycloalkyl or C3-10 heterocyclic alkyl, a C2-10 heteroalkyl substituted with a C3-10 cycloalkyl , a C3-10 heterocyclic group, a C1-10 alkyl substituted with a C3-10 alkyl, or a carboxyl or carboxyl substitute; or any two R2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further R The hydrogen on 2 is optionally replaced by 1 to 2 more preferably selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
R5、R6和R7可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且R5、R6和R7上的氢最佳任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者R5、R6和R7任意两个可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; The hydrogen on R7 is most preferably optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and C1-6 alkyl and C1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH , OCH3 , OCH2CH3 , and saturated or partially saturated C3-6 cycloalkyl; or R5 , R6 and R 7 Any two of the atoms to which they are attached may form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-2F)结构，
Figure PCTCN2024077920-ftappb-I100017
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-2F):
Figure PCTCN2024077920-ftappb-I100017
其中，in,
X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
L和L1各自独立地选自为-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L and L1 are each independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基 或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 1-10 alkyl substituted with C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted with carboxyl or carboxyl substitute; or any two R 2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
R5、R6和R7可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且R5、R6和R7上的氢最佳任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者R5、R6和R7任意两个可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; The hydrogen on R7 is most preferably optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and C1-6 alkyl and C1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH , OCH3 , OCH2CH3 , and saturated or partially saturated C3-6 cycloalkyl; or R5 , R6 and R 7 Any two of the atoms to which they are attached may form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-4A)结构，
Figure PCTCN2024077920-ftappb-I100018
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-4A),
Figure PCTCN2024077920-ftappb-I100018
其中，in,
Figure PCTCN2024077920-ftappb-I100019
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100019
Any independently selected from a single bond or a double bond;
X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、 C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl , C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R2 is optionally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH3 , carboxyl, OH, CN, C1-10 alkyl, C3-10 cycloalkyl, C C4-10 heterocyclyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-4B)结构，
Figure PCTCN2024077920-ftappb-I100020
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-4B):
Figure PCTCN2024077920-ftappb-I100020
其中，in,
Figure PCTCN2024077920-ftappb-I100021
任意独立地选自单键或双键；
Figure PCTCN2024077920-ftappb-I100021
Any independently selected from a single bond or a double bond;
X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR； X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环 烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cyclo Alkyl acyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , oxo, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two of R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
在某些实施例中，其中：
Figure PCTCN2024077920-ftappb-I100022
优先选自如下结构：
Figure PCTCN2024077920-ftappb-I100023
Figure PCTCN2024077920-ftappb-I100024
Figure PCTCN2024077920-ftappb-I100025
In certain embodiments, wherein:
Figure PCTCN2024077920-ftappb-I100022
Preferably selected from the following structures:
Figure PCTCN2024077920-ftappb-I100023
Figure PCTCN2024077920-ftappb-I100024
Figure PCTCN2024077920-ftappb-I100025
根据本发明的实施方案，环A选自3-10元杂环基、C3-8环烷基、C6-10芳基、5-10元杂芳基；According to an embodiment of the present invention, ring A is selected from 3-10 membered heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl;
根据本发明的实施方案，环A选自
Figure PCTCN2024077920-ftappb-I100026
Figure PCTCN2024077920-ftappb-I100027
According to an embodiment of the present invention, ring A is selected from
Figure PCTCN2024077920-ftappb-I100026
Figure PCTCN2024077920-ftappb-I100027
根据本发明的实施方案，环B不存在或选自4-6元杂环基、C6-10芳基；例如氮杂环丁烷基、四氢吡咯基、哌啶基、苯基；According to an embodiment of the present invention, ring B is absent or selected from 4-6 membered heterocyclyl, C 6-10 aryl; for example azetidinyl, tetrahydropyrrolyl, piperidinyl, phenyl;
根据本发明的实施方案，环B不存在或选自
Figure PCTCN2024077920-ftappb-I100028
According to an embodiment of the present invention, ring B is absent or selected from
Figure PCTCN2024077920-ftappb-I100028
根据本发明的实施方案，X、X1、X2、X3、X4、X5、X6选自N、C、CR；According to an embodiment of the present invention, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are selected from N, C, CR;
根据本发明的实施方案，R选自H、C1-6烷基、C3-8环烷基，例如乙基、异丙基、环丙基。According to an embodiment of the present invention, R is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, such as ethyl, isopropyl, cyclopropyl.
根据本发明的实施方案，Y不存在或选自O、C(O)、无取代或任选被一个或两个C1-6烷基取代的CH2-O。According to an embodiment of the present invention, Y is absent or selected from O, C(O), CH 2 —O which is unsubstituted or optionally substituted by one or two C 1-6 alkyl groups.
根据本发明的实施方案，L1选自NH、CH2-NH。According to an embodiment of the present invention, L 1 is selected from NH, CH 2 —NH.
根据本发明的实施方案，L2不存在或选自C(O)、NH、N(C1-6烷基)、N-亚C1-6烷基。According to an embodiment of the present invention, L 2 is absent or selected from C(O), NH, N(C 1-6 alkyl), N-C 1-6 alkylene.
根据本发明的实施方案，Y-L2选自OC(O)、无取代或任选被一个或两个C1-6烷基取代的下列基团：NH、CH2-OC(O)、C(O)NH、O-CH2-C(O)。According to an embodiment of the present invention, YL 2 is selected from the following groups: OC(O), unsubstituted or optionally substituted with one or two C 1-6 alkyl groups: NH, CH 2 —OC(O), C(O)NH, O—CH 2 —C(O).
根据本发明的实施方案，R0选自C1-6烷基、C3-8环烷基、卤代C1-6烷基、-L3R01。According to an embodiment of the present invention, R 0 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, -L 3 R 01 .
根据本发明的实施方案，L3不存在或选自O、NH、N-亚C1-6烷基(例如NH-CH2、NH-CH(CH3))。According to an embodiment of the present invention, L 3 is absent or selected from O, NH, N-C 1-6 alkylene (eg NH—CH 2 , NH—CH(CH 3 )).
根据本发明的实施方案，R01选自无取代或任选被一个、两个或更多个OH、氧代(＝O)、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C3-8环烷基-C1-6烷基、苄氧羰基取代的下列基团：C1-6烷基、5-6元杂环基(例如哌啶基、四氢吡咯基、四氢吡喃基、
Figure PCTCN2024077920-ftappb-I100029
)、5-10元杂芳基(例如吡啶基、嘧啶基)；According to an embodiment of the present invention, R 01 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more OH, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halogenated C 3-8 cycloalkyl-C 1-6 alkyl, benzyloxycarbonyl: C 1-6 alkyl, 5-6 membered heterocyclyl (e.g. piperidinyl, tetrahydropyrrolyl, tetrahydropyranyl,
Figure PCTCN2024077920-ftappb-I100029
), 5-10 membered heteroaryl (e.g. pyridyl, pyrimidinyl);
根据本发明的实施方案，R0选自甲基、异丙基、环丙基、三氟甲基、
Figure PCTCN2024077920-ftappb-I100030
Figure PCTCN2024077920-ftappb-I100031
According to an embodiment of the present invention, R 0 is selected from methyl, isopropyl, cyclopropyl, trifluoromethyl,
Figure PCTCN2024077920-ftappb-I100030
Figure PCTCN2024077920-ftappb-I100031
根据本发明的实施方案，R2选自H、C1-6烷基、C1-6烷氧基。According to an embodiment of the present invention, R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy.
根据本发明的实施方案，R3选自H、C2-6烯基-C(O)、C2-6烯基-C(O)NH、卤代C2-6烯基-C(O)、(C1-6烷基)2N-C2-6烯基-C(O)、3-8元含氮杂环基-C2-6烯基-C(O)、C1-6烷氧基-3-8元含氮杂环基-C2-6烯基-C(O)、C2-6炔基-C(O)；According to an embodiment of the present invention, R 3 is selected from H, C 2-6 alkenyl-C(O), C 2-6 alkenyl-C(O)NH, halogenated C 2-6 alkenyl-C(O), (C 1-6 alkyl) 2 NC 2-6 alkenyl-C(O), 3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 1-6 alkoxy-3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 2-6 alkynyl-C(O);
根据本发明的实施方案，R3选自H、
Figure PCTCN2024077920-ftappb-I100032
Figure PCTCN2024077920-ftappb-I100033
According to an embodiment of the present invention, R3 is selected from H,
Figure PCTCN2024077920-ftappb-I100032
Figure PCTCN2024077920-ftappb-I100033
根据本发明的实施方案，m选自0、1、2、3或4。According to an embodiment of the present invention, m is selected from 0, 1, 2, 3 or 4.
根据本发明的实施方案，n选自0、1、2、3、4或5。According to an embodiment of the present invention, n is selected from 0, 1, 2, 3, 4 or 5.
本发明的一个方案中，上述化合物或其药学上可接受的盐，或其对应异构体、同位素取代物，其为选自实施例中公开结构的化合物，如化合物1至113、化合物C1-1至C1-582、化合物C2-77至C2-335、化合物C3-77至C3-362、化合物C4-77至C4-258。In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution, is selected from the compounds with structures disclosed in the embodiments, such as compounds 1 to 113, compounds C1-1 to C1-582, compounds C2-77 to C2-335, compounds C3-77 to C3-362, and compounds C4-77 to C4-258.
本发明还提供一种药物组合物，其包含治疗有效量的式(I)所示的化合物、其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物中的至少一种。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution.
根据本发明的实施方案，所述药物组合物经配制而通过选自以下的途径给药：口服、注射、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外。According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
根据本发明的实施方案，所述药物组合物优选以口服方式给药。According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.
所述口服剂型没有特别限定，可以采用本领域熟知的任意口服剂型，优选包括片剂、胶囊、混悬剂或者口服溶液等本领域已知的口服剂型。作为口服剂型时，使用的剂量标准例如为1-1500mg/天。The oral dosage form is not particularly limited, and any oral dosage form known in the art may be used, preferably tablets, capsules, suspensions or oral solutions, etc. When used as an oral dosage form, the dosage standard used is, for example, 1-1500 mg/day.
根据本发明的实施方案，所述药物组合物还可以包含药学上可接受的辅料，其选自包括但不限于下列辅料中的至少一种：填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、矫味剂、湿润剂、pH调节剂、增溶剂或助溶剂、渗透压调节剂。本领域技术人员根据具体剂型的需要，可以容易地确定如何选择相应的辅料及其相应用量。According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipient and its corresponding dosage according to the needs of the specific dosage form.
根据本发明的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.
本发明的另一目的在于提供上述化合物在制备用于预防和/或治疗CDKs信号通路相关疾病包括肿瘤、炎症、自免疫性疾病(如红斑狼疮、牛皮癣、银屑病)等病症的药物中的用途。Another object of the present invention is to provide the use of the above-mentioned compounds in the preparation of drugs for preventing and/or treating diseases related to CDKs signaling pathways including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and the like.
本发明还提供所述式(I)所示的化合物、其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物，以及所述药物组合物在预防和/或治疗CDKs信号通路相关的疾病中的用途。所述的CDKs信号通路相关的疾病 具有上文所述的定义。The present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, and the use of the pharmaceutical composition in preventing and/or treating diseases related to CDKs signaling pathway. Has the definition given above.
本发明还提供一种预防和/或治疗CDKs信号通路相关的疾病的方法，包括给予患者预防或治疗有效量的式(I)所示的化合物、其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物中的至少一种，或者给予患者预防或治疗有效量的上述药物组合物。所述的CDKs信号通路相关的疾病具有上文所述的定义。The present invention also provides a method for preventing and/or treating diseases related to the CDKs signaling pathway, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, or administering to a patient a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition. The diseases related to the CDKs signaling pathway have the definitions described above.
在一些实施方案中，所述患者哺乳动物，优选是人。In some embodiments, the patient is a mammal, preferably a human.
定义和说明：Definition and Explanation:
C1-10选自C1、C2、C3、C4、C5、C6、C7、C8、C9和C10；C2-10选自C2、C3、C4、C5、C6、C7、C8、C9和C10；C3-10选自C3、C4、C5、C6、C7、C8、C9和C10； C1-10 is selected from the group consisting of C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ; C2-10 is selected from the group consisting of C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 and C10 ; C3-10 is selected from the group consisting of C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
术语“烷基”应理解为表示具有1～20个碳原子的直链或支链饱和一价烃基，也记为“C1-20烷基”。例如，“C1-10烷基”表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基，“C1-8烷基”表示具有1、2、3、4、5、6、7、或8个碳原子的直链和支链烷基，“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等或它们的异构体。The term "alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1 to 20 carbon atoms, also noted as "C 1-20 alkyl". For example, "C 1-10 alkyl" means straight and branched alkyl radicals having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 alkyl" means straight and branched alkyl radicals having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and "C 1-6 alkyl " means straight and branched alkyl radicals having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.
本文所用术语“亚烷基”是指式-(CH2)n-的直链或支链二价烃基团。非限制性示例包括乙烯和丙烯。As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon group of the formula -(CH 2 ) n - Non-limiting examples include ethylene and propylene.
本文所用术语“1至多个”是指1个以上，例如1个、2个、3个、4个、5个或更多个。As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.
术语“脂肪环”、“碳环(基)”或“环烷基”指饱和或部分不饱和的单环或多环环状烃基，碳环可以包含3至20个碳原子，优选包含3至12个(例如3、4、5、6、7、8、9、10、11、12个)碳原子，更优选包含3至6个碳原子。碳环可以是单环或多环的，其可以是饱和的环烷基或者在其环上可以任选地包含一个、两个或更多个双键和/或三键，由此形成所谓的环烯基或环炔基。碳环在具有多个环的情况下，这些环可以形成螺环、稠环和桥环结构。例如，单环碳环的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基、环辛四烯基等；多环碳环的非限制性实例包括十氢化萘基或异冰片基。The term "aliphatic ring", "carbocycle (base)" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the carbocycle can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl or can optionally contain one, two or more double bonds and/or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl. In the case of a carbocycle having multiple rings, these rings can form spirocyclic, condensed and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
术语“杂环(基)”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自N、O、NH、S、S(O)或S(O)2的杂原子或原子团，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1-4个是杂原子(例如1、2、3和4个)；更优选包含3至6个环原子(例如3、4、5、6个)。杂环基可以通过所述碳原子中的任一个碳原子或氮原子(如果存在的话)或者氧或者硫原子(特别是在形成鎓盐的情况下)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环和/或螺环的环。单环杂环基的非限制性实例包括氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、二氧杂环戊烯基、四氢吡喃基、吡咯啉基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二噻烷基、三噻烷基、高哌嗪基、二氮杂环庚烷基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基，也可以是苯并稠合的杂环基例如二氢异喹啉基。所述杂环基可以是双环的，其非限制性实例包括六氢环戊并[c]吡咯-2(1H)-基，六氢吡咯并[1，2-a]吡嗪-2(1H)-基。杂环基也可以是部分不饱和的，即它可以包含一个或多个双键，其非限制性实例包括二氢呋喃基、二氢吡喃基、2，5-二氢-1H-吡咯基、4H-[1，3，4]噻二嗪基、4，5-二氢噁唑基或4H-[1，4]噻嗪基。The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and/or spirocyclic rings. The non-limiting examples of monocyclic heterocyclic radical include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl.Polycyclic heterocyclic radical includes the heterocyclic radical of spirocycle, condensed ring and bridge ring, and can also be the heterocyclic radical of benzo condensation such as dihydroisoquinolinyl.The heterocyclic radical can be bicyclic, and its non-limiting examples include hexahydrocyclopenta [c] pyrrole -2 (1H) -base, hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -base. The heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“芳基”或“芳环”是指：应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、二环(如稠环、桥环、螺环)或三环烃环，其可以是单芳族环或稠合在一起的多芳族环，优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。当所述C6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。The term "aryl" or "aromatic ring" means: it should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl". The term "C 6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. When the C 6-20 aryl is substituted, it may be mono- or polysubstituted. Furthermore, there is no limitation on the substitution site, and for example, substitution may be at the ortho, para or meta position.
术语“螺环”是指两个环共用1个成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。The term "spirocyclic ring" refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
术语“并环”是指两个环共用2个成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。The term "paracyclic" refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
术语“桥环”是指两个环共用3个以上成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
本文中，术语“杂芳基/杂芳环”指包含1至4个杂原子、5至20个环原子的杂芳族体系，其中杂原子选自氧、硫、氮和磷。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元。杂芳基的非限制性实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯 并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基和/或吩噁嗪基等。As used herein, the term "heteroaryl/heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzo and isoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and/or phenoxazinyl, etc.
杂芳基/杂芳环可以是任选取代的或未取代的，当被取代时，取代基优选为一个、两个或更多个彼此独立地选自下组的基团：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl/heteroaromatic ring may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
除非另有说明，否则杂环基、杂芳基或杂芳环包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。Unless otherwise specified, heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at one, two or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.，″Pharmaceutical Salts″，Joumal of Pharmaceutical Science 66：1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into either base or acid addition salts.
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐如Na盐、钾盐、胺盐、母体化合物的季铵盐等。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸、无机碱和有机碱的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸等所述的无机碱和有机碱选自Na、钾、镁、钙等或胺、二乙胺、三乙胺、乙醇胺等。As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention, wherein the parent compound is modified by salification with an acid or alkali. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts such as Na salts, potassium salts, amine salts, quaternary ammonium salts of parent compounds, and the like. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene The inorganic base and organic base described in the following examples are selected from sodium, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to the form of salts, compounds provided by the present invention also exist in prodrug form. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.
在本文中，术语“溶剂合物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂合物的溶剂包括，但并不限于：水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。因此，术语“水合物”是指溶剂分子是水所形成的缔合物。As used herein, the term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. Therefore, the term "hydrate" refers to an association formed by a solvent molecule that is water.
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62：114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的 互变异构形式均包括在本发明的范围之内。The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all Tautomeric forms are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy，21st Ed.，Lippincott，Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to technicians in the field of cosmetics or topical drugs. For additional information about carriers, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When a substituent's bond can cross-link to two atoms on a ring, such substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to a compound included in the chemical structure but not specifically mentioned, such substituent can be bonded through any atom thereof. Combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
本发明现在进一步通过实施例描述。下面给出的实施例仅用于说明目的，而不是仅限于此发明的范围。本发明的化合物可以用有机合成领域中许多已知的方法来制备。本发明的实施例可以使用下面描述的方法来合成，以及有机合成化学领域中已知的合成方法，或在其基础上通过改进的方法。优选的方法包括，但不限于以下描述方法。The present invention is now further described by examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many known methods in the field of organic synthesis. The embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based thereon. Preferred methods include, but are not limited to, the following description methods.
未经特别说明，本发明所有使用的溶剂都是市售的，使用时无需进一步纯化。反应通常在氮气的惰性气氛下使用无水溶剂进行。核磁共振谱在Bruker-Avance-400(400mhz)谱仪测定，并以δ(ppm)形式报告化学位移。质谱用安捷伦1200系列(plus 6110/和1956A)LC/MS或岛津MS(DAD：SPD-M20A(LC))和岛津Micromass 2020检测仪。质谱仪配有一个正、负模式工作的电喷雾离子源(ESI)。Unless otherwise specified, all solvents used in the present invention are commercially available and do not require further purification when used. The reaction is usually carried out using anhydrous solvents under an inert atmosphere of nitrogen. The nuclear magnetic resonance spectrum is measured on a Bruker-Avance-400 (400 MHz) spectrometer, and the chemical shift is reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110/ and 1956A) LC/MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive and negative modes.
本发明采用下述缩略词：aq代表水；DCM代表二氯甲烷；PE代表石油醚；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲基亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，一种胺保护基；Boc代表叔丁基氧羰基，一种胺保护基；HOAc代表乙酸；NaBH(OAc)3代表三乙酰氧基硼氢化钠；r.t代表室温；THF代表四氢呋喃；Boc2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙胺；Pd(dppf)Cl2代表[1，1′-双(二苯基膦基)二茂铁]二氯化钯(II)；POCl3代表三氯氧磷；NaH代表氢化钠；LAH代表氢化铝锂；Pd(OAc)2代表钯(II)乙酸盐；Pd2(dba)3代表三(二亚苄基丙酮)二钯；Pd(PPh3)4代表四(三苯基膦)钯；Et3SiH代表三乙基硅烷；PPh3代表三苯基膦；Xantphos代表4，5-双(二苯基膦基)-9，9-二甲基；MeSO3H代表甲磺酸；Xphos代表2-二环己基膦基-2′，4′，6′-三异丙基联苯；劳森试剂代表2，4-二(4-甲氧基苯基)-1，3-二硫杂-2，4-二磷烷-2，4-二硫化物；NBS代表N-溴代丁二酰亚胺；t-BuOK代表叔丁醇钾DIPEA为二异丙基乙胺；SOCl2为亚硫酰氯；CS2为二硫化碳；TsOH为4-甲苯磺酸；MTBE为叔丁基甲醚；i-PrOH为2-丙醇；DAST为二乙氨基三氟化硫；DIAD为偶氮二甲酸二异丙酯；DEAD为偶氮二甲酸二乙酯；DBAD为偶氮二甲酸二叔丁酯；TES为三乙基硅烷；LDA二异丙基胺基锂；NBS为N-溴代琥珀酰亚胺；NIS为N-碘代琥珀酰亚胺；NCS为N-氯代琥珀酰亚胺；DMP为DMP试剂；DMF-DMA为1，1-二甲氧基-N，N-二甲基甲胺；TMP为2，2，6，6-四甲基哌啶；NMO为N-甲基吗啉N-氧化物；TBSC1为叔丁基二甲基硅氯；SEMC1为2-(三甲基硅基)乙氧基甲基氯；NFSI为N-氟苯磺酰胺；AIBN为偶氮二异丁腈；EDCI为1-乙基-3-(3-二甲氨基丙基)碳二亚胺；HOBT为羟基苯并三唑；TBAF为四正丁基氟化铵；HATU为1-[双(二甲氨基)亚甲基]-1H-1，2，3-三唑基[4，5-b]三氧化吡啶六氟磷酸盐；Xphos为2-二环己基膦-2′，4′，6′-三异丙基联苯；cataCXium A为正丁基-二(1-金刚烷基) 磷；DPPP为1，3-双(二苯基膦)丙烷；DPPF为1，1′-双(二苯基膦基)二茂铁；HMTA为1，3，5，7-四氮杂金刚烷；PMBC1为对甲氧基苄基氯；HEPES为4-(2-羟乙基)-1-哌嗪乙磺酸；EGTA为乙二醇双(2-氨基乙醚)-N，N，N′，N′-四乙酸。The present invention uses the following abbreviations: aq represents water; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, an amine protecting group; Boc represents tert-butyloxycarbonyl, an amine protecting group; HOAc represents acetic acid; NaBH(OAc) 3 represents sodium triacetoxyborohydride; rt represents room temperature; THF represents tetrahydrofuran; Boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; Pd(dppf)Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II); POCl 3 represents phosphorus oxychloride; NaH represents sodium hydride; LAH represents lithium aluminum hydride; Pd(OAc) 2 represents palladium(II) acetate; Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium; Pd(PPh 3 ) 4 represents tetrakis(triphenylphosphine)palladium; Et 3 SiH represents triethylsilane; PPh 3 represents triphenylphosphine; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethyl; MeSO 3 H represents methanesulfonic acid; Xphos represents 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; Lawesson's reagent represents 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphane-2,4-disulfide; NBS represents N-bromosuccinimide; t-BuOK represents potassium tert-butoxide; DIPEA is diisopropylethylamine; SOCl 2 is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonic acid; MTBE is tert-butyl methyl ether; i-PrOH is 2-propanol; DAST is diethylaminosulfur trifluoride; DIAD is diisopropyl azodicarboxylate; DEAD is diethyl azodicarboxylate; DBAD is di-tert-butyl azodicarboxylate; TES is triethylsilane; LDA is lithium diisopropylamide; NBS is N-bromosuccinimide; NIS is N-iodosuccinimide; NCS is N-chlorosuccinimide; DMP is DMP reagent; DMF-DMA is 1,1-dimethoxy-N,N-dimethylmethylamine; TMP is 2,2,6,6-tetramethyl 1-(1-(dimethylamino)methylene)-1H-1,2,3-triazolyl[4,5-b]pyridinium trioxide hexafluorophosphate; Xphos is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; cataCXium A is n-butyl-di(1-adamantyl)-1-(1-(dimethylamino)methylene)-1H-1,2,3-triazolyl[4,5-b]pyridinium trioxide hexafluorophosphate; Xphos is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; cataCXium A is n-butyl-di(1-adamantyl)-1-(1-(dimethylamino)methylene)-1H-1,2,3-triazolyl[4,5-b]pyridinium trioxide hexafluorophosphate; phosphorus; DPPP is 1,3-bis(diphenylphosphino)propane; DPPF is 1,1′-bis(diphenylphosphino)ferrocene; HMTA is 1,3,5,7-tetraazaadamantane; PMBC1 is p-methoxybenzyl chloride; HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; EGTA is ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid.
化合物可以手动命名，也可以使用
Figure PCTCN2024077920-ftappb-I100034
进行命名，如果商业购买的，也可以使用供应商的目录名称。通常使用TLC或LC-MS来判断反应是否完成。Compounds can be named manually or using
Figure PCTCN2024077920-ftappb-I100034
Name the product, or use the supplier's catalog name if purchased commercially. TLC or LC-MS is usually used to determine whether the reaction is complete.
具体实施方式DETAILED DESCRIPTION
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.
实施例1-1、3-丙烯酰胺-N-(3-((2-(((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)苯基)苯甲酰胺的2，2，2-三氟乙酸盐(化合物C1-1)的合成：Example 1-1, Synthesis of 2,2,2-trifluoroacetate of 3-acrylamide-N-(3-((2-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)phenyl)benzamide (Compound C1-1):
1)、8-异丙基-2-(甲硫基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺的合成：
Figure PCTCN2024077920-ftappb-I100035
1) Synthesis of 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine:
Figure PCTCN2024077920-ftappb-I100035
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑[1，5-a][1，3，5]三嗪(500.0mg，2.06mmol)、3-硝基苄胺(376.8mg，2.48mmol)和N，N-二异丙基乙胺(799.6mg，6.20mmol)异丙醇的混合溶液(10.0mL)加热至80℃，搅拌反应2小时。冷却后，将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和水(含有0.1％氨水)，梯度：5％-95％)纯化得到8-异丙基-2-(甲硫基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺(650mg，1.82mmol，产率：88％)。A mixed solution (10.0 mL) of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (500.0 mg, 2.06 mmol), 3-nitrobenzylamine (376.8 mg, 2.48 mmol) and N,N-diisopropylethylamine (799.6 mg, 6.20 mmol) in isopropanol was heated to 80° C. and stirred for 2 hours. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water (containing 0.1% ammonia water), gradient: 5%-95%) to obtain 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (650 mg, 1.82 mmol, yield: 88%).
LC-MS m/z：359[M+H]+.LC-MS m/z: 359 [M+H] + .
2)、8-异丙基-2-(甲磺酰基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺的合成：
Figure PCTCN2024077920-ftappb-I100036
2) Synthesis of 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine:
Figure PCTCN2024077920-ftappb-I100036
将溶有8-异丙基-2-(甲硫基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺(650.0mg，1.82mmol)和间氯过氧苯甲酸(1837mg，9.08mmol，纯度：85％)的甲苯溶液(15.0mL)室温搅拌反应过夜。反应结束，将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：含有0.1％甲酸的乙腈和含有0.1％甲酸的水，梯度：5％-95％)纯化得到8-异丙基-2-(甲磺酰基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺(400mg，1.02mmol，产率：56％)。LC-MS：m/z＝391[M+H]+.A toluene solution (15.0 mL) containing 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (650.0 mg, 1.82 mmol) and m-chloroperbenzoic acid (1837 mg, 9.08 mmol, purity: 85%) was stirred at room temperature overnight. After the reaction, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, gradient: 5%-95%) to obtain 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (400 mg, 1.02 mmol, yield: 56%). LC-MS: m/z=391[M+H] + .
3)、(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苄基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100037
3) Synthesis of tert-butyl (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100037
将溶有8-异丙基-2-(甲磺酰基)-N-(3-硝基苄基)吡唑[1，5-a][1，3，5]三嗪-4-胺(400.0mg，1.02mmol)和(3R，4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸叔丁酯(283.1mg，1.23mmol)的二氧六环(10.0mL)溶液升温至140℃，反应过夜。冷却后，将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苄基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯(300mg，0.56mmol，产率：55％)。LC-MS：m/z＝541[M+H]+。A solution of 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (400.0 mg, 1.02 mmol) and (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (283.1 mg, 1.23 mmol) in dioxane (10.0 mL) was heated to 140°C and reacted overnight. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% aqueous ammonia, gradient: 5%-95%) to give (3R,4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.56 mmol, yield: 55%). LC-MS: m/z=541[M+H] + .
4)、(3R，4R)-4-((4-((3-氨基苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100038
4) Synthesis of (3R, 4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100038
室温条件下，向溶有(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苄基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯(300.0mg，0.56mmol)和铁粉(155.6mg，2.78mmol)的乙醇(4mL)溶液中滴加饱和氯化铵溶液(1mL)。滴加完毕，升温70℃，反应2小时。冷却后，将反应液直接用硅藻土过滤，滤饼用甲醇(3×10mL)洗涤三次。所得的滤液经真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物(3R，4R)-4-((4-((3-氨基苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(120mg，0.24mmol，产率：42％)。LC-MS：m/z＝511[M+H]+.At room temperature, saturated ammonium chloride solution (1 mL) was added dropwise to a solution of tert-butyl (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazol[1,5-a][1,3,5]triazine-2-yl)amino)methyl)piperidine-1-carboxylate (300.0 mg, 0.56 mmol) and iron powder (155.6 mg, 2.78 mmol) in ethanol (4 mL). After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to proceed for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (3×10 mL). The obtained filtrate was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% aqueous ammonia, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.24 mmol, yield: 42%). LC-MS: m/z=511[M+H] + .
5)、(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100039
5) Synthesis of (3R, 4R)-4-((4-((3-(3-acrylamidobenzamide)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100039
将溶有(3R，4R)-4-((4-((3-氨基苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(120.0mg，0.24mmol)、3-丙烯酰胺苯甲酸(53.9mg，0.28mmol)、N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(134.4mg，0.48mmol)和N-甲基咪唑(78.7mg，0.96mmol)的N，N-二甲基甲酰胺(5.0mL)混合溶液在30℃搅拌反应2小时。反应结束，反应液直接用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(60mg，0.09mmol，产率：36％)。LC-MS：m/z＝684[M+H]+。A mixed solution of (3R,4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (120.0 mg, 0.24 mmol), 3-acrylamidebenzoic acid (53.9 mg, 0.28 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (134.4 mg, 0.48 mmol) and N-methylimidazole (78.7 mg, 0.96 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 30°C for 2 hours. After the reaction was completed, the reaction solution was directly purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain (3R, 4R)-4-((4-((3-(3-acrylamidobenzamide)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol, yield: 36%). LC-MS: m/z=684[M+H] + .
6)、3-丙烯酰胺-N-(3-((2-(((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)苯基)苯甲酰胺的2，2，2-三氟乙酸盐(化合物1)的合成：
Figure PCTCN2024077920-ftappb-I100040
6) Synthesis of 2,2,2-trifluoroacetate of 3-acrylamide-N-(3-((2-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)phenyl)benzamide (Compound 1):
Figure PCTCN2024077920-ftappb-I100040
向溶有(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苄基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(60mg，0.09mmol)的二氯甲烷(3mL)溶液中，滴加三氟乙酸(1mL)，室温反应2小时。反应结束，反应液经真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物3-丙烯酰胺-N-(3-((2-((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)苯基)苯甲酰胺的三氟乙酸盐(26.5mg，0.038mmol，产率：42％).LC-MS：m/z＝584[M+H]+。Trifluoroacetic acid (1 mL) was added dropwise to a solution of (3R,4R)-tert-butyl 4-((4-((3-(3-acrylamidobenzamide)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 0.09 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-((2-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide trifluoroacetate (26.5 mg, 0.038 mmol, yield: 42%). LC-MS: m/z=584[M+H] + .
1H NMR(400MHz，MeOD_d4)：8.39(s，1H)，7.93(d，J＝2.4Hz，2H)，7.67-7.61(m，2H)，7.48(t，J＝8Hz，2H)，7.38(t，J＝8Hz，1H)，7.23(d，J＝8Hz，1H)，6.46-6.38(m，2H)，5.82(d，J＝8Hz，1H)，4.86(s，2H)，3.83(s，1H)，3.64(s，2H)，3.07-3.00(m，1H)，2.86(t，J＝8Hz，1H)，2.73(t，J＝8Hz，1H)，1.98-1.94(m，2H)，1.45(s，1H)，1.29(d，J＝4Hz，6H)，1.14(s，2H)。 1 H NMR (400MHz, MeOD_d 4 ): 8.39 (s, 1H), 7.93 (d, J=2.4Hz, 2H), 7.67-7.61 (m, 2H), 7.48 (t, J=8Hz, 2H), 7.38 (t, J=8Hz, 1H), 7.23 (d, J=8Hz, 1H), 6.46-6.38 (m, 2H), 5.82 (d, J=8Hz, 1H), 4.8 6(s, 2H), 3.83(s, 1H), 3.64(s, 2H), 3.07-3.00(m, 1H), 2.86(t, J=8Hz, 1H), 2.73(t, J=8Hz, 1H ), 1.98-1.94 (m, 2H), 1.45 (s, 1H), 1.29 (d, J=4Hz, 6H), 1.14 (s, 2H).
实施例1-2、3-丙烯酰胺基-N-(3-((3R，4R)-3-羟基哌啶-4-基)甲基氨基)-8-异丙基吡唑[1，5-a][1，3，5] 三嗪-4-基)氨基)苯基)苯甲酰胺(化合物C1-2)的合成：Example 1-2, 3-acrylamide-N-(3-((3R, 4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazole [1,5-a] [1,3,5] Synthesis of triazine-4-yl)amino)phenyl)benzamide (compound C1-2):
1)、8-异丙基-2-(甲硫基)-N-(3-硝基苯基)吡唑[1，5-a][1，3，5]三嗪-4-胺的合成：
Figure PCTCN2024077920-ftappb-I100041
1) Synthesis of 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine:
Figure PCTCN2024077920-ftappb-I100041
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑[1，5-a][1，3，5]三嗪(1g，4.13mmol)、3-硝基苯胺(742mg，5.37mmol)和N，N-二异丙基乙胺(1.6g，12.39mmol)的乙腈的混合溶液(20.0mL)，加热80℃，反应4小时。冷却后，向反应液中加入水(40mL)，并用乙酸乙酯萃取三次(20mL x 3)。合并的有机相经饱和食盐水洗涤(30mLx 1)，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物8-异丙基-2-(甲硫基)-N-(3-硝基苯基)吡唑[1，5-a][1，3，5]三嗪-4-胺(1.2g，3.48mmol，产率：84％)。LC-MS：m/z＝345[M+H]+.A mixed solution (20.0 mL) of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1 g, 4.13 mmol), 3-nitroaniline (742 mg, 5.37 mmol) and N,N-diisopropylethylamine (1.6 g, 12.39 mmol) in acetonitrile was heated to 80°C for 4 hours. After cooling, water (40 mL) was added to the reaction solution, and extracted with ethyl acetate three times (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (1.2 g, 3.48 mmol, yield: 84%). LC-MS: m/z=345[M+H] + .
2)、8-异丙基-2-(甲磺酰基)-N-(3-硝基苯基)吡唑[1，5-a][1，3，5]三嗪-4-胺的合成：
Figure PCTCN2024077920-ftappb-I100042
2) Synthesis of 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine:
Figure PCTCN2024077920-ftappb-I100042
将溶有8-异丙基-2-(甲硫基)-N-(3-硝基苯基)吡唑[1，5-a][1，3，5]三嗪-4-胺(1g，2.91mmol))和间氯过氧苯甲酸(885mg，4.36mmol，纯度：85％)的二氯甲烷溶液(15.0mL)，室温搅拌，反应2小时。反应结束，将所得混合物真空浓缩除去溶剂得到粗产品，直接用于下一步反应。LC-MS：m/z＝377[M+H]+.A dichloromethane solution (15.0 mL) containing 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (1 g, 2.91 mmol)) and m-chloroperbenzoic acid (885 mg, 4.36 mmol, purity: 85%) was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated in vacuo to remove the solvent to obtain a crude product, which was directly used in the next step. LC-MS: m/z = 377 [M+H] + .
3)、(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苯基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100043
3) Synthesis of tert-butyl (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazol[1,5-a][1,3,5]triazine-2-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100043
将溶有8-异丙基-2-(甲磺酰基)-N-(3-硝基苯基)吡唑[1，5-a][1，3，5]三嗪-4-胺(800mg，2.12mmol)和(3R，4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸叔丁酯(587mg，2.55mmol)二氧六环溶液(10.0mL)升温100℃，反应过夜。冷却后，向反应体系中加水(20mL)，用乙酸乙酯萃取三次(20mL x 3)。合并有机相，饱和食盐水洗涤(30mL x 1)，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苯基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯(600mg，1.13mmol，产率：53％).LC-MS：m/z＝527[M+H]+。A dioxane solution (10.0 mL) containing 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine (800 mg, 2.12 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (587 mg, 2.55 mmol) was heated to 100° C. and reacted overnight. After cooling, water (20 mL) was added to the reaction system and extracted with ethyl acetate three times (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to give the target compound (3R,4R)-tert-butyl 3-hydroxy-4-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazol[1,5-a][1,3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylate (600 mg, 1.13 mmol, yield: 53%). LC-MS: m/z=527[M+H] + .
4)、(3R，4R)-4-((4-((3-氨基苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100044
4) Synthesis of (3R, 4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100044
室温条件下，向溶有(3R，4R)-3-羟基-4-((8-异丙基-4-((3-硝基苯基)氨基)吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)哌啶-1-羧酸叔丁酯(50mg，0.095mmol)和铁粉Fe(26.7mg，0.047mmol)的乙醇(2mL)溶液滴加饱和氯化铵溶液(0.5mL)。滴加完毕，升温70℃，反应2小时。冷却后，将反应液直接用硅藻土过滤，滤饼用甲醇(10mL×3)洗涤三次。所得的滤液经真空浓缩除去溶剂得到目标化合物(3R，4R)-4-((4-((3-氨基苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(30.0mg，0.06mmol，产率：63％)。LC-MS：m/z＝497[M+H]+。At room temperature, saturated ammonium chloride solution (0.5 mL) was added dropwise to a solution of tert-butyl (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazol[1,5-a][1,3,5]triazine-2-yl)amino)methyl)piperidine-1-carboxylate (50 mg, 0.095 mmol) and iron powder Fe (26.7 mg, 0.047 mmol) in ethanol (2 mL). After the addition was completed, the temperature was raised to 70°C and the reaction was allowed to proceed for 2 hours. After cooling, the reaction solution was directly filtered with diatomaceous earth, and the filter cake was washed three times with methanol (10 mL×3). The obtained filtrate was concentrated in vacuo to remove the solvent to obtain the target compound (3R,4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30.0 mg, 0.06 mmol, yield: 63%). LC-MS: m/z=497[M+H] + .
5)、(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100045
5) Synthesis of (3R, 4R)-4-((4-((3-(3-acrylamidobenzamide)phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100045
向溶有(3R，4R)-4-((4-((3-氨基苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(200mg，0.40mmol)和3-丙烯酰胺苯甲酸(116mg，0.60mmol)的N，N-二甲基甲酰胺(3mL)溶液中加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(201mg，0.53mmol)和N，N-二异丙基乙胺(69mg，0.53mmol)，氮气保护下，室温反应2小时。反应结束，向反应液中加入水(10mL)，乙酸乙酯萃取三次(20mL x 3)。合并的有机相经饱和食盐水洗涤(30mLx 1)，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(130mg，0.19mmol，产率：48％)。LC-MS：m/z＝670[M+H]+。2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (201 mg, 0.53 mmol) and N,N-diisopropylethylamine (69 mg, 0.53 mmol) were added to a solution of (3R, 4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.40 mmol) and 3-acrylamidebenzoic acid (116 mg, 0.60 mmol) in N,N-dimethylformamide (3 mL), and the mixture was reacted at room temperature for 2 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to give (3R, 4R)-4-((4-((3-(3-acrylamidobenzamide)phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.19 mmol, yield: 48%). LC-MS: m/z=670[M+H] + .
6)、3-丙烯酰胺基-N-(3-((3R，4R)-3-羟基哌啶-4-基)甲基氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)苯基)苯甲酰胺(化合物2)的合成：
Figure PCTCN2024077920-ftappb-I100046
6) Synthesis of 3-acrylamido-N-(3-((3R, 4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)phenyl)benzamide (Compound 2):
Figure PCTCN2024077920-ftappb-I100046
向溶有(3R，4R)-4-((4-((3-(3-丙烯酰胺苯甲酰胺)苯基)氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-2-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(60mg，0.089mmol)的二氯甲烷(1.5mL)溶液中，滴加三氟乙酸(0.3mL)，室温反应1小时。反应结束，反应液经真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到3-丙烯酰胺基-N-(3-((3R，4R)-3-羟基哌啶-4-基)甲基氨基)-8-异丙基吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)苯基)苯甲酰胺(化合物2)(40mg，0.07mmol，产率：78％)。Trifluoroacetic acid (0.3 mL) was added dropwise to a solution of (3R,4R)-tert-butyl 4-((4-((3-(3-acrylamidobenzamide)phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 0.089 mmol) in dichloromethane (1.5 mL), and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain 3-acrylamido-N-(3-((3R, 4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)phenyl)benzamide (compound 2) (40 mg, 0.07 mmol, yield: 78%).
LC-MS：m/z＝570[M+H]+；LC-MS: m/z=570 [M+H] + ;
1H NMR(400MHz，MeOD)δ8.40(m，3H)，8.23(s，1H)，7.70(s，1H)，7.60(d，J＝8.0Hz，2H)，7.41(t，J＝7.7Hz，2H)，7.31(m，2H)，6.36(dt，J＝21.3，12.3Hz，2H)，5.73(d，J＝9.2Hz，1H)，3.78(m，2H)，3.54(m，2H)，3.38(sm1H)，3.03(m，1H)，2.93(m，1H)，2.70(m 1H)，1.93(d，J＝8.7Hz，1H)，1.73(m，1H)，1.57(m，1H)，1.20(d，J＝6.8Hz，6H).1H NMR (400MHz, MeOD) δ8.40 (m, 3H), 8.23 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=8.0Hz, 2H), 7.41 (t, J=7.7Hz , 2H), 7.31 (m, 2H), 6.36 (dt, J=21.3, 12.3Hz, 2H), 5.73 (d, J =9.2Hz, 1H), 3.78(m, 2H), 3.54(m, 2H), 3.38(sm1H), 3.03(m, 1H), 2.93(m, 1H), 2.70(m 1H), 1.93(d, J=8.7Hz, 1H), 1.73 (m, 1H), 1.57 (m, 1H), 1.20 (d, J=6.8Hz, 6H).
实施例1-3、3-丙烯酰胺-N-(3-((5-((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-7-基)氨基)甲基)苯基)苯甲酰胺(化合物C1-3)的合成：Example 1-3, Synthesis of 3-acrylamide-N-(3-((5-((3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (Compound C1-3):
1)、5-氯-3-异丙基-N-(3-硝基苄基)吡唑[1，5-a]嘧啶-7-胺的合成：
Figure PCTCN2024077920-ftappb-I100047
1) Synthesis of 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine:
Figure PCTCN2024077920-ftappb-I100047
将溶有5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(300.0mg，1.30mmol)，和3-硝基苄胺(218mg，1.43mmol)和三乙胺(144mg，1.43mmol)的异丙醇(4.0mL)溶液，升温80℃，反应2小时。冷却后，将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到5-氯-3-异丙基-N-(3-硝基苄基)吡唑[1，5-a]嘧啶-7-胺(250mg，0.72mmol，产率56％)。LC-MS：m/z＝345.8[M+H]+.A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (300.0 mg, 1.30 mmol), 3-nitrobenzylamine (218 mg, 1.43 mmol) and triethylamine (144 mg, 1.43 mmol) in isopropanol (4.0 mL) was heated to 80°C and reacted for 2 hours. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (250 mg, 0.72 mmol, yield 56%). LC-MS: m/z=345.8[M+H] + .
2)、(5-氯-3-异丙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苄基)氨基甲酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100048
2) Synthesis of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-nitrobenzyl)carbamate:
Figure PCTCN2024077920-ftappb-I100048
将溶有5-氯-3-异丙基-N-(3-硝基苄基)吡唑[1，5-a]嘧啶-7-胺(250.0mg，0.72mmol)，二叔丁基二碳酸酯(205mg，0.94mmol)，4-二甲氨基吡啶(40mg，0.33mmol)和三乙胺(146mg，1.45mmol)的四氢呋喃(2.0mL)溶液，升温50℃，反应过夜。将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含0.1％氨水的水，梯度：5％-95％)纯化得到((5-氯-3-异丙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苄基)氨基甲酸叔丁酯(158mg，0.35mmol，产率：49％)。LC-MS：m/z＝446[M+H]+。A solution of 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (250.0 mg, 0.72 mmol), di-tert-butyl dicarbonate (205 mg, 0.94 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol) and triethylamine (146 mg, 1.45 mmol) in tetrahydrofuran (2.0 mL) was heated to 50°C and reacted overnight. The resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% aqueous ammonia, gradient: 5%-95%) to give tert-butyl ((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate (158 mg, 0.35 mmol, yield: 49%). LC-MS: m/z=446[M+H] + .
3)、(3R，4R)-4-((7-((叔丁氧羰基)(3-硝基苄基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100049
3) Synthesis of tert-butyl (3R, 4R)-4-((7-((tert-butyloxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100049
将溶有(5-氯-3-乙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苄基)氨基甲酸叔丁酯(50.0mg，0.11mmol)，(3R，4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸丁酯(31mg，0.13mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(8.4mg，0.01mmol)，碳酸铯(110mg，0.34mmol)的二氧六环(2mL)溶液升温90℃，反应过夜。冷却后，将所得混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物(3R，4R)-4-((7-((叔丁氧羰基)(3-硝基苄基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(38.8mg，0.06mmol，产率：54％)。LC-MS：m/z＝640[M+H]+.A solution of tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate (50.0 mg, 0.11 mmol), butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (31 mg, 0.13 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (8.4 mg, 0.01 mmol), and cesium carbonate (110 mg, 0.34 mmol) in dioxane (2 mL) was heated to 90°C and reacted overnight. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((tert-butyloxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.8 mg, 0.06 mmol, yield: 54%). LC-MS: m/z=640[M+H] + .
4)、(3R，4R)-4-((7-((3-氨基苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100050
4) Synthesis of tert-butyl (3R, 4R)-4-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100050
向溶有(3R，4R)-4-((7-((叔丁氧羰基)(3-硝基苄基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(38.8mg，0.06mmol)和铁粉(17mg，0.3mmol)的乙醇(2mL)溶液中滴加饱和氯化铵溶液(0.5mL)。滴加完毕，升温70℃，反应2小时。冷却后，将反应液直接用硅藻土过滤，滤饼用甲醇(10mL×3)洗涤三次。将所得滤液真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和0.1％氨水的水， 梯度：5％-95％)纯化得到目标化合物(3R，4R)-4-((7-((3-氨基苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(30mg，0.05mmol，产率：81％).LC-MS：m/z＝610[M+H]+.Saturated ammonium chloride solution (0.5 mL) was added dropwise to a solution of tert-butyl (3R, 4R)-4-((7-(tert-butyloxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (38.8 mg, 0.06 mmol) and iron powder (17 mg, 0.3 mmol) in ethanol (2 mL). After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to proceed for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (10 mL×3). The obtained filtrate was concentrated in vacuo to remove the solvent and chromatographed on a C18 column (mobile phase: acetonitrile and 0.1% ammonia water, Gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol, yield: 81%). LC-MS: m/z=610[M+H] + .
5)、(3R，4R)-4-((7-((3-(3-丙烯酰胺苯甲酰胺基)苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100051
5) Synthesis of tert-butyl (3R, 4R)-4-((7-((3-(3-acrylamidobenzamido)benzyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100051
将溶有(3R，4R)-4-((7-((3-氨基苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(30.0mg，0.05mmol)，3-丙烯酰胺苯甲酸(12mg，0.06mmol)的N，N-二甲基甲酰胺(3mL)溶液中加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(28mg，0.07mmol)和N，N-二异丙基乙胺(19mg，0.15mmol)，升温30℃，反应2小时。反应液过滤经C18柱色谱(流动相：乙腈和0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物(3R，4R)-4-((7-((3-(3-丙烯酰胺苯甲酰胺基)苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(30mg，0.039mmol，产率：78％)。LC-MS：m/z＝783[M+H]+.To a solution of (3R,4R)-4-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30.0 mg, 0.05 mmol) and 3-acrylamidobenzoic acid (12 mg, 0.06 mmol) in N,N-dimethylformamide (3 mL) were added 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (28 mg, 0.07 mmol) and N,N-diisopropylethylamine (19 mg, 0.15 mmol), the temperature was raised to 30°C, and the reaction was carried out for 2 hours. The reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3-(3-acrylamidobenzamido)benzyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.039 mmol, yield: 78%). LC-MS: m/z=783[M+H] + .
6)、3-丙烯酰胺-N-(3-((5-((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-7-基)氨基)甲基)苯基)苯甲酰胺的合成：
Figure PCTCN2024077920-ftappb-I100052
6) Synthesis of 3-acrylamide-N-(3-((5-((3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazol[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:
Figure PCTCN2024077920-ftappb-I100052
向溶有(3R，4R)-4-((7-((3-(3-丙烯酰胺苯甲酰胺基)苄基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(30mg，0.039mmol)的二氯甲烷溶液(3mL)中，滴加三氟乙酸(1mL)，室温反应2小时。反应结束，反应液经真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物3-丙烯酰胺-N-(3-((5-((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-7-基)氨基)甲基)苯基)苯甲酰胺(化合物3)(15.08mg，0.026mmol，收率：66％)。LC-MS：m/z＝583[M+H]+.Trifluoroacetic acid (1 mL) was added dropwise to a dichloromethane solution (3 mL) containing tert-butyl (3R,4R)-4-((7-((3-(3-acrylamidobenzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (30 mg, 0.039 mmol), and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-((5-((3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (Compound 3) (15.08 mg, 0.026 mmol, yield: 66%). LC-MS: m/z=583[M+H] + .
1H NMR(400MHz，MeOD)：δ8.37(s，1H)，7.89(s，2H)，7.77-7.54(m，2H)，7.51-7.40(m，3H)，7.22(d，J＝7.4Hz，1H)，6.58-6.32(m，2H)，5.82(dd，J＝9.4，2.1Hz，1H)，5.45(s，1H)，4.74(s，2H)，3.97-3.43(m，5H)，3.43-3.25(m，1H)，3.09-2.96(m，1H)，2.84(dt，J＝22.7，10.6Hz，1H)，2.02(d，J＝12.1Hz，1H)，1.84(s，1H)，1.52(d，J＝11.7Hz，1H)，1.30(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD): δ8.37 (s, 1H), 7.89 (s, 2H), 7.77-7.54 (m, 2H), 7.51-7.40 (m, 3H), 7.22 (d, J=7.4 Hz, 1H), 6.58-6.32 (m, 2H), 5.82 (dd, J=9.4, 2.1Hz, 1H), 5.45 (s, 1H), 4.74 (s , 2H), 3.97-3.43(m, 5H), 3.43-3.25(m, 1H), 3.09-2.96(m, 1H), 2.84(dt, J=22.7, 10.6Hz, 1H), 2.02(d, J =12.1Hz, 1H), 1.84 (s, 1H), 1.52 (d, J = 11.7Hz, 1H), 1.30 (d, J = 6.9Hz, 6H).
实施例1-4、(R)-3-丙烯酰胺基-N-(3-((3-异丙基-5-(哌啶-3-氧基)吡唑[1，5-a]嘧啶-7-基)氨基)苯基)苯甲酰胺(化合物C1-4)的合成：Example 1-4, Synthesis of (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (Compound C1-4):
1)、5-氯-3-异丙基-N-(3-硝基苯基)吡唑[1，5-a]嘧啶-7-胺的合成：
Figure PCTCN2024077920-ftappb-I100053
1) Synthesis of 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidine-7-amine:
Figure PCTCN2024077920-ftappb-I100053
在0℃条件下，向溶有3-硝基苯胺(180mg，1.31mmol)的N，N-二甲基甲酰胺(4mL)溶液中加入氢化钠(160mg，3.93mmol，纯度：60％分散在煤油中)，0℃条件下搅拌反应0.5小时。然后加入5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(300mg，1.31mmol)，升温至90℃，反应16小时。反应结束，冷却至室温加入甲醇(2mL)，得到混合溶液经过滤直接经经C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物5-氯-3-异丙基-N-(3-硝基苯基)吡唑[1，5-a]嘧啶-7-胺(380mg，1.14mmol，产率：87％)。LC-MS：m/z＝332[M+H]+。At 0°C, sodium hydride (160 mg, 3.93 mmol, purity: 60% dispersed in kerosene) was added to a solution of 3-nitroaniline (180 mg, 1.31 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at 0°C for 0.5 hours. Then 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (300 mg, 1.31 mmol) was added, the temperature was raised to 90°C, and the mixture was reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and methanol (2 mL) was added to obtain a mixed solution, which was filtered and directly purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidine-7-amine (380 mg, 1.14 mmol, yield: 87%). LC-MS: m/z=332 [M+H] + .
2)、(5-氯-3-异丙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苯基)氨基甲酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100054
2) Synthesis of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamate:
Figure PCTCN2024077920-ftappb-I100054
向溶有5-氯-3-异丙基-N-(3-硝基苯基)吡唑[1，5-a]嘧啶-7-胺(300mg，0.90mmol)、二叔丁基二碳酸酯(300mg，1.37mmol)的四氢呋喃(2.0mL)溶液中加入4-二甲氨基吡啶(254mg，2.08mmol)，室温搅拌反应4小时。反应结束，将混合物真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含0.1％氨水的水，梯度：5％-95％)纯化得到目标化合物5-氯-3-异丙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苯基)氨基甲酸叔丁酯(320mg，0.74mmol，产率：82％).LC-MS：m/z＝432[M+H]+.4-Dimethylaminopyridine (254 mg, 2.08 mmol) was added to a solution of 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.90 mmol) and di-tert-butyl dicarbonate (300 mg, 1.37 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound 5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (320 mg, 0.74 mmol, yield: 82%). LC-MS: m/z=432[M+H] + .
3)、(R)-3-((7-((叔丁氧羰基)(3-硝基苯基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100055
3) Synthesis of (R)-3-((7-((tert-butyloxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100055
在0℃条件下，向溶有(R)-3-羟基哌啶-1-羧酸叔丁酯(154mg，0.76mmol)的N，N-二甲基甲酰胺(2mL)中加入氢化钠(60mg，1.52mmol，纯度60％分散在煤油中)，恢复室温搅拌反应30分钟。然后室温条件下，加入溶有5-氯-3-异丙基吡唑[1，5-a]嘧啶-7-基)(3-硝基苯基)氨基甲酸叔丁酯(220mg，0.51mmol)四氢呋喃溶液(2mL)，室温继续搅拌反应4小时。反应结束，向反应体系中加入少量甲醇淬灭钠氢，然后将反应液过滤经C18柱色谱C18柱色谱(流动相：乙腈和含有0.1％的氨水的水，梯度：5％-95％)纯化得到目标化合物(R)-3-((7-((叔丁氧羰基)(3-硝基苯基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(80mg，0.13mmol，产率：26.3％)。LC-MS：m/z＝597[M+H]+。At 0°C, sodium hydride (60 mg, 1.52 mmol, 60% purity dispersed in kerosene) was added to N,N-dimethylformamide (2 mL) containing (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (154 mg, 0.76 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, a tetrahydrofuran solution (2 mL) containing 5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamate (220 mg, 0.51 mmol) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, a small amount of methanol was added to the reaction system to quench the sodium hydrogen, and then the reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (R)-3-((7-((tert-butyloxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol, yield: 26.3%). LC-MS: m/z=597[M+H] + .
4)、(R)-3-((7-((3-氨基苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100056
4) Synthesis of (R)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester:
Figure PCTCN2024077920-ftappb-I100056
向溶有(R)-3-((7-((叔丁氧羰基)(3-硝基苯基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(120mg，0.20mmol)和铁粉(57mg，1.0mmol)的乙醇(4mL)溶液中滴加饱和氯化铵溶液(1mL)滴加完毕，升温至70℃，搅拌反应2小时。冷却后，将反应液直接用硅藻土过滤，滤饼用甲醇(10mL×3)洗涤三次。将所得滤液真空浓缩除去溶剂并用C18柱色谱(流动相：乙腈和含有0.1％氨水的水，梯度：5％-95％)纯化得到(R)-3-((7-((3-氨基苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(100mg，0.17mmol，产率：85％)。LC-MS：m/z＝567[M+H]+。Saturated ammonium chloride solution (1 mL) was added dropwise to a solution of (R)-3-((7-(tert-butyloxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) and iron powder (57 mg, 1.0 mmol) in ethanol (4 mL). After the addition was complete, the temperature was raised to 70°C and stirred for 2 hours. After cooling, the reaction solution was directly filtered with diatomaceous earth, and the filter cake was washed three times with methanol (10 mL×3). The obtained filtrate was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% aqueous ammonia, gradient: 5%-95%) to give (R)-tert-butyl 3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (100 mg, 0.17 mmol, yield: 85%). LC-MS: m/z=567[M+H] + .
5)、(R)-3-((7-((3-(3-丙烯酰胺苯甲酰胺基)苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100057
5) Synthesis of tert-butyl (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100057
将溶有(R)-3-((7-((3-氨基苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(100mg，0.17mmol)和3-丙烯酰胺苯甲酸(40mg，0.21mmol)的N，N-二甲基甲酰胺(2mL)溶液中加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(100mg，0.26mmol)和N，N-二异丙基乙胺(34mg，0.26mmol)，氮气保护下室温反应3小时。反应液过滤经C18柱色谱(流动相：乙腈和含0.1％氨水的水，梯度：5％-95％)纯化得到(R)-3-((7-((3-(3-丙烯酰胺苯甲酰胺基)苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(30mg，0.04mmol，产率：23％)。LC-MS：m/z＝740[M+H]+。2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (34 mg, 0.26 mmol) were added to a solution of (R)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol) and 3-acrylamidebenzoic acid (40 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 3 hours under nitrogen protection. The reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol, yield: 23%). LC-MS: m/z=740[M+H] + .
6)、(R)-3-丙烯酰胺基-N-(3-((3-异丙基-5-(哌啶-3-氧基)吡唑[1，5-a]嘧啶-7-基)氨基)苯基)苯甲酰胺的合成：
Figure PCTCN2024077920-ftappb-I100058
6) Synthesis of (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-oxy)pyrazol[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide:
Figure PCTCN2024077920-ftappb-I100058
向溶有(R)-3-((7-((3-(3-丙烯酰胺苯甲酰胺基)苯基)(叔丁氧羰基)氨基)-3-异丙基吡唑[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(40mg，0.054mmol)的二氯甲烷(2.0mL)溶液中加入三氟乙酸(0.5mL)，室温搅拌反应1小时。反应结束，反应液真空浓缩除去溶剂并经C18柱色谱(流动相：乙腈和含0.1％氨水的水，梯度：5％-95％)纯化得到(R)-3-丙烯酰胺基-N-(3-((3-异丙基-5-(哌啶-3-氧基)吡唑[1，5-a]嘧啶-7-基)氨基)苯基)苯甲酰胺(化合物4)(20mg，0.037mmol，产率：68％)。LC-MS：m/z＝540[M+H]+；Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)(tert-butyloxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.054 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia water, gradient: 5%-95%) to obtain (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (Compound 4) (20 mg, 0.037 mmol, yield: 68%). LC-MS: m/z=540 [M+H] + ;
1H NMR(400MHz，DMSO)δ10.47(s，1H)，10.42(s，1H)，8.20(s，1H)，7.94(d，J＝11.5Hz，2H)，7.87(s，1H)，7.73-7.62(m，2H)，7.50(t，J＝7.9Hz，1H)，7.42(t，J＝7.9Hz，1H)，7.16(d，J＝8.1Hz，1H)，6.47(dd，J＝16.8，9.8Hz，1H)，6.30(d，J＝16.7Hz，1H)，5.79(d，J＝10.3Hz，1H)，5.66(s，1H)，5.07(s，1H)，3.19(d，J＝9.7Hz，1H)，3.07(d，J＝7.2Hz，1H)，2.79(m，1H)，2.73(m，1H)，2.66(m，J＝12.9Hz，1H)，2.01(s，1H)，1.76-1.44(m，4H)，1.32(d，J＝6.8Hz，6H).1H NMR (400MHz, DMSO) δ10.47 (s, 1H), 10.42 (s, 1H), 8.20 (s, 1H), 7.94 (d, J=11.5Hz, 2H), 7.87 (s, 1H), 7.73 -7.62 (m, 2H), 7.50 (t, J=7.9Hz, 1H), 7.42 (t, J=7.9Hz, 1H), 7.16 (d, J=8.1Hz, 1H), 6.47 (dd, J= 16.8, 9.8Hz, 1H), 6. 30 (d, J=16.7Hz, 1H), 5.79 (d, J=10.3Hz, 1H), 5.66 (s, 1H), 5.07 (s, 1H), 3.19 (d, J=9.7Hz, 1H), 3.07(d, J=7.2Hz, 1H), 2.79(m, 1H), 2.73(m, 1H), 2.66(m, J=12.9Hz, 1H), 2.01(s, 1H), 1.76-1.44(m , 4H), 1.32 (d, J=6.8Hz, 6H).
实施例1、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物1)： Example 1, 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 1):
1)、8-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100059
1) Synthesis of tert-butyl 8-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate:
Figure PCTCN2024077920-ftappb-I100059
将溶有8-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(500mg，0.96mmol)，四氢-2H-吡喃-4-胺(145mg，1.44mmol)，碳酸铯(938mg，2.88mmol)和(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(81mg，0.096mmol)的1，4-二氧六环(5mL)，氩气保护下，加热100℃搅拌3小时。冷却后，将所得混合反应液加水(50mL)稀释并用二氯甲烷(3×50mL)萃取。合并的有机相用饱和食盐水(1×50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(甲醇：二氯甲烷＝0-5％洗脱)纯化得到8-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(487mg，86.6％)，LC-MS m/z：585[M+H]+；8-((tert-Butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (500 mg, 0.96 mmol), tetrahydro-2H-pyran-4-amine (145 mg, 1.44 mmol), cesium carbonate (938 mg, 2.88 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (81 mg, 0.096 mmol) were dissolved in 1,4-dioxane (5 mL) and heated at 100°C with stirring for 3 hours under argon protection. After cooling, the obtained mixed reaction liquid was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give 8-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (487 mg, 86.6%), LC-MS m/z: 585[M+H] + ;
2)、N7-(3-氮杂双环[3.2.1]辛-8-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺的合成：
Figure PCTCN2024077920-ftappb-I100060
2) Synthesis of N 7 -(3-azabicyclo[3.2.1]oct-8-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine:
Figure PCTCN2024077920-ftappb-I100060
将8-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(200mg，0.34mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)的混合溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物(115mg)，无需进一步纯化即可直接用于下一步。LC-MS m/z：385[M+H]+；A mixed solution of tert-butyl 8-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.34 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give a crude product (115 mg), which was used directly in the next step without further purification. LC-MS m/z: 385[M+H] + ;
3)、1-(叔丁氧羰基)氮杂环丁烷-3-基8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸酯的合成：
Figure PCTCN2024077920-ftappb-I100061
3) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate:
Figure PCTCN2024077920-ftappb-I100061
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(146mg，0.84mmol)和双(三氯甲基)碳酸酯(0.12g，0.42mmol)的二氯甲烷(2mL)和三乙胺(0.35mL)的混合反应液在0℃搅拌0.5小时。然后将N7-(3-氮杂双环[3.2.1]辛-8-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(322mg，0.84mmol)加入到上述反应液中，所得混合反应液加热40℃搅拌17小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱法(乙 腈和水洗脱)纯化得到1-(叔丁氧羰基)氮杂环丁烷-3-基8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸酯(60mg，收率：12.3％)，LC-MS m/z：584[M+H]+；A mixed reaction liquid of dichloromethane (2 mL) and triethylamine (0.35 mL) containing tert-butyl 3-hydroxyazetidine-1-carboxylate (146 mg, 0.84 mmol) and bis(trichloromethyl) carbonate (0.12 g, 0.42 mmol) was stirred at 0°C for 0.5 hours. Then, N 7 -(3-azabicyclo[3.2.1]octan-8-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (322 mg, 0.84 mmol) was added to the above reaction liquid, and the obtained mixed reaction liquid was heated at 40°C and stirred for 17 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (ethyl acetate). The product was purified by eluting with 1-(tert-butyloxycarbonyl)azetidin-3-yl 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (60 mg, yield: 12.3%), LC-MS m/z: 584 [M+H] + ;
4)、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100062
4) Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100062
将溶有1-(叔丁氧羰基)氮杂环丁烷-3-基8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸酯(300mg，0.51mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)混合反应液室温搅拌4小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(甲醇：二氯甲烷＝0-10％洗脱)纯化得到8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯(65mg，收率：26.2％)，LC-MS m/z：484[M+H]+；A solution of 1-(tert-butyloxycarbonyl)azetidin-3-yl 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (300 mg, 0.51 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) were mixed and stirred at room temperature for 4 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester (65 mg, yield: 26.2%), LC-MS m/z: 484 [M+H] + ;
5)、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100063
5) Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100063
将溶有8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯(65mg，0.135mmol)，2-氟丙-2-烯酸(18mg，0.20mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(75.6mg，0.27mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：水＝5-95％洗脱)纯化得到8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(3.2mg，收率：4.2％)，LC-MS m/z：556[M+H]+；A solution of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester (65 mg, 0.135 mmol), 2-fluoroprop-2-enoic acid (18 mg, 0.20 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (75.6 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours, and the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:water = 5-95% elution) to give 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (3.2 mg, yield: 4.2%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.93(s，1H)，5.61-5.47(m，2H)，5.21(dd，J＝15.7，3.7Hz，2H)，4.74(s，1H)，4.39(s，2H)，4.00(d，J＝11.6Hz，4H)，3.79(dd，J＝22.8，13.5Hz，2H)，3.58(t，J＝10.7Hz，2H)，3.40(d，J＝13.6Hz，2H)，3.19(d，J＝45.3Hz，2H)，2.50(s，2H)，2.01(d，J＝12.0Hz，4H)，1.76-1.59(m，4H)，1.32(d，J＝6.9Hz，6H). 1 H NMR (400 MHz, MeOD-d 4 )δ7.93 (s, 1H), 5.61-5.47 (m, 2H), 5.21 (dd, J=15.7, 3.7Hz, 2H), 4.74 (s, 1H), 4.39 (s, 2H), 4.00 (d, J=11.6Hz, 4H), 3.79 (dd, J=22.8, 13.5Hz, 2H), 3.58 ( t, J=10.7Hz, 2H), 3.40 (d, J=13.6Hz, 2H), 3.19 (d, J=45.3Hz, 2H), 2.50 (s, 2H), 2.01 (d, J=12.0Hz, 4H), 1.76-1.59 (m, 4H), 1.32 (d, J=6.9Hz, 6H).
实施例2、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物2)的合成：
Figure PCTCN2024077920-ftappb-I100064
Example 2, Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 2):
Figure PCTCN2024077920-ftappb-I100064
将溶有8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯(90mg，0.186mmol)，(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(46mg，0.28mmol)，N，N，N，将N-四甲基氯甲脒六氟磷酸盐(104mg，0.37mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：水＝5-95％洗脱)纯化得到8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(2.4mg，收率：2.1％)，LC-MS m/z：595[M+H]+； A solution of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester (90 mg, 0.186 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (46 mg, 0.28 mmol), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (104 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:water = 5-95% elution) to give (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (2.4 mg, yield: 2.1%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.65(s，1H)，6.89-6.60(m，1H)，6.24-6.11(m，1H)，5.39(d，J＝4.8Hz，1H)，5.17(s，1H)，4.61(dd，J＝10.1，5.8Hz，1H)，4.36(dt，J＝11.3，5.8Hz，1H)，4.23(d，J＝11.2Hz，1H)，4.12(ddd，J＝14.4，10.2，3.9Hz，1H)，3.98(t，J＝11.8Hz，3H)，3.81-3.65(m，3H)，3.60-3.41(m，3H)，3.26-3.12(m，2H)，3.07(dt，J＝13.8，6.9Hz，1H)，2.53-2.41(m，2H)，2.36-2.22(m，6H)，1.98(dd，J＝44.9，15.1Hz，4H)，1.77-1.62(m，2H)，1.60-1.48(m，2H)，1.30(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.65 (s, 1H), 6.89-6.60 (m, 1H), 6.24-6.11 (m, 1H), 5.39 (d, J=4.8Hz, 1H) , 5.17 (s, 1H), 4.61 (dd, J = 10.1, 5.8Hz, 1H), 4.36 (dt, J = 11.3, 5.8Hz, 1H), 4.23 (d, J = 11.2Hz, 1H), 4.12 ( ddd, J=14.4, 10.2, 3.9Hz, 1H), 3.98 (t, J=11. 8Hz, 3H), 3.81-3.65(m, 3H), 3.60-3.41(m, 3H), 3.26-3.12(m, 2H), 3.07(dt, J=13.8, 6.9Hz, 1H), 2.53-2.41( m, 2H), 2.36-2.22 (m, 6H), 1.98 (dd, J=44.9, 15.1Hz, 4H), 1.77-1.62 (m, 2H), 1.60-1.48 (m, 2H), 1.30 (d, J=6.9Hz, 6H).
实施例3、4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物3)的合成：Example 3, Synthesis of (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (Compound 3):
1)、4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100065
1) Synthesis of tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100065
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(1g，4.13mmol)，N，N-二异丙基乙胺(1.60g，12.3mmol)和4-(氨基甲基)哌啶-1-羧酸叔丁酯(1.06g，4.95mmol)的异丙醇(15mL)溶液加热90℃搅拌8小时。冷却后，将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.8g，收率：46.1％)，LC-MS m/z：421[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1 g, 4.13 mmol), N,N-diisopropylethylamine (1.60 g, 12.3 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.06 g, 4.95 mmol) in isopropanol (15 mL) was heated at 90°C and stirred for 8 hours. After cooling, the resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.8 g, yield: 46.1%), LC-MS m/z: 421 [M+H] + ;
2)、4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100066
2) Synthesis of tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100066
将溶有4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.8g，1.90mmol)和间氯过氧苯甲酸(1.31g，7.62mmol)的二氯甲烷(10mL)溶液室温搅拌8小时。过滤后，将滤液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.65g，收率：75.5％)，LC-MS m/z：453[M+H]+；A solution of tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (0.8 g, 1.90 mmol) and m-chloroperbenzoic acid (1.31 g, 7.62 mmol) in dichloromethane (10 mL) was stirred at room temperature for 8 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (0.65 g, yield: 75.5%), LC-MS m/z: 453[M+H] + ;
3)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100067
3) Synthesis of tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100067
将溶有4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-A][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.65g，1.43mmol)，N，N-二异丙基乙胺(0.56g，4.31mmol)和四氢-2H-吡喃-4-胺(0.58g，5.75mmol) 的异丙醇(7mL)溶液，加热90℃搅拌8小时。所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.5g，收率：73.5％)，LC-MS m/z：474[M+H]+；4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.43 mmol), N,N-diisopropylethylamine (0.56 g, 4.31 mmol) and tetrahydro-2H-pyran-4-amine (0.58 g, 5.75 mmol) were dissolved in 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.43 mmol), N,N-diisopropylethylamine (0.56 g, 4.31 mmol) and tetrahydro-2H-pyran-4-amine (0.58 g, 5.75 mmol) were added. isopropanol (7 mL) solution, heated at 90 ° C and stirred for 8 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (0.5 g, yield: 73.5%), LC-MS m/z: 474[M+H] + ;
4)、8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成：
Figure PCTCN2024077920-ftappb-I100068
4) Synthesis of 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine:
Figure PCTCN2024077920-ftappb-I100068
在室温条件下，向溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸叔丁酯(0.5g，1.06mmol)的二氯甲烷(1.5mL)溶液中，加入2，2，2-三氟乙酸(0.5mL)。所得混合反应液室温搅拌2小时。将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(0.25g，收率：63.4％)，LC-MS m/z：374[M+H]+；To a solution of tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (0.5 g, 1.06 mmol) in dichloromethane (1.5 mL) at room temperature was added 2,2,2-trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (0.25 g, yield: 63.4%), LC-MS m/z: 374 [M+H] + ;
5)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100069
5) Synthesis of 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100069
在0℃条件下，向溶有3-羟基吡咯烷-1-甲酸叔丁酯(0.15g，0.80mmol)的二氯甲烷(3ml)溶液中分批加入三乙胺(0.22g，2.01mmol)和三光气(99mg，0.33mmol)。所得混合反应液在0℃条件搅拌30分钟。在0℃条件下，将8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑[1，5-a][1，3，5]三嗪-2，4-二胺(250mg，0.67mmol)加入到上述反应液中。所得混合反应液室温搅拌8小时。将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯(190mg，收率：48.4％)，LC-MS m/z：587[M+H]+；Triethylamine (0.22 g, 2.01 mmol) and triphosgene (99 mg, 0.33 mmol) were added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.15 g, 0.80 mmol) in dichloromethane (3 ml) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 30 minutes. 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (250 mg, 0.67 mmol) was added to the above reaction solution at 0°C. The resulting mixed reaction solution was stirred at room temperature for 8 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0%-100% elution) to give 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (190 mg, yield: 48.4%), LC-MS m/z: 587 [M+H] + ;
6)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100070
6) Synthesis of 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100070
在室温条件下，向溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯(190mg，0.32mmol)的二氯甲烷(1.5mL)溶液中，加入2，2，2-三氟乙酸(0.5mL)。所得混合反应液室温搅拌2小时。将所得混和反应液加水(40mL)稀释并用乙酸乙酯(3x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯：石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯(100mg，收率：63.5％)，LC-MS m/z：487[M+H]+；To a solution of 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (190 mg, 0.32 mmol) in dichloromethane (1.5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0%-100% elution) to give 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, yield: 63.5%), LC-MS m/z: 487 [M+H] + ;
7)、4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100071
7) Synthesis of (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100071
将溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯(100mg，0.21mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(32mg，0.24mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(156mg，0.41mmol)和N，N-二异丙基乙胺(80mg，0.62mmol)的二氯甲烷(2mL)溶液，室温搅拌8小时。将得到的混合反应液加水(5mL)稀释，并用乙酸乙酯(3x 50mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3H2O的纯水＝5-95％洗脱)纯化得到4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(50mg，收率：40.7％)，LC-MS m/z：598[M+H]+；A solution of 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.21 mmol), (E)-4-(dimethylamino)but-2-enoic acid (32 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (156 mg, 0.41 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol) in dichloromethane (2 mL) was stirred at room temperature for 8 hours. The resulting mixed reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 H 2 O=5-95% elution) to give (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (50 mg, yield: 40.7%), LC-MS m/z: 598 [M+H] + ;
1H NMR(400MHz，DMSO-d6)：δ8.29(s，1H)，7.67(s，1H)，6.65-6.59(m，1H)，6.40-6.34(m，1H)，5.13(d，J＝24.0Hz，1H)，3.90-3.85(m，4H)，3.79-3.70(m，2H)，3.59-3.48(m，3H)，3.39-3.30(m，5H)，3.04(d，J＝8.0Hz，1H)，2.90-2.88(m，1H)，2.75-2.70(m，2H)，2.15(s，6H)，2.05-2.02(m，1H)，1.85-1.83(m，3H)，1.65(d，J＝12.0Hz，2H)，1.55-1.48(m，2H)，1.22(d，J＝8.0Hz，6H)，1.06-1.03(m，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.29 (s, 1H), 7.67 (s, 1H), 6.65-6.59 (m, 1H), 6.40-6.34 (m, 1H), 5.13 (d, J＝24.0Hz, 1H), 3.90-3.85 (m, 4H), 3.79-3.70 (m, 2H), 3.59-3.48 (m, 3H), 3.39-3.30 (m, 5H), 3.04 (d, J＝ 8.0 Hz, 1H), 2.90-2.88 (m, 1H), 2.75-2.70 (m, 2H), 2.15 (s, 6H), 2.05-2.02 (m, 1H), 1.85-1.83 (m, 3H), 1.65 ( d, J=12.0Hz, 2H), 1.55-1.48 (m, 2H), 1.22 (d, J=8.0Hz, 6H), 1.06-1.03 (m, 3H).
实施例4、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物4)的合成：Example 4. Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 4):
1)、(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸的合成：
Figure PCTCN2024077920-ftappb-I100072
1) Synthesis of (1r, 4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid:
Figure PCTCN2024077920-ftappb-I100072
在0℃条件下，向溶有(1r，4r)-4-氨基环己烷-1-羧酸(0.62g，4.35mmol)的N，N-二甲基甲酰胺(10mL)溶液，分批加入氢化钠(0.31g，13.05mmol)，0℃搅拌1小时，然后将5，7-二氯-3-(丙-2-基)吡唑并[1，5-a]嘧啶(1g，4.35mmol)加入上述反应液。所得混合反应液室温搅拌溶液3小时。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸(900mg，收率：61.5％)，LC-MS m/z：337[M+H]+；At 0°C, sodium hydride (0.31 g, 13.05 mmol) was added in batches to a solution of (1r, 4r)-4-aminocyclohexane-1-carboxylic acid (0.62 g, 4.35 mmol) in N,N-dimethylformamide (10 mL), stirred at 0°C for 1 hour, and then 5,7-dichloro-3-(propan-2-yl)pyrazolo[1,5-a]pyrimidine (1 g, 4.35 mmol) was added to the reaction solution. The resulting mixed reaction solution was stirred at room temperature for 3 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3·H2O = 5-95% elution) to give (1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid (900 mg, yield: 61.5%), LC-MS m/z: 337 [M+H] + ;
2)、3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100073
2) Synthesis of tert-butyl 3-(((1r, 4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100073
在0℃条件下，向溶有(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸(600mg，1.78mmol)，3-羟基吡咯烷-1-羧酸叔丁酯(667mg，3.56mmol)和4-二甲氨基吡啶(43.5mg，0.36mmol)的二氯甲烷(6mL)溶液中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(409.5mg，2.14mmol)。所得混合反应液室温下搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(700mg，收率：77.7％)，LC-MS m/z：506[M+H]+；To a solution of (1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid (600 mg, 1.78 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (667 mg, 3.56 mmol) and 4-dimethylaminopyridine (43.5 mg, 0.36 mmol) in dichloromethane (6 mL) at 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (409.5 mg, 2.14 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 3-(((1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (700 mg, yield: 77.7%), LC-MS m/z: 506 [M+H] + ;
3)、3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100074
3) Synthesis of tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate:
Figure PCTCN2024077920-ftappb-I100074
将溶有3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(700mg，1.38mmol)，四氢-2H-吡喃-4-胺(153.6mg，1.52mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(116mg，0.14mmol)和碳酸铯(2248mg，6.90mmol)的1，4-二氧六环(7mL)溶液，氮气保护下，加热90℃搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(500mg，收率：63.5％)，LC-MS m/z：571[M+H]+；A solution of tert-butyl 3-(((1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (700 mg, 1.38 mmol), tetrahydro-2H-pyran-4-amine (153.6 mg, 1.52 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (116 mg, 0.14 mmol) and cesium carbonate (2248 mg, 6.90 mmol) in 1,4-dioxane (7 mL) was heated at 90° C. under nitrogen protection and stirred for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (500 mg, yield: 63.5%), LC-MS m/z: 571 [M+H] + ;
4)、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100075
4) Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100075
向溶有3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(500mg，0.88mmol)的1，4-二氧六环(2mL)溶液，滴加盐酸/二氧六环(3mL，4M)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化即可直接用于下一步，LC-MS m/z：471[M+H]+；To a solution of tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (500 mg, 0.88 mmol) in 1,4-dioxane (2 mL) was added dropwise hydrochloric acid/dioxane (3 mL, 4 M). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 471 [M+H] + ;
5)、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100076
5) Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100076
将溶有(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯(100mg，0.21mmol)，(2E)-4-(二甲基氨基)丁-2-烯酸(40.7mg，0.32mmol)和2-乙氧基-1-乙氧碳酰基-1，2-二氢喹啉(52mg，0.21mmol)的二氯甲烷(1mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有(0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：16.2％)，LC-MS m/z：582[M+H]+；A solution of (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.21 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (40.7 mg, 0.32 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (52 mg, 0.21 mmol) in dichloromethane (1 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing (0.1% NH 3 ·H 2 O=5-95% elution) to give (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (20 mg, yield: 16.2%), LC-MS m/z: 582 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.59(s，1H)，6.886.80(m，1H)，6.516.38(m，1H)，5.405.28(m，2H)，4.13-4.05(m，1H)，3.99-3.93(m，2H)，3.89-3.79(m，1H)，3.77-3.64(m，3H)，3.59-3.52(m，2H)，3.45-3.38(m，1H)，3.19-3.15(m，2H)，3.09-3.01(m，1H)，2.45-2.36(m，1H)，2.28(d，J＝4.0Hz，6H)，2.22-2.16(m，3H)，2.10-1.99(m，4H)，1.66-1.50(m，4H)，1.49-1.37(m，3H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.59 (s, 1H), 6.886.80 (m, 1H), 6.516.38 (m, 1H), 5.405.28 (m, 2H), 4.13-4.05 (m, 1H), 3.99-3.93 (m, 2H), 3.89-3.79 (m, 1H), 3.77-3.64 (m, 3H), 3.59-3.52 (m, 2H), 3.45-3 .38 (m, 1H), 3.19-3.15 (m, 2H), 3.09-3.01 (m, 1H), 2.45-2.36 (m, 1H), 2.28 (d, J=4.0Hz, 6H), 2.22-2.16 (m, 3H), 2.10-1.99 (m, 4H), 1.66-1.50 (m, 4H), 1.49-1.37 (m, 3H), 1.29 (s, 3H), 1.27 (s, 3H).
实施例5、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物5)的合成：Example 5, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 5):
1)、6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100077
1) Synthesis of tert-butyl 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
Figure PCTCN2024077920-ftappb-I100077
在0℃条件下，向溶有6-氨基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(839mg，3.95mmol)的四氢呋喃(5mL)溶液中，加入氢化钠(158mg，3.95mmol，含量：60％)，在0℃搅拌0.5小时。然后将5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(1.09g，4.76mmol)的四氢呋喃(1mL)溶液滴加上述反应液中，所得混合反应液在室温搅拌3小时。LCMS检测反应完成。将混合反应液加水(20mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯：石油醚＝0-50％洗脱)纯化得到6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2- 羧酸叔丁酯(1.5g，收率：93.7％)，LC-MS m/z：406[M+H]+；At 0°C, sodium hydride (158 mg, 3.95 mmol, content: 60%) was added to a solution of 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (839 mg, 3.95 mmol) in tetrahydrofuran (5 mL), and stirred at 0°C for 0.5 hours. Then a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (1.09 g, 4.76 mmol) in tetrahydrofuran (1 mL) was added dropwise to the above reaction solution, and the resulting mixed reaction solution was stirred at room temperature for 3 hours. LCMS detected that the reaction was complete. The mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-yl)-1,2-dihydro-1,4-dihydro-2-thiazolyl-1,4 ... Tert-butyl carboxylate (1.5 g, yield: 93.7%), LC-MS m/z: 406 [M+H] + ;
2)、6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成：
Figure PCTCN2024077920-ftappb-I100078
2) Synthesis of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate:
Figure PCTCN2024077920-ftappb-I100078
将溶有6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(1.4g，3.46mmol)，二碳酸二叔丁酯(905mg，4.15mmol)，4-二甲氨基吡啶(633mg，5.19mmol)和N，N-二异丙基乙胺(2.2g，17.3mmol)的二氯甲烷(7mL)溶液加热40℃搅拌16小时。LCMS检测反应完成。冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯：石油醚＝20-65％洗脱)纯化得到6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(749mg，收率：44％)，LC-MS m/z：506[M+H]+；A solution of tert-butyl 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (1.4 g, 3.46 mmol), di-tert-butyl dicarbonate (905 mg, 4.15 mmol), 4-dimethylaminopyridine (633 mg, 5.19 mmol) and N,N-diisopropylethylamine (2.2 g, 17.3 mmol) in dichloromethane (7 mL) was heated at 40° C. and stirred for 16 hours. The reaction was completed by LCMS. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20-65% elution) to give tert-butyl 6-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (749 mg, yield: 44%), LC-MS m/z: 506 [M+H] + ;
3)、6-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100079
3) Synthesis of tert-butyl 6-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
Figure PCTCN2024077920-ftappb-I100079
将溶有6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(701mg，1.38mmol)和四氢-2H-吡喃-4-胺(169mg，1.67mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(117mg，0.139mmol)和碳酸铯(1.36g，4.16mmol)的1，4-二氧六环(3mL)溶液加热100℃搅拌16小时。所得混合反应液氩气保护下，加热100℃搅拌16小时。LCMS检测反应完成。冷却后，将所得混合反应液加水(20mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用食盐水(1×30mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩粗产物(923mg)，无需进一步纯化即可直接用于下一步，LC-MS m/z：571[M+H]+；A solution of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (701 mg, 1.38 mmol) and tetrahydro-2H-pyran-4-amine (169 mg, 1.67 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (117 mg, 0.139 mmol) and cesium carbonate (1.36 g, 4.16 mmol) in 1,4-dioxane (3 mL) was heated at 100° C. and stirred for 16 hours. The resulting mixed reaction solution was heated at 100° C. and stirred for 16 hours under argon protection. The reaction was completed by LCMS. After cooling, the resulting mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (1×30 mL) and dried over anhydrous sodium sulfate. The crude product (923 mg) was concentrated under reduced pressure and used directly in the next step without further purification. LC-MS m/z: 571 [M+H] + ;
4)、3-异丙基-N7-(2-氮杂螺[3.3]庚烷-6-基)-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺的合成：
Figure PCTCN2024077920-ftappb-I100080
4) Synthesis of 3-isopropyl-N 7 -(2-azaspiro[3.3]heptane-6-yl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine:
Figure PCTCN2024077920-ftappb-I100080
将溶有6-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(923mg，1.62mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)混合反应液室温搅拌2小时。LCMS检测反应完成。将所得混合反应液减压浓缩得到粗产品(2g)，直接用于下一步无需进一步纯化，LC-MS m/z：371[M+H]+；The reaction mixture containing tert-butyl 6-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (923 mg, 1.62 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The reaction was completed by LCMS. The obtained mixed reaction mixture was concentrated under reduced pressure to obtain a crude product (2 g), which was used directly in the next step without further purification. LC-MS m/z: 371[M+H] + ;
5)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100081
5) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100081
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(514mg，2.97mmol)的二氯甲烷(2mL)溶液中加入三乙胺(1.1g，10.8mmol)和双(三氯甲基)碳酸酯(440mg，1.485mmol)，0℃搅拌0.5小时。将3-异丙基-N7-(2-氮杂螺[3.3]庚烷-6-基)-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(1g，2.7mmol)的二氯甲烷(2mL)加入上述混合反应液中。所得混合反应液搅拌16小时。LCMS检测反应完全，将所得混合反应液加入饱和氯化铵水溶液(10mL)淬灭并乙酸乙酯(3×10mL)萃取。合并的有机想用食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(188mg，收率：12.3％)，LC-MS m/z：570[M+H]+；Triethylamine (1.1 g, 10.8 mmol) and bis(trichloromethyl)carbonate (440 mg, 1.485 mmol) were added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (514 mg, 2.97 mmol) in dichloromethane (2 mL) at 0°C, and stirred at 0°C for 0.5 hours. 3-isopropyl-N 7 -(2-azaspiro[3.3]heptane-6-yl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (1 g, 2.7 mmol) in dichloromethane (2 mL) was added to the above mixed reaction solution. The obtained mixed reaction solution was stirred for 16 hours. LCMS detected that the reaction was complete, and the obtained mixed reaction solution was quenched by adding saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (188 mg, yield: 12.3%), LC-MS m/z: 570 [M+H] + ;
6)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100082
6) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100082
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(188mg，0.33mmol)的2，2，2-三氟乙酸(0.4mL)和二氯甲烷(1.2mL)混合溶液在室温搅拌2小时。残余物通过LCMS检测反应完全。将所得混合反应液减压浓缩的粗产品(308mg)，直接用于下一步，无需进一步纯化(308mg)，LC-MS m/z：470[M+H]+；A mixed solution of 2,2,2-trifluoroacetic acid (0.4 mL) and dichloromethane (1.2 mL) containing 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butyloxycarbonyl)azetidine-3-yl ester (188 mg, 0.33 mmol) was stirred at room temperature for 2 hours. The residue was detected by LCMS to be complete. The crude product (308 mg) obtained by concentrating the mixed reaction solution under reduced pressure was used directly in the next step without further purification (308 mg), LC-MS m/z: 470[M+H] + ;
7)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成：
Figure PCTCN2024077920-ftappb-I100083
7) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester:
Figure PCTCN2024077920-ftappb-I100083
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯(100mg，0.213mmol)，2-氟丙烯酸(29mg，0.32mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(119mg，0.42mmol)和N-甲基咪唑(70mg，0.852mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。LCMS检测反应完成。将混合反应液通过制备级高效液相色谱纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(5mg，收率：4.3％)，LC-MS m/z：542[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester (100 mg, 0.213 mmol), 2-fluoroacrylic acid (29 mg, 0.32 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (119 mg, 0.42 mmol) and N-methylimidazole (70 mg, 0.852 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The reaction was completed by LCMS. The mixed reaction solution was purified by preparative HPLC to obtain 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (5 mg, yield: 4.3%), LC-MS m/z: 542 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.88(s，1H)，5.61(d，J＝3.5Hz，1H)，5.49(d，J＝3.5Hz，1H)，5.38(s，1H)，5.21(dd，J＝16.1，3.5Hz，1H)，5.16(d，J＝4.1Hz，1H)，4.73(s，1H)，4.34(t，J＝29.2Hz，5H)，4.00(d，J＝11.3Hz， 5H)，3.60(t，J＝10.6Hz，2H)，3.09(dd，J＝15.7，9.2Hz，1H)，2.84-2.71(m，2H)，2.52-2.41(m，2H)，2.02(d，J＝10.7Hz，2H)，1.64(d，J＝9.0Hz，2H)，1.30(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.88 (s, 1H), 5.61 (d, J=3.5Hz, 1H), 5.49 (d, J=3.5Hz, 1H), 5.38 (s, 1H) , 5.21 (dd, J=16.1, 3.5Hz, 1H), 5.16 (d, J=4.1Hz, 1H), 4.73 (s, 1H), 4.34 (t, J=29.2Hz, 5H), 4.00 (d, J=11.3Hz, 5H), 3.60 (t, J=10.6Hz, 2H), 3.09 (dd, J=15.7, 9.2Hz, 1H), 2.84-2.71 (m, 2H), 2.52-2.41 (m, 2H), 2.02 (d , J=10.7Hz, 2H), 1.64 (d, J=9.0Hz, 2H), 1.30 (d, J=6.9Hz, 6H).
实施例6、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物6)的合成：
Figure PCTCN2024077920-ftappb-I100084
Example 6, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 6):
Figure PCTCN2024077920-ftappb-I100084
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯(100mg，0.113mmol)，(E)-4-(二甲氨基)丁-2-烯酸(53mg，0.32mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(119mg，0.426mmol)和N-甲基咪唑(70mg，0.852mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。LCMS检测反应完全完。将混合反应液通过制备级高效液相色谱纯化得到(5mg，收率：4.1％)，LC-MS m/z：581[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester (100 mg, 0.113 mmol), (E)-4-(dimethylamino)but-2-enoic acid (53 mg, 0.32 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (119 mg, 0.426 mmol) and N-methylimidazole (70 mg, 0.852 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The mixed reaction solution was purified by preparative HPLC to obtain (5 mg, yield: 4.1%), LC-MS m/z: 581[M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.60(s，1H)，6.85-6.71(m，1H)，6.17(d，J＝15.6Hz，1H)，5.15(d，J＝7.8Hz，2H)，4.58(d，J＝11.6Hz，2H)，4.37-3.89(m，12H)，3.56(t，J＝10.7Hz，3H)，3.19-2.98(m，3H)，2.83-2.68(m，2H)，2.29(d，J＝16.5Hz，8H)，2.02(d，J＝12.4Hz，2H)，1.53(td，J＝15.3，4.2Hz，2H)，1.28(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.60 (s, 1H), 6.85-6.71 (m, 1H), 6.17 (d, J=15.6Hz, 1H), 5.15 (d, J=7.8Hz, 2H), 4.58 (d, J=11.6Hz, 2H), 4.37-3.89 (m, 12H), 3.56 (t , J=10.7Hz, 3H), 3.19-2.98 (m, 3H), 2.83-2.68 (m, 2H), 2.29 (d, J=16.5Hz, 8H), 2.02 (d, J=12.4Hz, 2H), 1.53 (td, J=15.3, 4.2Hz, 2H), 1.28 (d, J=6.9Hz, 6 H).
实施例7、4-((5-(((((((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物7)的合成：Example 7, Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 7):
1)、4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100085
1) Synthesis of (R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100085
在0℃条件下，向溶有(R)-3-羟基吡咯烷-1-羧酸苄基酯(470mg，2.12mmol)和三乙胺(430mg，4.25mmol)的二氯甲烷(2.5mL)溶液中分批加入碳酸双(三氯甲基)酯(126mg，0.42mmol)。所得混合反应液在0℃搅拌30分钟。然后0℃条件下，将5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(250mg，0.85mmol)，分批加入上述反应液中。所得混合反应液室温搅拌2.5小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝50-70％洗脱)纯化得到4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((苄氧基)羰基)吡咯烷-3-基酯(443mg，收率：96.0％)，LC-MS m/z：541[M+H]+；At 0°C, bis(trichloromethyl) carbonate (126 mg, 0.42 mmol) was added in batches to a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (470 mg, 2.12 mmol) and triethylamine (430 mg, 4.25 mmol) in dichloromethane (2.5 mL). The resulting mixed reaction solution was stirred at 0°C for 30 minutes. Then, 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (250 mg, 0.85 mmol) was added in batches to the above reaction solution at 0°C. The resulting mixed reaction solution was stirred at room temperature for 2.5 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=50-70% elution) to give (R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (443 mg, yield: 96.0%), LC-MS m/z: 541 [M+H] + ;
2)、(3R，4R)-4-(((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100086
2) Synthesis of tert-butyl (3R, 4R)-4-(((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100086
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((苄氧基)羰基)吡咯 烷-3-基酯(300mg，0.56mmol)，(3R，4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸叔丁酯(192mg 0.83mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(93mg，0.11mmol)和碳酸铯(543mg，1.66mmol)的1，4-二六环(5mL)溶液，氮气保护下，加热100℃搅拌过夜。冷却后，将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝60-80％洗脱)纯化得到(3R，4R)-4-(((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(85mg，收率：21％)，LC-MS m/z：735[M+H]+；4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (R)-1-((benzyloxy)carbonyl)pyrrole A solution of 1,4-hexacyclopentane (5 mL) with 3-alkyl ester (300 mg, 0.56 mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (192 mg 0.83 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (93 mg, 0.11 mmol) and cesium carbonate (543 mg, 1.66 mmol) was heated at 100° C. and stirred overnight under nitrogen protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 60-80% elution) to give (3R,4R)-4-(((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (85 mg, yield: 21%), LC-MS m/z: 735 [M+H] + ;
3)、(3R，4R)-3-羟基-4-(((3-异丙基-7-((1-((((((R)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100087
3) Synthesis of tert-butyl (3R, 4R)-3-hydroxy-4-(((3-isopropyl-7-((1-((((((R)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100087
将溶有(3R，4R)-4-(((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(371mg，0.50mmol)和钯碳(185mg)的2，2，2-三氟乙醇(4mL)溶液氢气氛围下，加热50℃搅拌16小时。冷却后，将所得混合反应液用二氯甲烷溶解，并过滤，收集滤液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：601[M+H]+；A solution of (3R, 4R)-4-(((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (371 mg, 0.50 mmol) and palladium on carbon (185 mg) in 2,2,2-trifluoroethanol (4 mL) was heated at 50° C. and stirred for 16 hours under a hydrogen atmosphere. After cooling, the obtained mixed reaction liquid was dissolved in dichloromethane and filtered. The collected filtrate was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 601[M+H] + ;
4)、(3R，4R)-4-(((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100088
4) Synthesis of tert-butyl (3R, 4R)-4-(((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100088
将溶有(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(86mg，0.52mmol)和三乙胺(177mg，1.75mmol)和2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(200mg，0.52mmol)的二氯甲烷(3mL)溶液，室温搅拌搅10分钟。然后，在室温条件下，将(3R，4R)-3-羟基-4-(((3-异丙基-7-((1-((((((R)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)哌啶-1-羧酸叔丁酯(210mg，0.35mmol)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH4HCO3的纯水＝60-80％洗脱)纯化得到(3R，4R)-4-(((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(160mg，收率：64％)，LC-MS m/z：712[M+H]+；A solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (86 mg, 0.52 mmol), triethylamine (177 mg, 1.75 mmol) and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol) in dichloromethane (3 mL) was stirred at room temperature for 10 minutes. Then, tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-((1-((((((R)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (210 mg, 0.35 mmol) was added at room temperature. The resulting mixed reaction liquid was stirred at room temperature for 1 hour. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 4 HCO 3 =60-80% pure water) was purified to give (3R,4R)-4-(((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (160 mg, yield: 64%), LC-MS m/z: 712 [M+H] + ;
5)、4-((5-(((((((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100089
5) Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100089
将溶有(3R，4R)-4-(((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(160mg，0.22mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH4HCO3的纯水＝30-70％洗脱)纯化得到(30mg，收率：22％)LC-MS m/z：612[M+H]+；A solution of (3R,4R)-tert-butyl 4-(((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (160 mg, 0.22 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 30-70% elution) to give (30 mg, yield: 22%). LC-MS m/z: 612 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.86(s，1H)，6.81-6.73(m，2H)，5.70(s，1H)，5.34-5.26(m，1H)，4.17(s，2H)，3.98-3.87(m，4H)，3.83-3.67(m，5H)，3.55-3.37(m，4H)，3.06-3.02(m，4H)，2.91(s，6H)，2.81(t，J＝8.0Hz，1H)，2.31-2.23(m，1H)，2.20-2.13(m，2H)，2.08(s，2H)，1.95-1.91(m，1H)，1.68-1.63(m，3H)，1.29(d，J＝4.0Hz，6H). 1 H NMR (400MHz, MeOD): δ7.86 (s, 1H), 6.81-6.73 (m, 2H), 5.70 (s, 1H), 5.34-5.26 (m, 1H), 4.17 (s, 2H), 3.98-3.87(m, 4H), 3.83-3.67(m, 5H), 3.55-3.37(m, 4H), 3.06 -3.02(m, 4H), 2.91(s, 6H), 2.81(t, J=8.0Hz, 1H), 2.31-2.23(m, 1H), 2.20-2.13(m, 2H), 2.08(s, 2H ), 1.95-1.91 (m, 1H), 1.68-1.63 (m, 3H), 1.29 (d, J=4.0Hz, 6H).
实施例8、4-((5-(((((((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物8)的合成：Example 8. Synthesis of (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 8):
1)、5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100090
1) Synthesis of 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100090
向溶有的4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(500mg，1.27mmol)的二氯甲烷(6mL)溶液中，滴加2，2，2-三氟乙酸(2mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤，无需进一步纯化，LC-MS m/z：294[M+H]+；2,2,2-trifluoroacetic acid (2 mL) was added dropwise to a solution of tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (500 mg, 1.27 mmol) in dichloromethane (6 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 294 [M+H] + ;
2)、4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100091
2) Synthesis of 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100091
在0℃条件下，向溶有(S)-3-羟基吡咯烷-1-羧酸苄基酯(302mg，1.37mmol)的四氢呋喃(15mL)溶液中分批加入碳酸双(三氯甲基)酯(252mg，0.86mmol)。所得混合反应液在0℃搅拌30分钟。然后将5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(500mg，1.71mmol)在室温条件，分批加入上述反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((苄氧基)羰基)吡咯烷-3-基酯(350mg，收率：47.4％)，LC-MS m/z：541[M+H]+；At 0°C, bis(trichloromethyl) carbonate (252 mg, 0.86 mmol) was added in batches to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (302 mg, 1.37 mmol) in tetrahydrofuran (15 mL). The resulting mixed reaction solution was stirred at 0°C for 30 minutes. Then 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (500 mg, 1.71 mmol) was added in batches to the above reaction solution at room temperature. The resulting mixed reaction solution was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (350 mg, yield: 47.4%), LC-MS m/z: 541 [M+H] + ;
3)、(3R，4R)-4-(((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100092
3) Synthesis of tert-butyl (3R, 4R)-4-(((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100092
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((苄氧基)羰基)吡咯烷-3-基酯(350mg，0.65mmol)，(3R，4R)-4-(氨基甲基)-3-羟基哌啶-1-羧酸叔丁酯(179mg，0.78mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(59mg，0.07mmol)和碳酸铯(634mg，1.95mmol)的二氧六环(4mL)溶液加热100℃搅拌过夜。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3R，4R)-4-(((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(180mg，收率：38％)，LC-MS m/z：735[M+H]+；A solution of (S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (350 mg, 0.65 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (179 mg, 0.78 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (59 mg, 0.07 mmol) and cesium carbonate (634 mg, 1.95 mmol) in dioxane (4 mL) was heated at 100° C. and stirred overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH3·H2O=5-95% elution) to give (3R,4R)-4-(((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (180 mg, yield: 38%), LC-MS m/z: 735 [M+H] + ;
4)、(3R，4R)-3-羟基-4-(((3-异丙基-7-((1-((((((S)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100093
4) Synthesis of tert-butyl (3R, 4R)-3-hydroxy-4-(((3-isopropyl-7-((1-((((((S)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100093
将溶有(3R，4R)-4-(((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(180mg，0.25mmol)和钯碳(60mg)的2，2，2-三氟乙醇(5mL)溶液，在氢气氛围下搅拌4小时。将混合反应液过滤，收集滤液减压浓缩得到粗产品，直接用于下一步，无需进一步纯化，LC-MS：m/z：601[M+H]+；A solution of (3R, 4R)-4-(((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.25 mmol) and palladium on carbon (60 mg) in 2,2,2-trifluoroethanol (5 mL) was stirred under a hydrogen atmosphere for 4 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS: m/z: 601 [M+H] + ;
5)、(3R，4R)-4-(((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100094
5) Synthesis of tert-butyl (3R, 4R)-4-(((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100094
将溶有(3R，4R)-3-羟基-4-(((3-异丙基-7-((1-((((((S)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)哌啶-1-羧酸叔丁酯(130mg，0.22mmol)，(E)-4-(二甲氨基)丁-2-烯酸(34mg，0.26mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(126mg，0.33mmol)和三乙胺(67mg，0.66mmol)的二氯甲烷(2.5mL)溶液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3H2O的纯水＝5-95％洗脱)纯化得到(3R，4R)-4-(((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(60mg，收率：39％)，LC-MS m/z：712[M+H]+；A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-((1-((((((S)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (130 mg, 0.22 mmol), (E)-4-(dimethylamino)but-2-enoic acid (34 mg, 0.26 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) and triethylamine (67 mg, 0.66 mmol) in dichloromethane (2.5 mL) was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3 H 2 O pure water = 5-95% elution) to give (3R,4R)-4-(((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, yield: 39%), LC-MS m/z: 712 [M+H] + ;
6)、4-((5-(((((((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100095
6) Synthesis of (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100095
向溶有(3R，4R)-4-(((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)甲基)-3-羟基哌啶-1-羧酸叔丁酯(60mg，0.084mmol)的二氯甲烷(1.2mmol)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液在室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-(((((((3R，4R)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(8.1mg，收率：31.8％)，LC-MS m/z：612[M+H]+；To a solution of (3R,4R)-tert-butyl 4-(((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 0.084 mmol) in dichloromethane (1.2 mmol) was added dropwise 2,2,2-trifluoroacetic acid (0.4 mL). The resulting mixed reaction liquid was stirred at room temperature for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3 ·H 2 O pure water = 5-95% elution) to give 4-((5-(((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (8.1 mg, yield: 31.8%), LC-MS m/z: 612 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.77(s，1H)，6.78-6.73(m，2H)，5.55(s，1H)，5.29(d，J＝16.0Hz，1H)，4.13(s，2H)，3.95(t，J＝5.6Hz，2H)，3.91-3.78(m，3H)，3.75-3.71(m，2H)，3.67-3.48(m，3H)，3.45-3.37(m，2H)，3.10-3.03(m，3H)，2.99-2.96(m，1H)，2.90(s，6H)，2.81(t，J＝11.2Hz，1H)，2.30-2.17(m，2H)，2.09-2.03(m，3H)，1.84(s，1H)，1.72-1.62(m，3H)，1.29(d，J＝2.8Hz，3H)，1.27(d，J＝2.8Hz，3H). 1 H NMR (400MHz, MeOD-d4): δ7.77 (s, 1H), 6.78-6.73 (m, 2H), 5.55 (s, 1H), 5.29 (d, J=16.0Hz, 1H), 4.13 ( s, 2H), 3.95 (t, J=5.6Hz, 2H), 3.91-3.78 (m, 3H), 3.75-3.71 (m, 2H), 3.67-3.48 (m, 3H), 3.45-3.37 (m, 2H), 3.10-3.03 (m, 3H), 2.99-2.96 (m, 1H), 2.90 (s, 6H), 2.81 (t, J=11.2Hz, 1H), 2.30-2.17 (m, 2H ), 2.09-2.03(m, 3H), 1.84(s, 1H), 1.72-1.62(m, 3H), 1.29(d, J＝2.8Hz, 3H), 1.27(d, J＝2.8Hz, 3H) .
实施例9、4-((5-((((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物9)的合成：Example 9, Synthesis of 4-((5-((((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 9):
1)、1-((苄氧基)羰基)吡咯烷-3-基4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100096
1) Synthesis of tert-butyl 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100096
向溶有1-((苄氧基)羰基)吡咯烷-3-基4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.0g，1.85mmol)，三乙胺(56mg，0.56mmol)和二碳酸二叔丁酯(604mg，2.77mmol)的四氢呋喃(10mL)溶液中，加入4-二氨基吡啶(22mg，0.185mmol)。所得混合反应液室温搅拌1小时。将混合反应液加水(20mL)稀释，并用(3×50mL)萃取。合并的有机相用饱和食盐水(1×50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-30％)洗脱)纯化得到1-((苄氧基)羰基)吡咯烷-3-基4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(0.92g，收率：78％)，LC-MS m/z：641[M+H]+；To a solution of tert-butyl 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.0 g, 1.85 mmol), triethylamine (56 mg, 0.56 mmol) and di-tert-butyl dicarbonate (604 mg, 2.77 mmol) in tetrahydrofuran (10 mL) was added 4-diaminopyridine (22 mg, 0.185 mmol). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with water (20 mL) and extracted with (3×50 mL). The combined organic phase was washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 0-30%) to give tert-butyl 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (0.92 g, yield: 78%), LC-MS m/z: 641 [M+H] + ;
2)、4-((叔丁氧基羰基)(5-(((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100097
2) Synthesis of 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-(((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100097
在0℃和氮气保护下，向溶有1-((苄氧基)羰基)吡咯烷-3-基4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.0g，1.56mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(0.13mg，0.16mmol)，碳酸铯(0.51g，1.56mmol)的1，4-二氧六环(10mL)溶液中，加入(S)-6，6-二甲基哌啶-3-胺(0.24g，1.87mmol)。所得混合反应氮气保护下，加热110℃搅拌16小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×30mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝15-50％洗脱)纯化得到4-((叔丁氧基羰基)(5-(((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(0.23g，收率：21％)，LC-MS m/z 733[M+H]+；To a solution of tert-butyl 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.0 g, 1.56 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (0.13 mg, 0.16 mmol), and cesium carbonate (0.51 g, 1.56 mmol) in 1,4-dioxane (10 mL) at 0°C under nitrogen protection was added (S)-6,6-dimethylpiperidin-3-amine (0.24 g, 1.87 mmol). The resulting mixed reaction mixture was heated at 110° C. and stirred for 16 hours under nitrogen protection. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 15-50% elution) to give 4-((tert-butoxycarbonyl)(5-(((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (0.23 g, yield: 21%), LC-MS m/z 733[M+H] + ;
3)、(5S)-5-((7-((1-((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100098
3) Synthesis of tert-butyl (5S)-5-((7-((1-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100098
在0℃条件下，向溶有4-((叔丁氧基羰基)(5-(((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(0.4g，0.55mmol)，4-二甲氨基吡啶(6.7mg，0.06mmol)和三乙胺(0.17g，1.65mmol)的四氢呋喃(4mL)溶液中，分批加入二碳酸二叔丁酯(3.47g，86.82mmol)。所得混合反应液室温搅拌1小时。0℃条件下，将混合反应液加水淬灭，并用乙酸乙酯(1×30mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(甲醇∶二氯甲烷＝0-10％洗脱)纯化得到(5S)-5-((7-((1-((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(0.16g，收率：35％)，LC-MS m/z：833[M+H]+；At 0°C, di-tert-butyl dicarbonate (3.47 g, 86.82 mmol) was added in portions to a solution of 4-((tert-butoxycarbonyl)(5-(((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (0.4 g, 0.55 mmol), 4-dimethylaminopyridine (6.7 mg, 0.06 mmol) and triethylamine (0.17 g, 1.65 mmol) in tetrahydrofuran (4 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. At 0°C, the mixed reaction solution was quenched with water and extracted with ethyl acetate (1×30 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10%) to give (5S)-5-((7-((1-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.16 g, yield: 35%), LC-MS m/z: 833 [M+H] + ;
4)(5S)-5-((7-((叔丁氧基羰基)(1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100099
4. Synthesis of tert-butyl (5S)-5-((7-((tert-butoxycarbonyl)(1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100099
将溶有(5S)-5-((7-((1-((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(0.26g，0.312mmol) 和钯碳(26mg，10％含量)乙酸乙酯(2mL)溶液，氢气(1atm)氛围下，加热50℃，搅拌4小时。将混合反应液过滤，滤饼用乙酸乙酯(3×20mL)洗涤。收集滤液减压浓缩得到(5S)-5-((7-((叔丁氧基羰基)(1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(0.15g，收率：68.8％)，LC-MS m/z：699[M+H]+；A mixture of tert-butyl (5S)-5-((7-((1-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate (0.26 g, 0.312 mmol) and 4-(tert-butyl)-piperidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate was added. and palladium carbon (26 mg, 10% content) ethyl acetate (2 mL) solution, heated to 50 ° C under a hydrogen atmosphere (1 atm), and stirred for 4 hours. The mixed reaction solution was filtered and the filter cake was washed with ethyl acetate (3×20 mL). The filtrate was collected and concentrated under reduced pressure to give (5S)-5-((7-((tert-butoxycarbonyl)(1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.15 g, yield: 68.8%), LC-MS m/z: 699[M+H] + ;
5)、(5S)-5-((7-((叔丁氧羰基)(1-((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100100
5) Synthesis of tert-butyl (5S)-5-((7-((tert-butyloxycarbonyl)(1-((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100100
将溶有(E)-4-(二甲氨基)丁-2-烯酸(33mg，0.258mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(0.196g，0.515mmol)，N，N-二异丙基乙胺(0.132g，1.03mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌0.5小时。然后将(5S)-5-((7-((叔丁氧基羰基)(1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(0.15g，0.215mmol)加入到上述反应液中，所得混合反应液室温搅拌2小时。将所得混合反应液加水(10mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(甲醇∶二氯甲烷＝0-10％洗脱)纯化得到(5S)-5-((7-((叔丁氧羰基)(1-((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(0.05g，收率：28.7％)，LC-MS m/z：810[M+H]+；A solution of (E)-4-(dimethylamino)but-2-enoic acid (33 mg, 0.258 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.196 g, 0.515 mmol), and N,N-diisopropylethylamine (0.132 g, 1.03 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 hours. Then, (5S)-5-((7-((tert-butoxycarbonyl)(1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.215 mmol) was added to the above reaction solution, and the resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give (5S)-5-((7-((tert-butyloxycarbonyl)(1-((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.05 g, yield: 28.7%), LC-MS m/z: 810 [M+H] + ;
6)、4-((5-((((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100101
6) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-((((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100101
将溶有(5S)-5-((7-((叔丁氧羰基)(1-((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氨基)-2，2-二甲基哌啶-1-羧酸叔丁酯(50mg，0.0617mmol)的2，2，2-三氟乙酸(0.5mL)和二氯甲烷(2mL)溶液室温搅拌1小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱法(甲醇∶二氯甲烷＝0-10％洗脱)纯化得到4-((5-((((S)-6，6-二甲基哌啶-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：53.1％)，LC-MS m/z：610[M+H]+；A solution of (5S)-5-((7-((tert-butyloxycarbonyl)(1-((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.0617 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) and dichloromethane (2 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give 4-((5-((((S)-6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (20 mg, yield: 53.1%), LC-MS m/z: 610 [M+H] + ;
1H NMR(400MHz，MeOH-d4)：δ7.61(s，1H)，6.90-6.76(m，1H)，6.45(dd，J＝27.2，15.6Hz，1H)，5.33(s，1H)，5.27(d，J＝18.4Hz，1H)，4.07(s，2H)，3.96(s，1H)，3.90-3.79(m，1H)，3.70(dt，J＝13.2，12.0Hz，4H)，3.22(s，1H)，3.14(dd，J＝19.6，8.8Hz，5H)，2.80-2.73(m，1H)，2.27(s，6H)，2.22(s，1H)，2.15(s，1H)，2.08(d，J＝14.0Hz，2H)，1.97(d，J＝10.4Hz，1H)，1.70(d，J＝12.0Hz，2H)，1.58(s，3H)，1.28(d，J＝6.8Hz，6H)，1.22(d，J＝6.0Hz，6H). 1 H NMR (400MHz, MeOH-d4): δ7.61 (s, 1H), 6.90-6.76 (m, 1H), 6.45 (dd, J=27.2, 15.6Hz, 1H), 5.33 (s, 1H), 5.27 (d, J=18.4Hz, 1H), 4.07 (s, 2H), 3.96 (s, 1H), 3.90-3.79 (m, 1H), 3.70 (dt, J=13.2, 12.0Hz, 4H), 3.22 (s,1H),3 .14(dd, J=19.6, 8.8Hz, 5H), 2.80-2.73(m, 1H), 2.27(s, 6H), 2.22(s, 1H), 2.15(s, 1H), 2.08(d, J =14.0Hz, 2H), 1.97 (d, J = 10.4Hz, 1H), 1.70 (d, J = 12.0Hz, 2H), 1.58 (s, 3H), 1.28 (d, J = 6.8Hz, 6H), 1.22 (d, J=6.0Hz, 6H).
实施例10、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物10)的合成：Example 10. Synthesis of (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 10):
1)、(R)-3-((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100102
1) Synthesis of tert-butyl (R)-3-((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100102
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((苄氧基)羰基)吡咯烷-3-基酯(200mg，0.37mmol)，(R)-3-羟基哌啶-1-羧酸叔丁酯(186mg，0.93mmol)的，Pd2(dba)3(34mg，0.037mmol)，(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(42mg，0.076mmol)和碳酸铯(362mg，1.11mmol)的甲苯(3mL)溶液，在氮气保护下，微波加热140℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱纯化(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-3-((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(160mg，收率：61.3％)，LC-MS m/z：706[M+H]+；A solution of (S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (200 mg, 0.37 mmol), (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (186 mg, 0.93 mmol), Pd 2 (dba) 3 (34 mg, 0.037 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (42 mg, 0.076 mmol) and cesium carbonate (362 mg, 1.11 mmol) in toluene (3 mL) was heated in a microwave at 140° C. for 2 hours under nitrogen protection. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give (R)-tert-butyl 3-((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (160 mg, yield: 61.3%), LC-MS m/z: 706 [M+H] + ;
2)、(R)-3-((7-((叔丁氧基羰基)(1-(((((S)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100103
2) Synthesis of tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(1-(((((S)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100103
将溶有(R)-3-((7-((1-((((S)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(160mg，22.70mmol)和钯碳(30mg)的2，2，2-三氟乙醇(2mL)溶液，在氢气氛围下，室温搅拌4小时。将所得混合反应液过滤，滤饼用2，2，2-三氟乙醇(2×3mL)洗涤。将所得混合反应液减压浓缩的粗产物，无需进一步纯化，直接用于下一步，LC-MS m/z：572[M+H]+；A solution of (R)-3-((7-((1-((((S)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 22.70 mmol) and palladium on carbon (30 mg) in 2,2,2-trifluoroethanol (2 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The obtained mixed reaction liquid was filtered and the filter cake was washed with 2,2,2-trifluoroethanol (2×3 mL). The crude product obtained by concentrating the obtained mixed reaction liquid under reduced pressure was directly used in the next step without further purification, LC-MS m/z: 572[M+H] + ;
3)、(R)-3-((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100104
3) Synthesis of tert-butyl (R)-3-((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100104
将溶有(R)-3-((7-((叔丁氧基羰基)(1-(((((S)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(100mg，0.175mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(44mg，0.265mmol)和2-乙氧基-1-乙氧碳酰基-1，2-二氢喹啉(43mg，0.174mmol)的二氯甲烷(4mL)溶液室温搅拌8小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-3-((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(60mg，收率：50.1％)，LC-MS m/z：683[M+H]+；(R)-tert-butyl 3-((7-((tert-butoxycarbonyl)(1-(((((S)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (100 mg, 0.175 mmol), (E)-4-(dimethylamino)but-2-enoic acid (44 mg, 0.265 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (43 mg, 0.174 mmol) were dissolved in dichloromethane ( 4mL) solution was stirred at room temperature for 8 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give (R)-3-((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (60 mg, yield: 50.1%), LC-MS m/z: 683[M+H] + ;
4)、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100105
4) Synthesis of (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100105
室温条件下，向溶有(R)-3-((7-((1-(((((S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(60mg，0.088mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合物在室温搅拌4小时。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(12mg，收率：23.4％)，LC-MS m/z：583[M+H]+；To a solution of (R)-tert-butyl 3-((7-((1-(((((S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (60 mg, 0.088 mmol) in dichloromethane (1.2 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.4 mL) at room temperature. . The resulting mixture was stirred at room temperature for 4 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (S)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (12 mg, yield: 23.4%), LC-MS m/z: 583 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.77(s，1H)，6.83-6.77(m，1H)，6.67-6.57(m，1H)，5.64(s，1H)，5.50(s，1H)，5.29(d，J＝16.8Hz，1H)，4.10(s，2H)，3.92-3.70(m，5H)，3.61-3.49(m，4H)，3.43(d，J＝12.8Hz，1H)，3.29(s，1H)，3.17-3.06(m，4H)，2.62(s，6H)，2.29-2.24(m，1H)，2.16-1.97(m，6H)，1.86-1.83(m，1H)，1.61(d，J＝8.4Hz，2H)，1.32(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.77 (s, 1H), 6.83-6.77 (m, 1H), 6.67-6.57 (m, 1H), 5.64 (s, 1H), 5.50 (s, 1H), 5.29 (d, J=16.8Hz, 1H), 4.10 (s, 2H), 3.92-3.70 (m, 5H), 3.61-3.49 (m, 4H), 3.43 (d , J=12.8Hz, 1H), 3.29 (s, 1H), 3.17-3.06 (m, 4H), 2.62 (s, 6H), 2.29-2.24 (m, 1H), 2.16-1.97 (m, 6H), 1.86-1.83 (m, 1H), 1.61 (d, J = 8.4Hz, 2H), 1.32 (d, J = 6.8Hz, 6H).
实施例11、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物11)的合成：Example 11, Synthesis of 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 11):
1)、(3R)-3-((7-((1-(((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100106
1) Synthesis of tert-butyl (3R)-3-((7-((1-(((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100106
将溶有(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(56mg，0.34mmol)和三乙胺(113mg，1.12mmol)和2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(128mg，0.34mmol)的二氯甲烷(3mL)溶液室温搅拌10分钟。然后将(3R)-3-((3-异丙基-7-((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(128mg，0.22mmol)加入上述混合反应液中。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH4HCO3的纯水＝50-70％洗脱)纯化得到(3R)-3-((7-((1-(((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(79mg，收率：52％)，LC-MS m/z：683[M+H]+；A solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (56 mg, 0.34 mmol), triethylamine (113 mg, 1.12 mmol) and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol) in dichloromethane (3 mL) was stirred at room temperature for 10 minutes. Then, (3R)-3-((3-isopropyl-7-((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (128 mg, 0.22 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 4 HCO 3 = 50-70% elution) to give (3R)-3-((7-((1-(((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (79 mg, yield: 52%), LC-MS m/z: 683 [M+H] + ;
2)、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100107
2) Synthesis of 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100107
将溶有(3R)-3-((7-((1-(((1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(79mg，0.12mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH4HCO3的纯水＝30-70％洗脱)纯化得到4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：22％)，LC-MS m/z：583[M+H]+；A solution of (3R)-tert-butyl 3-((7-((1-(((1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (79 mg, 0.12 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 4 HCO 3 = 30-70% elution) to give 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (20 mg, yield: 22%), LC-MS m/z: 583 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.74(s，1H)，6.88-6.78(m，1H)，6.47-6.43(m，1H)，5.59(s，1H)，5.32-5.18(m，2H)，4.09(s，2H)，3.89-3.79(m，1H)，3.79-3.47(m，5H)，3.24-3.18(m，3H)，3.10-3.06(m，3H)，2.89-2.85(m，3H)，2.27(s，6H)，2.15(s，1H)，2.07(s，3H)，1.89(s，2H)，1.60(s，3H)，1.31(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD): δ7.74 (s, 1H), 6.88-6.78 (m, 1H), 6.47-6.43 (m, 1H), 5.59 (s, 1H), 5.32-5.18 (m, 2H), 4.09 (s, 2H), 3.89-3.79 (m, 1H), 3.79-3.47 (m, ) ).
实施例12、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物12)的合成：Example 12, Synthesis of (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 12):
1)、(S)-(4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100108
1) Synthesis of (S)-(4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100108
在0℃条件下，向溶有(S)-3-羟基吡咯烷-1-羧酸苄基酯(641mg，2.90mmol)和三乙胺(879mg，8.70mmol)的二氯甲烷(10mL)溶液中，分批加入三光气(345mg，1.16mmol)。所得混合反应液搅拌1小时。然后在室温条件下，将5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(850mg，2.90mmol)。所得混合反应液室温搅拌1小时。所将所得混合反应液加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(S)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(800mg，收率：51.1％)，LC-MS m/z：541[M+H]+；At 0°C, triphosgene (345 mg, 1.16 mmol) was added in batches to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (641 mg, 2.90 mmol) and triethylamine (879 mg, 8.70 mmol) in dichloromethane (10 mL). The resulting mixed reaction solution was stirred for 1 hour. Then, 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (850 mg, 2.90 mmol) was added at room temperature. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid = 25%-65% elution) to give (S)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (800 mg, yield: 51.1%), LC-MS m/z: 541 [M+H] + ;
2)、(S)-4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100109
2) Synthesis of (S)-4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100109
室温条件下，向溶有(S)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(800mg，1.48mmol)和二碳酸二叔丁酯(646mg，2.96mmol)的四氢呋喃(8mL)加入4-二甲基氨基吡啶(90mg，0.74mmol)。所得混合反应液加热50℃搅拌2小时。冷却后，将所得混合反应液加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥。过滤后，将滤液真空浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(S)-4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(700mg，收率：73.8％)，LC-MS m/z：641[M+H]+；At room temperature, 4-dimethylaminopyridine (90 mg, 0.74 mmol) was added to tetrahydrofuran (8 mL) containing (S)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (800 mg, 1.48 mmol) and di-tert-butyl dicarbonate (646 mg, 2.96 mmol). The resulting mixed reaction liquid was heated at 50°C and stirred for 2 hours. After cooling, the resulting mixed reaction liquid was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (1×30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid = 25%-65% elution) to give (S)-4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (700 mg, yield: 73.8%), LC-MS m/z: 641 [M+H] + ;
3)、(S)-4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100110
3) Synthesis of (S)-4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100110
将(S)-4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(700mg，1.09mmol)和环丙基三氟硼酸钾(243mg，1.64mmol)的加入到盛有预搅拌的Pd(dppf)Cl2(80mg，0.11mmol)和碳酸铯(1069mg，3.28mmol)的1，4-二氧六环(8mL)溶液的微波瓶中。将反应容器密封并在微波加热110℃加热2小时。将所得混合物加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用保护食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(S)-4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(600mg，收率：85％)，LC-MS m/z：647[M+H]+； (S)-4-((tert-Butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (700 mg, 1.09 mmol) and potassium cyclopropyltrifluoroborate (243 mg, 1.64 mmol) were added to a microwave vial containing a pre-stirred solution of Pd(dppf)Cl 2 (80 mg, 0.11 mmol) and cesium carbonate (1069 mg, 3.28 mmol) in 1,4-dioxane (8 mL). The reaction vessel was sealed and heated in a microwave at 110°C for 2 hours. The resulting mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (1×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid = 25%-65% elution) to give (S)-4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (600 mg, yield: 85%), LC-MS m/z: 647 [M+H] + ;
4)、(S)-4-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100111
4) Synthesis of (S)-4-((tert-butyloxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100111
将溶有(S)-4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(600mg，0.93mmol)和氢氧化钯(520mg，3.72mmol)的甲醇(6mL)溶液，氢气保护下，室温搅拌2小时。将混合反应液过滤，滤饼用甲醇洗涤。收集滤液减压浓缩得到(S)-4-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯(500mg，粗品)，LC-MS m/z：513[M+H]+；A solution of (S)-4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (600 mg, 0.93 mmol) and palladium hydroxide (520 mg, 3.72 mmol) in methanol (6 mL) was stirred at room temperature for 2 hours under hydrogen protection. The mixed reaction liquid was filtered and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to give (S)-4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (500 mg, crude product), LC-MS m/z: 513[M+H] + ;
5)、4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100112
5) Synthesis of 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100112
室温条件下，向溶有(S)-4-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯(100mg，0.20mmol)和(E)-4-(二甲基氨基)丁-2-烯酸(30mg，0.23mmol)的乙腈(2mL)溶液中加入1-甲基咪唑(110mg，0.39mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(220mg，0.78mmol)。所得混合反应液室温搅拌2小时。冷却后，将所得混合反应液加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(60mg，收率：49％)，LC-MS m/z：624[M+H]+；At room temperature, 1-methylimidazole (110 mg, 0.39 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (220 mg, 0.78 mmol) were added to a solution of (S)-4-((tert-butyloxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.20 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (30 mg, 0.23 mmol) in acetonitrile (2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid = 25%-65% elution) to give (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (60 mg, yield: 49%), LC-MS m/z: 624 [M+H] + ;
6)、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100113
6) Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100113
将溶有4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(60mg，0.10mmol)的二氯甲烷(2mL)溶液和2，2，2-三氟乙酸(0.5mL)室温搅拌2小时。所得混合反应液加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(S)-4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7- 基)氨基)哌啶-1-羧酸(S，E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：39.7％)，LC-MS m/z：524[M+H]+；A solution of (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) were stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid = 25%-65% elution) to give (S)-4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidine-7-yl)- (S,E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)piperidine-1-carboxylate (20 mg, yield: 39.7%), LC-MS m/z: 524 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.83(s，1H)，6.85-6.66(m，2H)，5.98(s，1H)，5.35-5.29(m，1H)，4.13(s，2H)，3.99-3.62(m，7H)，3.29-3.08(m，3H)，2.86(d，J＝1.2Hz，6H)，2.32-2.29(m，1H)，2.20(m，1H)，2.11-2.04(m，3H)，1.66-1.60(m，2H)，1.34(d，J＝6.8Hz，6H)，1.12-1.00(m，4H). 1 H NMR (400MHz, MeOD): δ7.83 (s, 1H), 6.85-6.66 (m, 2H), 5.98 (s, 1H), 5.35-5.29 (m, 1H), 4.13 (s, 2H), 3.99-3.62(m, 7H), 3.29-3.08(m, 3H), 2.86(d, J=1.2Hz, 6H), 2.32-2.29(m, 1H), 2.20(m, 1H), 2.11-2.04( m, 3H), 1.66-1.60 (m, 2H), 1.34 (d, J=6.8Hz, 6H), 1.12-1.00 (m, 4H).
实施例13、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物13)的合成：Example 13. Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 13):
1)、(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100114
1) Synthesis of tert-butyl (R)-3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100114
将溶有(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(0.087g，0.52mmol)，三乙胺(0.177g，1.75mmol)和2-(7-氮杂-1H-苯并三唑-1-基)-1，1，3，3-四甲基铀六氟磷酸盐(0.20g，0.52mmol)的二氯甲烷(3mL)溶液0℃搅拌10分钟，然后将(R)-3-((3-异丙基-7-((1-(((((R)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(198mg，0.35mmol)加入上述混合反应液中。所得混合反应液室温搅拌3小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈纯水＝5～95％洗脱)纯化得到(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(140mg，收率：59％)，LC-MS m/z：683[M+H]+；A solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.087 g, 0.52 mmol), triethylamine (0.177 g, 1.75 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluranium hexafluorophosphate (0.20 g, 0.52 mmol) in dichloromethane (3 mL) was stirred at 0°C for 10 minutes, and then (R)-3-((3-isopropyl-7-((1-(((((R)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidin -1-carboxylic acid tert-butyl ester (198 mg, 0.35 mmol) was added to the above mixed reaction liquid. The obtained mixed reaction liquid was stirred at room temperature for 3 hours. The mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile pure water = 5-95% elution) to give (R)-3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (140 mg, yield: 59%), LC-MS m/z: 683[M+H] + ;
2)、4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100115
2) Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100115
将溶有(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(140mg，0.21mol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液，室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过制备HPLC纯化得到4-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(62mg，收率：52％)，LC-MS m/z：583[M+H]+；(R)-tert-butyl 3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (140 mg, 0.21 mol) and 2,2,2-trifluoroacetic acid (1 mL) were dissolved in dichloromethane (3 mL). ) solution and stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (62 mg, yield: 52%), LC-MS m/z: 583 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.77(s，1H)，6.77(s，1H)，6.72(t，J＝12.0Hz，1H)，5.65(s，1H)，5.50(s，1H)，5.29(d，J＝12.0Hz，1H)，4.10(s，2H)，3.95-3.91(m，2H)，3.79-3.72(m，4H)，3.65-3.46(m，2H)，3.47-3.41(m，1H)，3.33(s，1H)，3.18(s，1H)，3.10-3.06(m，4H)，2.88(s，6H)，2.31-2.22(m，1H)，2.21-2.01(m，6H)，1.89-1.83(m，1H)，1.64-1.58(m，2H)，1.32(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.77 (s, 1H), 6.77 (s, 1H), 6.72 (t, J = 12.0Hz, 1H), 5.65 (s, 1H), 5.50 (s , 1H), 5.29 (d, J=12.0Hz, 1H), 4.10 (s, 2H), 3.95-3.91 (m, 2H), 3.79-3.72 (m, 4H), 3.65-3.46 (m, 2H), 3 .47-3.41(m, 1H), 3.33(s, 1H), 3.18(s, 1H), 3.10-3.06(m, 4H), 2.88(s, 6H), 2.31-2.22(m, 1H), 2.21 -2.01(m, 6H), 1.89-1.83(m, 1H), 1.64-1.58(m, 2H), 1.32(d, J=8.0Hz, 6H).
实施例14、4-((3-乙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物14)的合成：Example 14. Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-ethyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 14):
1)、4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100116
1) Synthesis of tert-butyl 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100116
室温条件下，向溶有5，7-二氯-3-乙基吡唑并[1，5-a]嘧啶(500mg，2.33mmol)和4-氨基哌啶-1-羧酸叔丁酯(560mg，2.79mmol)的异丙醇(7mL)溶液，加入N，N-二异丙基乙胺(900mg，6.98mmol)。所得混合反应液加热70℃搅拌2小时。冷却后，将所得混合反应液加水稀释并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过用C18柱色谱(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(560mg，收率：63.5％)，LC-MS m/z：380[M+H]+；At room temperature, N,N-diisopropylethylamine (900 mg, 6.98 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (500 mg, 2.33 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (560 mg, 2.79 mmol) in isopropanol (7 mL). The resulting mixed reaction solution was heated at 70°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:purified water containing 0.1% formic acid=25%-65% elution) to give tert-butyl 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (560 mg, yield: 63.5%), LC-MS m/z: 380 [M+H] + ;
2)、5-氯-3-乙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100117
2) Synthesis of 5-chloro-3-ethyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100117
室温条件下，向溶有4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(560mg，1.48mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌1小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过用C18柱色谱法()含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-氯-3-乙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(350mg，收率：84.9％)，LC-MS m/z：280[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (560 mg, 1.48 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-chloro-3-ethyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (350 mg, yield: 84.9%), LC-MS m/z: 280 [M+H] + ;
3)4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100118
3) Synthesis of 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100118
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸苄基酯(333mg，1.51mmol)和三乙胺(380mg，3.76mmol)的四氢呋喃(2mL)溶液中，分批加入三光气(186mg，0.63mmol)。所得混合反应液在0℃搅拌30分钟。在室温条件下，将溶有5-氯-3-乙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(350mg，1.25mmol)加入上述混合反应液体系中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯At 0°C, triphosgene (186 mg, 0.63 mmol) was added in batches to a solution of 3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (333 mg, 1.51 mmol) and triethylamine (380 mg, 3.76 mmol) in tetrahydrofuran (2 mL). The resulting mixed reaction solution was stirred at 0°C for 30 minutes. At room temperature, 5-chloro-3-ethyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (350 mg, 1.25 mmol) was added to the above mixed reaction solution system. The resulting mixed reaction solution was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-((benzyloxy)carbonyl)pyrrolidin-3-yl 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
(200mg，收率：30.3％)，LC-MS m/z：527[M+H]+；(200 mg, yield: 30.3%), LC-MS m/z: 527 [M+H] + ;
4)、(R)-3-((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100119
4) Synthesis of tert-butyl (R)-3-((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100119
将三(二亚苄基丙酮)二钯(35mg，0.038mmol)和(R)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(42mg，0.076mmol)加入到除氧和预搅拌4-((5-氯-3-乙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-((苄氧基)羰基)吡咯烷-3-基酯(200mg，0.380mmol)，(R)-3-羟基哌啶-1-羧酸叔丁酯(92mg，0.46mmol)和碳酸铯(371mg，1.14mmol)的甲苯溶液(2mL)的微波管中。将微波管密封并在微波条件加热140℃搅拌2小时。所得混合反应液盐水/水(10mL，1∶1)稀释，并用乙醚(3×50mL)萃取。合并的有机相用盐水/水(4×10mL，1∶1)洗涤，干燥，减压浓缩。残余物通过C18柱色谱法(乙腈：含有0.1％甲酸的纯水＝25-95％洗脱)纯化得到(R)-3-((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(90mg，收率：34.3％)，LC-MS m/z：692[M+H]+；Tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (42 mg, 0.076 mmol) were added to a deoxygenated and pre-stirred toluene solution (2 mL) of 4-((5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-((benzyloxy)carbonyl)pyrrolidin-3-yl ester (200 mg, 0.380 mmol), (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (92 mg, 0.46 mmol) and cesium carbonate (371 mg, 1.14 mmol). The microwave tube was sealed and heated at 140° C. under microwave conditions for 2 hours. The resulting mixed reaction solution was diluted with brine/water (10 mL, 1:1) and extracted with ether (3×50 mL). The combined organic phase was washed with brine/water (4×10 mL, 1:1), dried, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid=25-95% elution) to give (R)-3-((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (90 mg, yield: 34.3%), LC-MS m/z: 692 [M+H] + ;
5)、(R)-3-((3-乙基-7-((1-(((((R)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100120
5) Synthesis of tert-butyl (R)-3-((3-ethyl-7-((1-(((((R)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100120
向溶有(R)-3-((7-((1-(((((R)-1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(90mg，0.130mmol)的甲醇(5mL)溶液中，加入钯碳(28mg)。所得混合反应液在氢气氛围下，室温搅拌过夜。将混合反应液过滤，滤饼用甲醇(3×20mL)洗涤。收集滤液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：558[M+H]+；Palladium on carbon (28 mg) was added to a solution of (R)-tert-butyl 3-((7-((1-(((((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (90 mg, 0.130 mmol) in methanol (5 mL). The resulting mixed reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. The mixed reaction solution was filtered and the filter cake was washed with methanol (3×20 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 558 [M+H] + ;
6)、(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100121
6) Synthesis of tert-butyl (R)-3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100121
室温条件下，向溶有(R)-3-((3-乙基-7-((1-(((((R)-吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(60mg，0.11mmol)，(E)-4-(二甲氨基)丁-2-烯酸(17mg，0.13mmol)的二氯甲烷(2mL)溶液中，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(49.1mg，0.13mmol)和N，N-二异丙基乙胺(42mg，0.323mmol)。所得混合反应液室温搅拌2小时。将混合反应液加水稀释，并用乙酸乙酯(3×80mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸干燥，过滤、减压浓缩。残余物通过用C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯 烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(50mg，收率：69.5％)，LC-MS m/z：669[M+H]+；To a solution of (R)-tert-butyl 3-((3-ethyl-7-((1-(((((R)-pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (60 mg, 0.11 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (17 mg, 0.13 mmol) in dichloromethane (2 mL) at room temperature were added 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (49.1 mg, 0.13 mmol) and N,N-diisopropylethylamine (42 mg, 0.323 mmol). The resulting mixed reaction liquid was stirred at room temperature for 2 hours. The mixed reaction liquid was diluted with water and extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrole tert-butyl ester (50 mg, yield: 69.5%), LC-MS m/z: 669 [M+H] + ;
7)、4-((3-乙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100122
7) Synthesis of (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-((3-ethyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100122
向溶有(R)-3-((7-((1-(((((R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)氨基)-3-乙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(50mg，0.075mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.3mL)。所得混合反应液室温搅拌2小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×30mL)萃取。合并的有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过用C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到4-((3-乙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(R)-1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(15mg，收率：35.3％)，LC-MS m/z：569[M+H]+；To a solution of (R)-tert-butyl 3-((7-((1-(((((R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (50 mg, 0.075 mmol) in dichloromethane (1.2 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 4-((3-ethyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (R)-1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (15 mg, yield: 35.3%), LC-MS m/z: 569 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，6.84-6.72(m，2H)，5.54(s，1H)，5.34-5.30(m，1H)，4.13-4.11(m，2H)，3.99-3.97(m，2H)，3.83-3.73(m，4H)，3.62-3.53(m，2H)，3.47-3.43(m，1H)，3.2-3.09(m，4H)，2.93(s，6H)，2.69-2.63(m，2H)，2.32-2.29(m，1H)，2.20-2.02(m，6H)，1.89-1.85(m，1H)，1.64-1.62(m，2H)，1.29-1.25(m，3H). 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 6.84-6.72 (m, 2H), 5.54 (s, 1H), 5.34-5.30 (m, 1H), 4.13-4.11 (m , 2H), 3.99-3.97(m, 2H), 3.83-3.73(m, 4H), 3.62-3.53(m, 2H) , 3.47-3.43(m, 1H), 3.2-3.09(m, 4H), 2.93(s, 6H), 2.69-2.63(m, 2H), 2.32-2.29(m, 1H), 2.20-2.02(m, 6H), 1.89-1.85(m, 1H), 1.64-1.62(m, 2H), 1.29-1.25(m, 3H).
实施例15、8-((5-((((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物15)的合成：Example 15. Synthesis of 8-((5-((((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 15):
1)、8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100123
1) Synthesis of 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100123
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(99mg，0.53mmol)和三乙胺(106mg，1.05mmol)的二氯甲烷(3mL)溶液中，分批加入双(三氯甲基)碳酸酯(52mg，0.175mmol)0℃，0℃搅拌0.5小时。在0℃条件下，将(5R)-5-((7-((3-氮杂双环[3.2.1]辛-8-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)-2，2-二甲基哌啶-1-羧酸苄基酯(285mg，0.53mmol)加入到上述混合反应液中。所得混合反应液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH4HCO3＝70-95％洗脱)纯化得到8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(312mg，收率：79％)，LC-MS m/z：760[M+H]+；At 0°C, bis(trichloromethyl)carbonate (52 mg, 0.175 mmol) was added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (99 mg, 0.53 mmol) and triethylamine (106 mg, 1.05 mmol) in dichloromethane (3 mL) and stirred at 0°C for 0.5 hours. At 0°C, (5R)-5-((7-((3-azabicyclo[3.2.1]oct-8-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid benzyl ester (285 mg, 0.53 mmol) was added to the mixed reaction solution. The mixed reaction solution was stirred at room temperature for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 4 HCO 3 = 70-95% elution) to give 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (312 mg, yield: 79%), LC-MS m/z: 760 [M+H] + ;
2)、8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100124
2) Synthesis of 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100124
将溶有8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(312mg，0.44mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌2小时。所得混合反应液减压浓缩。残余物通过C18柱纯色谱(乙腈：含有0.1％甲酸的纯水＝70-90％洗脱)纯化得到8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(187mg，收率：69％)，LC-MS m/z：660[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (312 mg, 0.44 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 70-90% elution) to give 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (187 mg, yield: 69%), LC-MS m/z: 660 [M+H] + ;
3)、8-((5-((((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100125
3) Synthesis of 8-((5-((((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100125
将溶有8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(120mg，0.18mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(113mg，0.40mmol)和1-甲基-1H-咪唑(59mg，0.72mmol)的N，N-二甲基甲酰胺(3mL)溶液搅拌16小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％NH4HCO3＝50-70％洗脱)纯化得到8-((5-((((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(79mg，收率：59％)，LC-MS m/z：732[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (120 mg, 0.18 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (113 mg, 0.40 mmol) and 1-methyl-1H-imidazole (59 mg, 0.72 mmol) in N,N-dimethylformamide (3 mL) was stirred for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 4 HCO 3 = 50-70% elution) to give 8-((5-((((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (79 mg, yield: 59%), LC-MS m/z: 732 [M+H] + ;
4)、8-((5-((((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100126
4) Synthesis of 8-((5-((((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100126
将溶有8-((5-((((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(79mg，0.11mmol)的2，2，2-三氟乙酸(1mL)溶液，加热50℃搅拌3小时。将所得混合反应液减压浓缩。残余物通过过C18柱色谱(乙腈：含有0.1％NH4HCO3的纯水＝30-70％洗脱)纯化得到(20mg，收率：31％)，LC-MS m/z：598[M+H]+；A solution of 8-((5-((((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (79 mg, 0.11 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was heated at 50°C and stirred for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 30-70% elution) to obtain (20 mg, yield: 31%), LC-MS m/z: 598 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.79(s，1H)，5.62(s，1H)，5.46(d，J＝47.2Hz，1H)，5.28-5.20(m，2H)，5.14(s，1H)，4.72-4.52(m，1H)，3.94-3.88(m，1H)，3.86-3.55(m，7H)，3.39(d，J＝13.0Hz，1H)，3.17-3.04(m，2H)，2.98(s，1H)，2.49-2.41(m，2H)，2.21-2.15(m，2H)，2.10-2.01(m，1H)，1.96-1.89(m，3H)，1.71-1.63(m，3H)，1.54-1.47(m， 1H)，1.32(d，J＝8.0Hz，6H)，1.19(s，6H).1H NMR (400MHz, MeOD): δ7.79 (s, 1H), 5.62 (s, 1H), 5.46 (d, J=47.2Hz, 1H), 5.28-5.20 (m, 2H), 5.14 (s, 1H) ), 4.72-4.52(m, 1H), 3.94-3.88(m, 1H), 3.86-3.55(m, 7H), 3. 39(d, J=13.0Hz, 1H), 3.17-3.04(m, 2H), 2.98(s, 1H), 2.49-2.41(m, 2H), 2.21-2.15(m, 2H), 2.10-2.01( m, 1H), 1.96-1.89 (m, 3H), 1.71-1.63 (m, 3H), 1.54-1.47 (m, 1H), 1.32(d, J=8.0Hz, 6H), 1.19(s, 6H).
实施例16、8-((5-(((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂二环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物16)的合成：Example 16, Synthesis of 8-((5-(((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compound 16):
1)、8-((5-(((R)-1-(苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100127
1) Synthesis of 8-((5-(((R)-1-(benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100127
将溶有8-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂二环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(76mg，0.12mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(65mg，0.23mmol)和1-甲基-1H-咪唑(38mg，0.46mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌16小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤。减压浓缩。残余物通过硅胶柱色谱法(甲醇∶二氯甲烷＝0-10％洗脱)纯化得到8-((5-(((R)-1-(苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(72mg，收率：81％)，LC-MS m/z：771[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (76 mg, 0.12 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (65 mg, 0.23 mmol) and 1-methyl-1H-imidazole (38 mg, 0.46 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give 8-((5-(((R)-1-(benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (72 mg, yield: 81%), LC-MS m/z: 771 [M+H] + ;
2)、8-((5-(((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂二环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100128
2) Synthesis of 8-((5-(((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100128
将溶有8-((5-(((R)-1-(苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(72mg，0.09mmol)的2，2，2-三氟乙酸(1mL)溶液加热50℃搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝30-70％洗脱)纯化得到(10mg，收率：17％)，LC-MS m/z：637[M+H]+；A solution of 8-((5-(((R)-1-(benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (72 mg, 0.09 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was heated at 50° C. and stirred for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 30-70% elution) to obtain (10 mg, yield: 17%), LC-MS m/z: 637[M+H] + ;
1H NMR(400MHz，MeOD)：δ7.78(s，1H)，6.86-6.80(m，1H)，6.46-6.40(m，1H)，5.61(s，1H)，5.31-5.26(m，1H)，5.17-5.12(m，1H)，3.89-3.82(m，1H)，3.79-3.64(m，6H)，3.59-3.50(m，1H)，3.40-3.32(m，1H)，3.20-3.13(m，3H)，3.14-3.04(m，1H)，3.01-2.92(m，1H)，2.48-2.42(m，2H)，2.27(s，6H)，2.13(s，1H)，2.09-2.01(m，1H)，1.97-1.91(m，3H)，1.74-1.64(m，3H)，1.55-1.45(m，1H)，1.32(d，J＝8.0Hz，6H)，1.19(s，6H). 1 H NMR (400MHz, MeOD): δ7.78 (s, 1H), 6.86-6.80 (m, 1H), 6.46-6.40 (m, 1H), 5.61 (s, 1H), 5.31-5.26 (m, 1H) ), 5.17-5.12(m, 1H), 3.89-3.82(m, 1H), 3.79-3.64(m, 6H), 3.59-3.50(m, 1H), 3.40-3.32(m, 1H), 3.20-3 .13(m, 3H), 3.14-3.04(m, 1H), 3.01-2.92(m, 1H), 2.48-2.42(m, 2H), 2.27(s, 6H), 2.13(s, 1H), 2.09 -2.01(m, 1H), 1.97-1.91(m, 3H), 1.74-1.64(m, 3H), 1.55-1.45(m, 1H), 1.32(d, J=8.0Hz, 6H), 1.19(s , 6H).
实施例17、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物17)的合成：Example 17, Synthesis of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 17):
1)、3-(((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100129
1) Synthesis of tert-butyl 3-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100129
将溶有5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(1000mg，4.37mmol)，3-(氨基甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1260mg，5.24mmol)和N，N-二异丙基乙胺(1.69g，13.11mmol)的异丙醇(15mL)溶液加热70℃搅拌过夜。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-25％洗脱)纯化得到3-(((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.25g，收率：66％)，LC-MS m/z：434[M+H]+；A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (1000 mg, 4.37 mmol), tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1260 mg, 5.24 mmol) and N,N-diisopropylethylamine (1.69 g, 13.11 mmol) in isopropanol (15 mL) was heated to 70° C. and stirred overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give tert-butyl 3-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.25 g, yield: 66%), LC-MS m/z: 434 [M+H] + ;
2)、3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100130
2) Synthesis of tert-butyl 3-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100130
将溶3-(((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.25g，2.89mmol)，二碳酸二叔丁基酯(944mg，4.33mmol)，N，N-二异丙基乙胺(1117mg，8.66mmol)和4-二甲氨基吡啶(35mg，0.29mmol)的二氯甲烷(15mL)溶液室温搅拌16小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-20％洗脱)纯化得到3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.3g，收率：84.5％)，LC-MS m/z：534[M+H]+；A solution of tert-butyl 3-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.25 g, 2.89 mmol), di-tert-butyl dicarbonate (944 mg, 4.33 mmol), N,N-diisopropylethylamine (1117 mg, 8.66 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol) in dichloromethane (15 mL) was stirred at room temperature for 16 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20% elution) to give tert-butyl 3-(((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.3 g, yield: 84.5%), LC-MS m/z: 534 [M+H] + ;
3)、3-(((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100131
3) Synthesis of tert-butyl 3-(((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100131
将溶有3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(500mg，0.94mmol)，四氢-2H-吡喃-4-胺(284mg，2.81mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(79mg，0.09mmol)和碳酸铯(917mg，2.81mmol)的1，4-二氧六环(2.0mL)溶液氩气保护下，加热90℃搅拌16小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(550mg，收率：98.0％)，LC-MS m/z：599[M+H]+；A solution of tert-butyl 3-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.94 mmol), tetrahydro-2H-pyran-4-amine (284 mg, 2.81 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (79 mg, 0.09 mmol) and cesium carbonate (917 mg, 2.81 mmol) in 1,4-dioxane (2.0 mL) was heated at 90° C. and stirred for 16 hours under argon protection. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give tert-butyl 3-(((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (550 mg, yield: 98.0%), LC-MS m/z: 599 [M+H] + ;
4)、N7-(((8-氮杂双环[3.2.1]辛-3-基)甲基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺的合成
Figure PCTCN2024077920-ftappb-I100132
4) Synthesis of N 7 -(((8-azabicyclo[3.2.1]oct-3-yl)methyl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine
Figure PCTCN2024077920-ftappb-I100132
将溶有3-(((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(550mg，0.92mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅32小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：399[M+H]+；A solution of tert-butyl 3-(((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.92 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 32 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 399 [M+H] + ;
5)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100133
5) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100133
将溶有N7-((8-氮杂双环[3.2.1]辛-3-基)甲基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(360mg，0.90mmol)，三乙胺(91mg，0.90mmol)和N，N′-羰基二(1，2，4-三氮唑)(297mg，1.81mmol)的N，N-二甲基甲酰胺(5mL)溶液氩气保护下，室温搅拌1小时。然后将3-羟基氮杂环丁烷-1-羧酸叔丁酯(469mg，2.71mmol)和叔丁醇钾(3mL，1M的四氢呋喃溶液)加入到上述混合反应液中，加热50℃搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(300mg，收率：55.6％)，LC-MS m/z：598[M+H]+；A solution of N 7 -((8-azabicyclo[3.2.1]octan-3-yl)methyl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (360 mg, 0.90 mmol), triethylamine (91 mg, 0.90 mmol) and N,N′-carbonylbis(1,2,4-triazole) (297 mg, 1.81 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour under argon protection. Then tert-butyl 3-hydroxyazetidine-1-carboxylate (469 mg, 2.71 mmol) and potassium tert-butoxide (3 mL, 1 M tetrahydrofuran solution) were added to the above mixed reaction solution, heated at 50° C. and stirred for 16 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, yield: 55.6%), LC-MS m/z: 598 [M+H] + ;
6)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100134
6) Synthesis of azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100134
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(300mg，0.50mmol)的二氯甲烷(5mL)和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌2小时。所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：498[M+H]+；A solution of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (300 mg, 0.50 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 498[M+H] + ;
7)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100135
7) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100135
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(100mg，0.20mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(39mg，0.30mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐(115mg，0.30mmol)和N，N-二异丙基乙胺(78mg，0.60mmol)的N，N-二甲基甲酰胺(5mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(40mg，收率：32.8％)，LC-MS m/z：609[M+H]+；A solution of azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.20 mmol), (E)-4-(dimethylamino)but-2-enoic acid (39 mg, 0.30 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (40 mg, yield: 32.8%), LC-MS m/z: 609 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.63(s，1H)，6.79-6.70(m，1H)，6.41(d，J＝15.2Hz，1H)，5.20(s，1H)，4.63(s，1H)，4.37(s，2H)，4.28(s，2H)，4.11-4.01(m，2H)，3.97(d，J＝11.6Hz，2H)，3.76(d，J＝6.8Hz，2H)，3.60-3.51(m，2H)，3.17(d，J＝6.4Hz，2H)，3.10-3.03(m，1H)，2.75(s，6H)，2.42-2.30(m，1H)，2.07-1.92(m，5H)，1.77(s，4H)，1.60-1.43(m，4H)，1.29(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD) δ7.63 (s, 1H), 6.79-6.70 (m, 1H), 6.41 (d, J=15.2Hz, 1H), 5.20 (s, 1H), 4.63 (s, 1H ), 4.37 (s, 2H), 4.28 (s, 2H), 4.11-4.01 (m, 2H), 3.97 (d, J=11.6Hz, 2H), 3.76 (d, J＝6.8Hz, 2H), 3.60-3.51(m, 2H), 3.17(d, J＝6.4Hz, 2H), 3.10-3.03(m, 1H), 2.75(s, 6H), 2.42-2.30(m , 1H), 2.07-1.92 (m, 5H), 1.77 (s, 4H), 1.60-1.43 (m, 4H), 1.29 (d, J=6.8Hz, 6H).
实施例18、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物6)的合成：Example 18, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 6):
1)、3-((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)胺基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100136
1) Synthesis of tert-butyl 3-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100136
将溶有3-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.0g，1.9mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(160mg，0.19mmol)、四氢-2H-吡喃-4-胺(288mg，2.85mmol)和碳酸铯(1.86g，5.7mmol)的1，4-二氧六环(10mL)溶液氩气保护下，加热100℃搅拌过夜。冷却后，将混合反应液减压浓缩。残余物通过C18柱色谱法(已经：含有0.1％甲酸的纯水＝＝5-95％洗脱)纯化得到3-((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)胺基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(800mg，收率：71.0％)，LC-MS m/z：585[M+H]+；A solution of tert-butyl 3-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.9 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (160 mg, 0.19 mmol), tetrahydro-2H-pyran-4-amine (288 mg, 2.85 mmol) and cesium carbonate (1.86 g, 5.7 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. and stirred overnight under argon protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (pure water containing 0.1% formic acid == 5-95% elution) to give tert-butyl 3-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, yield: 71.0%), LC-MS m/z: 585 [M+H] + ;
2)、N7-(8-氮杂双环[3.2.1]辛-3-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺的合成
Figure PCTCN2024077920-ftappb-I100137
2) Synthesis of N 7 -(8-azabicyclo[3.2.1]oct-3-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine
Figure PCTCN2024077920-ftappb-I100137
将溶有3-((叔丁氧基羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)胺基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(800mg，1.37mmol)的二氯甲烷(9mL)和2，2，2-三氟乙酸(3mL)溶液室温搅拌2小时。所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到N7-(8-氮杂双环[3.2.1]辛-3-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(500mg，收率：95％)，LC-MS m/z：385[M+H]+；A solution of tert-butyl 3-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.37 mmol) in dichloromethane (9 mL) and 2,2,2-trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give N 7 -(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (500 mg, yield: 95%), LC-MS m/z: 385 [M+H] + ;
3)、3-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100138
3) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl 3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100138
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(337mg，1.95mmol)，三乙胺(132mg，1.30mmol)和二(1H-1，2，4-三唑-1-基)甲酮(221mg，1.35mmol)的N，N-二甲甲酰胺(5mL)溶液，氩气保护下，搅拌1小时。然后将N7-(8-氮杂双环[3.2.1]辛-3-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(500mg，1.30mmol)加入到上述混合反应液中。所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(500mg，收率：65.9％)，LC-MS m/z：584[M+H]+；A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (337 mg, 1.95 mmol), triethylamine (132 mg, 1.30 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (221 mg, 1.35 mmol) in N,N-dimethylformamide (5 mL) was stirred for 1 hour under argon protection. Then N 7 -(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (500 mg, 1.30 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, yield: 65.9%), LC-MS m/z: 584 [M+H] + ;
4)、3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100139
4) Synthesis of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100139
将3-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(500mg，0.86mmol)的2，2，2-三氟乙酸(2.0mL)和二氯甲烷(6mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：484[M+H]+；A solution of 3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (500 mg, 0.86 mmol) in 2,2,2-trifluoroacetic acid (2.0 mL) and dichloromethane (6 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give a crude product, which was used directly in the next step without further purification. LC-MS m/z: 484 [M+H] + ;
5)、3-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸(E)-1-(4-(二甲基氨基)丁-2-烯基)氮杂环丁烷-3-基酯异构体(化合物18A和18B)的合成
Figure PCTCN2024077920-ftappb-I100140
5) Synthesis of 3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester isomers (Compounds 18A and 18B)
Figure PCTCN2024077920-ftappb-I100140
将溶有3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(100mg，0.21mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(51mg，0.31mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲基六氟磷酸盐(120mg，0.31mmol)和N，N二异丙基乙胺(136mg，1.05mol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到两个异构体；A solution of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (100 mg, 0.21 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (51 mg, 0.31 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylureido hexafluorophosphate (120 mg, 0.31 mmol) and N,N-diisopropylethylamine (136 mg, 1.05 mol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain two isomers;
BIOT-002-9043(化合物18A)：峰：1.667min；(38mg，收率：30.8％)，LC-MS m/z：595[M+H]+；BIOT-002-9043 (Compound 18A): Peak: 1.667 min; (38 mg, yield: 30.8%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.58(s，1H)，6.84-6.75(m，1H)，6.19(d，J＝16.0Hz，1H)，5.39(s，1H)，5.25-5.20(m，1H)，4.67-4.59(m，1H)，4.46-4.22(m，4H)，4.13-3.94(m，5H)，3.60-3.52(m，2H)，3.16(dd，J＝4.0，4.0Hz，2H)，3.08-3.01(m，1H)，2.27(s，6H)，2.18-2.10(m，3H)，2.08-2.00(m，3H)，1.98-1.90(m，2H)，1.74(t，J＝12.0Hz，2H)，1.59-1.48(m，2H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD) δ7.58 (s, 1H), 6.84-6.75 (m, 1H), 6.19 (d, J=16.0Hz, 1H), 5.39 (s, 1H), 5.25-5.20 (m , 1H), 4.67-4.59(m, 1H), 4.46-4.22(m, 4H), 4.13-3.94(m, 5H), 3.60-3.52(m, 2H), 3 .16(dd, J=4.0, 4.0Hz, 2H), 3.08-3.01(m, 1H), 2.27(s, 6H), 2.18-2.10(m, 3H), 2.08-2.00(m, 3H), 1.98 -1.90 (m, 2H), 1.74 (t, J=12.0Hz, 2H), 1.59-1.48 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H).
BIOT-002-90912(化合物18B)：峰：1.725min；(1R，3r，5S)-3-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸(E)-1-(4-(二甲基氨基)丁-2-烯基)氮杂环丁烷-3-基酯(20mg，收率：16.2％)，LC-MS m/z：595[M+H]+；BIOT-002-90912 (Compound 18B): Peak: 1.725 min; (1R, 3r, 5S)-3-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester (20 mg, yield: 16.2%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.63(d，J＝4.0Hz，1H)，6.86-6.76(m，1H)，6.20(d，J＝20.0Hz，1H)，5.24-5.21(m，1H)，5.20-5.18(m，1H)，4.67-4.59(m，1H)，4.42-4.26(m，4H)，4.19-4.05(m，2H)，4.04-3.95(m，3H)，3.89-3.84(m，1H)，3.56(t，J＝16.0Hz，2H)，3.16(d，J＝8.0Hz，2H)，3.09-3.03(m，1H)，2.35-2.30(m，2H)，2.28(d，J＝4.0Hz，6H)，2.19-2.09(m，4H)，2.06-1.98(m，4H)，1.60-1.49(m，2H)，1.31(d，J＝4.0Hz，3H)，1.29(d，J＝4.0Hz，3H). 1 H NMR (400MHz, MeOD) δ7.63 (d, J=4.0Hz, 1H), 6.86-6.76 (m, 1H), 6.20 (d, J=20.0Hz, 1H), 5.24-5.21 (m, 1H ), 5.20-5.18(m, 1H), 4.67-4.59(m, 1H), 4.42-4.26(m, 4H), 4.19-4.05(m, 2H), 4.04-3.95(m, 3H), 3.89-3.84 (m, 1H), 3.56 (t, J=16.0Hz, 2H), 3.16 (d, J=8.0Hz, 2H), 3.09-3.03 (m, 1H), 2.35-2.30 (m, 2H), 2.28 (d, J =4.0Hz, 6H), 2.19-2.09(m, 4H), 2.06-1.98(m, 4H), 1.60-1.49(m, 2H), 1.31(d, J=4.0Hz, 3H), 1.29(d, J=4.0Hz, 3H).
实施例19、1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基-3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)胺基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯异构体(化合物19A和19B)的合成：Example 19, Synthesis of 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl-3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate isomers (Compounds 19A and 19B):
1)、3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸-1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100141
1) Synthesis of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100141
在0℃和氩气保护下，向溶有3-羟基吡咯烷-1-甲酸叔丁酯(175mg，0.94mmol)和三乙胺(118mg，1.17mmol)的N，N-二甲基甲酰胺(4mL)溶液中，滴加二(1H-1，2，4-三唑-1-基)甲酮(192mg，1.17mmol)的N，N-二甲甲酰胺(1mL)溶液。将所得混合反应液室温搅拌1小时。然后将N7-(8-氮杂双环[3.2.1]辛-3-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(450mg，1.17mmol)的N，N-二甲基甲酰胺(1mL)溶液滴加到上述混合反应液中。添加结束后，所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(420mg，收率：75％)，LC-MS m/z：598[M+H]+；To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (175 mg, 0.94 mmol) and triethylamine (118 mg, 1.17 mmol) in N,N-dimethylformamide (4 mL) was added dropwise a solution of di(1H-1,2,4-triazol-1-yl)methanone (192 mg, 1.17 mmol) in N,N-dimethylformamide (1 mL) at 0°C under argon protection. The resulting mixed reaction liquid was stirred at room temperature for 1 hour. Then a solution of N 7 -(8-azabicyclo[3.2.1]octan-3-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (450 mg, 1.17 mmol) in N,N-dimethylformamide (1 mL) was added dropwise to the above mixed reaction liquid. After the addition was completed, the obtained mixed reaction liquid was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (420 mg, yield: 75%), LC-MS m/z: 598 [M+H] + ;
2)、3-((3-异丙基-5-(四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷 -8-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100142
2), 3-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane Synthesis of 8-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100142
将溶有3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(420mg，0.7mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)溶有室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-((3-异丙基-5-(四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(300mg，86.0％)，LC-MS m/z：498[M+H]+；A solution of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (420 mg, 0.7 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 3-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (300 mg, 86.0%), LC-MS m/z: 498 [M+H] + ;
3)、1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基-3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)胺基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯异构体(化合物19A和19B)的合成
Figure PCTCN2024077920-ftappb-I100143
3) Synthesis of 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl-3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate isomers (Compounds 19A and 19B)
Figure PCTCN2024077920-ftappb-I100143
将溶有3-((3-异丙基-5-(四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(300mg，0.60mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(93mg，0.72mmol)，1-甲基-1H-咪唑(198mg，2.42mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(339mg，1.21mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将混合反应液过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到两个异构体：A solution of 3-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (300 mg, 0.60 mmol), (E)-4-(dimethylamino)but-2-enoic acid (93 mg, 0.72 mmol), 1-methyl-1H-imidazole (198 mg, 2.42 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (339 mg, 1.21 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain two isomers:
BIOT-002-9046(化合物19A)(15mg，收率：4％)：峰1：1.030；LC-MS m/z：609[M+H]+；BIOT-002-9046 (Compound 19A) (15 mg, yield: 4%): Peak 1: 1.030; LC-MS m/z: 609 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.58(s，1H)，6.87-6.75(m，1H)，6.52-6.39(m，1H)，5.33(d，J＝36.0Hz，2H)，4.33(s，2H)，4.11(t，J＝10.5Hz，1H)，3.97(d，J＝11.5Hz，3H)，3.77(dd，J＝53.9，12.1Hz，4H)，3.56(t，J＝10.6Hz，3H)，3.16(d，J＝23.2Hz，2H)，3.05(dt，J＝13.6，6.8Hz，1H)，2.28(s，6H)，2.16-1.99(m，7H)，1.94-1.88(m，2H)，1.75(s，2H)，1.59-1.48(m，2H)，1.28(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ7.58 (s, 1H), 6.87-6.75 (m, 1H), 6.52-6.39 (m, 1H), 5.33 (d, J=36.0Hz, 2H), 4.33 (s , 2H), 4.11 (t, J=10.5Hz, 1H), 3.97 (d, J=11.5Hz, 3H), 3.77 (dd, J=53.9, 12.1Hz, 4H ), 3.56 (t, J=10.6Hz, 3H), 3.16 (d, J=23.2Hz, 2H), 3.05 (dt, J=13.6, 6.8Hz, 1H), 2.28 (s, 6H), 2.16-1.99 (m, 7H), 1.94-1.88 (m, 2H), 1.75 (s, 2H), 1.59-1.48 (m, 2H), 1.28 (d, J=6.9Hz, 6H).
BIOT-002-90216(化合物19B)(15mg，收率：4％)：峰2：1.066；LC-MS m/z：609[M+H]+；BIOT-002-90216 (Compound 19B) (15 mg, yield: 4%): Peak 2: 1.066; LC-MS m/z: 609 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.61(s，1H)，6.84(d，J＝15.0Hz，1H)，6.54-6.40(m，1H)，5.29(s，1H)，5.18(s，1H)，4.29(s，2H)，4.09(s，1H)，3.96(d，J＝11.6Hz，2H)，3.84(s，2H)，3.70(d，J＝17.9Hz，2H)，3.53(dd，J＝25.4，16.0Hz，3H)，3.21(d，J＝5.8Hz，2H)，3.11-3.01(m，1H)，2.31(s，8H)，2.13(d，J＝9.0Hz，5H)，2.00(dd，J＝26.7，13.6Hz，5H)，1.53(dd，J＝20.1，10.4Hz，2H)，1.29(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ7.61 (s, 1H), 6.84 (d, J=15.0Hz, 1H), 6.54-6.40 (m, 1H), 5.29 (s, 1H), 5.18 (s, 1H ), 4.29 (s, 2H), 4.09 (s, 1H), 3.96 (d, J = 11.6Hz, 2H), 3.84 (s, 2H), 3.70 (d, J = 17.9Hz, 2H), 3 .53 (dd, J=25.4, 16.0Hz, 3H), 3.21 (d, J=5.8Hz, 2H), 3.11-3.01 (m, 1H), 2.31 (s, 8H), 2.13 (d, J=9.0 Hz, 5H), 2.00 (dd, J=26.7, 13.6Hz, 5H), 1.53 (dd, J=20.1, 10.4Hz, 2H), 1.29 (d, J=6.9Hz, 6H).
实施例20、3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸-1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯及异构体(化合物20A和20B)的合成：
Figure PCTCN2024077920-ftappb-I100144
Example 20, Synthesis of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid-1-(2-fluoroacryloyl)azetidin-3-yl ester and isomers (Compounds 20A and 20B):
Figure PCTCN2024077920-ftappb-I100144
将溶有3-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(100mg，0.21mmol)，2-氟丙烯酸(28mg，0.31mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-六氟磷酸四甲基脲(120mg，0.31mmol)和N，N-二异丙基乙胺(136mg，1.05mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到两个异构体：A solution of 3-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid azetidin-3-yl ester (100 mg, 0.21 mmol), 2-fluoroacrylic acid (28 mg, 0.31 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) and N,N-diisopropylethylamine (136 mg, 1.05 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain two isomers:
BIOT-002-9047(化合物20A)(20mg，收率：17.4％)：峰1：1.682min；LC-MS m/z：556[M+H]+；BIOT-002-9047 (Compound 20A) (20 mg, yield: 17.4%): Peak 1: 1.682 min; LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.86(s，1H)，5.63-5.48(m，2H)，5.26-5.18(m，2H)，4.80-4.73(m，1H)，4.48-4.35(m，4H)，4.29-4.20(m，1H)，4.15-4.05(m，2H)，4.04-3.98(m，2H)，3.62-3.55(m，2H)，3.16-3.11(m，1H)，2.15-2.08(m，2H)，2.06-1.99(m，4H)，1.98-1.86(m，4H)，1.70-1.60(m，2H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD) δ7.86 (s, 1H), 5.63-5.48 (m, 2H), 5.26-5.18 (m, 2H), 4.80-4.73 (m, 1H), 4.48-4.35 (m, 4H), 4.29-4.20(m, 1H), 4.15-4.05(m, 2H), 4.04- 3.98(m, 2H), 3.62-3.55(m, 2H), 3.16-3.11(m, 1H), 2.15-2.08(m, 2H), 2.06-1.99(m, 4H), 1.98-1.86(m, 4H ), 1.70-1.60(m, 2H), 1.31(s, 3H), 1.29(s, 3H).
BIOT-002-90193(化合物20B)(20mg，收率：17.4％)：峰2：1.747min；LC-MS m/z：556[M+H]+；BIOT-002-90193 (Compound 20B) (20 mg, yield: 17.4%): Peak 2: 1.747 min; LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.91(s，1H)，5.63-5.49(m，1H)，5.40(s，1H)，5.26-5.19(m，2H)，4.80-4.73(m，1H)，4.48-4.39(m，3H)，4.37-4.31(m，1H)，4.13(s，1H)，4.08-3.97(m，4H)，3.61-3.53(m，2H)，3.17-3.09(m，1H)，2.40-2.32(m，2H)，2.21-2.12(m，2H)，2.09-1.98(m，6H)，1.71-1.60(m，2H)，1.32(s，3H)，1.31(s，3H). 1 H NMR (400MHz, MeOD) δ7.91 (s, 1H), 5.63-5.49 (m, 1H), 5.40 (s, 1H), 5.26-5.19 (m, 2H), 4.80-4.73 (m, 1H) ,4.48-4.39(m,3H),4.37-4.31(m,1H),4.13(s,1H),4. 08-3.97(m, 4H), 3.61-3.53(m, 2H), 3.17-3.09(m, 1H), 2.40-2.32(m, 2H), 2.21-2.12(m, 2H), 2.09-1.98(m , 6H), 1.71-1.60 (m, 2H), 1.32 (s, 3H), 1.31 (s, 3H).
实施例21、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物21)的合成：Example 21, Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 21):
1)、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100145
1) Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100145
将溶有3-羟基吡咯烷-1-羧酸叔丁酯(60mg，0.32mmol)，三乙胺(98mg，0.97mmol)和三光气(48mg，0.16mmol)的二氯甲烷(5mL)溶液0℃搅拌1小时。然后在0℃条件下，将N7-(3-氮杂双环[3.2.1]辛-8-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(124mg，0.32mmol)的二氯甲烷(2mL)溶液滴加上述混合反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(40mg，收率：20.8％)，LC-MS m/z：598[M+H]+；A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (60 mg, 0.32 mmol), triethylamine (98 mg, 0.97 mmol) and triphosgene (48 mg, 0.16 mmol) in dichloromethane (5 mL) was stirred at 0°C for 1 hour. Then, a solution of N 7 -(3-azabicyclo[3.2.1]octan-8-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (124 mg, 0.32 mmol) in dichloromethane (2 mL) was added dropwise to the mixed reaction solution at 0°C. The obtained mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (40 mg, yield: 20.8%), LC-MS m/z: 598 [M+H] + ;
2)、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100146
2) Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100146
将溶有8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1] 辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(40mg，0.07mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：498[M+H]+；8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1] A solution of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl octane-3-carboxylate (40 mg, 0.07 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 498 [M+H] + ;
3)、8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100147
3) Synthesis of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100147
将溶有8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(33mg，0.07mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(13mg，0.10mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(39mg，0.14mmol)和1-甲基-1H-咪唑(23mg，0.28mmol)的N，N-二甲基甲酰胺(3mL)溶液室温搅拌16小时。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：49％)，LC-MS m/z：609[M+H]+；A solution of 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (33 mg, 0.07 mmol), (E)-4-(dimethylamino)but-2-enoic acid (13 mg, 0.10 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) and 1-methyl-1H-imidazole (23 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 8-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (20 mg, yield: 49%), LC-MS m/z: 609 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.64(s，1H)，6.83(dd，J＝14.4，7.2Hz，1H)，6.44(dd，J＝31.2，15.6Hz，1H)，5.36(s，1H)，5.28(d，J＝17.2Hz，1H)，4.17-4.06(m，1H)，3.96(d，J＝11.2Hz，2H)，3.84-3.82(m，1H)，3.74(d，J＝14.0Hz，2H)，3.70-3.63(m，3H)，3.58-3.54(m，2H)，3.38(d，J＝13.2Hz，1H)，3.18(d，J＝6.4Hz，2H)，3.08-3.05(m，1H)，2.43(d，J＝24.4Hz，2H)，2.27(d，J＝5.2Hz，7H)，2.19-2.10(m，2H)，2.03(d，J＝10.4Hz，2H)，1.94-1.92(m，2H)，1.71-1.60(m，2H)，1.56-1.48(m，3H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD) δ7.64 (s, 1H), 6.83 (dd, J=14.4, 7.2Hz, 1H), 6.44 (dd, J=31.2, 15.6Hz, 1H), 5.36 (s, 1H ), 5.28 (d, J = 17.2Hz, 1H), 4.17-4.06 (m, 1H), 3.96 (d, J = 11.2Hz, 2H), 3.84-3.82 (m, 1H), 3.74 (d, J = 14.0Hz, 2H), 3.70-3.63 (m, 3H), 3.58-3.54 (m, 2H), 3.38 (d, J = 13.2Hz, 1H), 3.18 (d, J = 6.4Hz, 2H), 3.08-3.05 (m, 1H), 2.43 (d, J = 24.4Hz, 2H) , 2.27 (d, J = 5.2Hz, 7H), 2.19-2.10 (m, 2H), 2.03 (d, J = 10.4Hz, 2H), 1.94-1.92 (m, 2H), 1.71-1.60 (m, 2H ), 1.56-1.48(m, 3H), 1.31(s, 3H), 1.29(s, 3H).
实施例22、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物22)的合成：Example 22, Synthesis of (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (Compound 22):
1)、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成报告
Figure PCTCN2024077920-ftappb-I100148
1) Synthesis report of 1-(tert-butyloxycarbonyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100148
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(419mg，2.42mmol)和三乙胺(489mg，4.84mmol)的二氯甲烷(4mL)溶有中，滴加三光气(240mg，0.81mmol)。所得混合反应液0℃搅拌1小时。在0℃条件下，将3-异丙基-N7-(哌啶-4-基甲基)-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(600mg，1.61mmol)。加料完毕，所得混合反应液0℃搅拌12小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(498mg，收率：54-0％)，LC-MS m/z：572[M+H]+；Triphosgene (240 mg, 0.81 mmol) was added dropwise to dichloromethane (4 mL) containing tert-butyl 3-hydroxyazetidine-1-carboxylate (419 mg, 2.42 mmol) and triethylamine (489 mg, 4.84 mmol) at 0°C. The resulting mixed reaction liquid was stirred at 0°C for 1 hour. 3-isopropyl-N 7 -(piperidin-4-ylmethyl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (600 mg, 1.61 mmol) was added at 0°C. After the addition, the resulting mixed reaction liquid was stirred at 0°C for 12 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (498 mg, yield: 54-0%), LC-MS m/z: 572 [M+H] + ;
2)、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100149
2) Synthesis of azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100149
向溶有4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(185mg，0.32mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(117mg，收率：76.6％)，LC-MS m/z：472[M+H]+；2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of 1-(tert-butyloxycarbonyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (185 mg, 0.32 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction liquid was stirred at room temperature for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give (117 mg, yield: 76.6%), LC-MS m/z: 472 [M+H] + ;
3)、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100150
3) Synthesis of (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100150
将溶有4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸氮杂环丁烷-3-基酯(75mg，0.16mmol)，(E)-4-(二甲氨基)丁-2-烯酸(32mg，0.19mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(91mg，0.24mmol)和N，N-二异丙基乙胺(62mg，0.48mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(65.8mg，收率：71.0％)，LC-MS m/z：583[M+H]+；A solution of 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate azetidine-3-yl ester (75 mg, 0.16 mmol), (E)-4-(dimethylamino)but-2-enoic acid (32 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (65.8 mg, yield: 71.0%), LC-MS m/z: 583 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.60(s，1H)，6.79(dt，J＝15.4，6.5Hz，1H)，6.17(d，J＝15.4Hz，1H)，5.27(s，1H)，5.17-5.12(m，1H)，4.59(dd，J＝9.7，7.6Hz，1H)，4.35(dd，J＝11.6，6.8Hz，1H)，4.30-4.03(m，5H)，3.98-3.95(m，3H)，3.56(td，J＝11.5，2.0Hz，2H)，3.22(d，J＝6.8Hz，2H)，3.14(d，J＝6.5Hz，2H)，3.06(dt，J＝13.8，6.9Hz，1H)，2.96(s，1H)，2.92-2.82(m，2H)，2.26(s，6H)，2.03(d，J＝10.5Hz，2H)，1.95(s，1H)，1.85(d，J＝12.8Hz，2H)，1.58-1.48(m，2H)，1.29(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d4) δ7.60 (s, 1H), 6.79 (dt, J＝15.4, 6.5Hz, 1H), 6.17 (d, J＝15.4Hz, 1H), 5.27 (s, 1H) , 5.17-5.12 (m, 1H), 4.59 (dd, J=9.7, 7.6Hz, 1H), 4.35 (dd, J=11.6, 6.8Hz, 1H), 4.30-4.03 (m, 5H), 3.98-3.95 (m, 3H), 3.56 (td, J=11 .5, 2.0Hz, 2H), 3.22 (d, J=6.8Hz, 2H), 3.14 (d, J=6.5Hz, 2H), 3.06 (dt, J=13.8, 6.9Hz, 1H), 2.96 (s , 1H), 2.92-2.82 (m, 2H), 2.26 (s, 6H), 2.03 (d, J=10.5Hz, 2H), 1.95 (s, 1H), 1.85 (d, J=12.8Hz, 2H) , 1.58-1.48 (m, 2H), 1.29 (d, J=6.9Hz, 6H).
实施例23、4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物23)的合成：Example 23, Synthesis of (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (Compound 23):
1)、4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100151
1) Synthesis of tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100151
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(1g，4.13mmol)，N，N-二异丙基乙胺(1.60g，12.3mmol)和4-(氨基甲基)哌啶-1-羧酸叔丁酯(1.06g，4.95mmol)的异丙醇(15mL)溶液加热90℃搅拌8小时。冷却后，将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.8g，收 率：46.1％)，LC-MS m/z：421[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1 g, 4.13 mmol), N,N-diisopropylethylamine (1.60 g, 12.3 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.06 g, 4.95 mmol) in isopropanol (15 mL) was heated at 90°C and stirred for 8 hours. After cooling, the resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.8 g, yield rate: 46.1%), LC-MS m/z: 421[M+H] + ;
2)、4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100152
2) Synthesis of tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100152
将溶有4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.8g，1.90mmol)和间氯过氧苯甲酸(1.31g，7.62mmol)的二氯甲烷(10mL)溶液室温搅拌8小时。过滤后，将滤液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.65g，收率：75.5％)，LC-MS m/z：453[M+H]+；A solution of tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.8 g, 1.90 mmol) and m-chloroperbenzoic acid (1.31 g, 7.62 mmol) in dichloromethane (10 mL) was stirred at room temperature for 8 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.65 g, yield: 75.5%), LC-MS m/z: 453[M+H] + ;
3)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100153
3) Synthesis of tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100153
将溶有4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-A][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.65g，1.43mmol)，N，N-二异丙基乙胺(0.56g，4.31mmol)和四氢-2H-吡喃-4-胺(0.58g，5.75mmol)的异丙醇(7mL)溶液，加热90℃搅拌8小时。所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(0.5g，收率：73.5％)，LC-MS m/z：474[M+H]+；A solution of tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-A][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (0.65 g, 1.43 mmol), N,N-diisopropylethylamine (0.56 g, 4.31 mmol) and tetrahydro-2H-pyran-4-amine (0.58 g, 5.75 mmol) in isopropanol (7 mL) was heated at 90° C. and stirred for 8 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.5 g, yield: 73.5%), LC-MS m/z: 474 [M+H] + ;
4)、8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
Figure PCTCN2024077920-ftappb-I100154
4) Synthesis of 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
Figure PCTCN2024077920-ftappb-I100154
在室温条件下，向溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸叔丁酯(0.5g，1.06mmol)的二氯甲烷(1.5mL)溶液中，加入2，2，2-三氟乙酸(0.5mL)。所得混合反应液室温搅拌2小时。将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3 x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(0.25g，收率：63.4％)，LC-MS m/z：374[M+H]+； To a solution of tert-butyl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (0.5 g, 1.06 mmol) in dichloromethane (1.5 mL) at room temperature was added 2,2,2-trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (0.25 g, yield: 63.4%), LC-MS m/z: 374 [M+H] + ;
5)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100155
5) Synthesis of 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100155
在0℃条件下，向溶有3-羟基吡咯烷-1-甲酸叔丁酯(0.15g，0.80mmol)的二氯甲烷(3ml)溶液中分批加入三乙胺(0.22g，2.01mmol)和三光气(99mg，0.33mmol)。所得混合反应液在0℃条件搅拌30分钟。在0℃条件下，将8-异丙基-N4-(哌啶-4-基甲基)-N2-(四氢-2H-吡喃-4-基)吡唑[1，5-a][1，3，5]三嗪-2，4-二胺(250mg，0.67mmol)加入到上述反应液中。所得混合反应液室温搅拌8小时。将所得混合反应液加水(40mL)稀释，并用乙酸乙酯(3 x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯(190mg，收率：48.4％)，LC-MS m/z：587[M+H]+；Triethylamine (0.22 g, 2.01 mmol) and triphosgene (99 mg, 0.33 mmol) were added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.15 g, 0.80 mmol) in dichloromethane (3 ml) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 30 minutes. 8-isopropyl-N 4 -(piperidin-4-ylmethyl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (250 mg, 0.67 mmol) was added to the above reaction solution at 0°C. The resulting mixed reaction solution was stirred at room temperature for 8 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (190 mg, yield: 48.4%), LC-MS m/z: 587 [M+H] + ;
6)、4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100156
6) Synthesis of 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100156
在室温条件下，向溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸1-(叔丁氧基羰基)吡咯烷-3-基酯(190mg，0.32mmol)的二氯甲烷(1.5mL)溶液中，加入2，2，2-三氟乙酸(0.5mL)。所得混合反应液室温搅拌2小时。将所得混和反应液加水(40mL)稀释并用乙酸乙酯(3 x 200mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0％-100％洗脱)纯化得到4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯(100mg，收率：63.5％)，LC-MS m/z：487[M+H]+；To a solution of 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (190 mg, 0.32 mmol) in dichloromethane (1.5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to give 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, yield: 63.5%), LC-MS m/z: 487 [M+H] + ;
7)、4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100157
7) Synthesis of (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100157
将溶有4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸吡咯烷-3-基酯(100mg，0.21mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(32mg，0.24mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(156mg，0.41mmol)和N，N-二异丙基乙胺(80mg，0.62mmol)的二氯甲烷(2mL)溶液，室温搅拌8小时。将得到的混合反应液加水(5mL)稀释，并用乙酸乙酯(3 x 50mL)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)甲基)哌啶-1-甲酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(50mg，收率：40.7％)，LC-MS m/z：598[M+H]+；A solution of 4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.21 mmol), (E)-4-(dimethylamino)but-2-enoic acid (32 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (156 mg, 0.41 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol) in dichloromethane (2 mL) was stirred at room temperature for 8 hours. The resulting mixed reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (50 mg, yield: 40.7%), LC-MS m/z: 598 [M+H] + ;
1H NMR(400MHz，DMSO-d6)：δ8.29(s，1H)，7.67(s，1H)，6.65-6.59(m，1H)，6.40-6.34(m，1H)，5.13(d，J＝24.0Hz，1H)，3.90-3.85(m，4H)，3.79-3.70(m，2H)，3.59-3.48(m，3H)，3.39-3.30(m，5H)，3.04(d，J＝8.0Hz，1H)，2.90-2.88(m，1H)，2.75-2.70(m，2H)，2.15(s，6H)，2.05-2.02(m，1H)，1.85-1.83(m，3H)，1.65(d，J＝12.0Hz，2H)，1.55-1.48(m，2H)，1.22(d，J＝8.0Hz，6H)，1.06-1.03(m，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.29 (s, 1H), 7.67 (s, 1H), 6.65-6.59 (m, 1H), 6.40-6.34 (m, 1H), 5.13 (d, J＝24.0Hz, 1H), 3.90-3.85 (m, 4H), 3.79-3.70 (m, 2H), 3.59-3.48 (m, 3H), 3.39-3.30 (m, 5H), 3.04 (d, J＝ 8.0 Hz, 1H), 2.90-2.88 (m, 1H), 2.75-2.70 (m, 2H), 2.15 (s, 6H), 2.05-2.02 (m, 1H), 1.85-1.83 (m, 3H), 1.65 ( d, J=12.0Hz, 2H), 1.55-1.48 (m, 2H), 1.22 (d, J=8.0Hz, 6H), 1.06-1.03 (m, 3H).
实施例24、4-(((8-异丙基-2-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物24)的合成：Example 24, Synthesis of 4-(((8-isopropyl-2-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 24):
1)、(R)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄酯的合成
Figure PCTCN2024077920-ftappb-I100158
1) Synthesis of (R)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100158
在0℃条件下，向溶有(R)-3-羟基哌啶-1-羧酸苄酯(206mg，0.876mmol)的四氢呋喃(2mL)溶液中，分批加入氢化钠(35.0mg，1.46mmol)，室温搅拌30分钟。然后将4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(330mg，0.73mmol)的四氢呋喃(2mL)溶液滴加到上述混合反应液中。所得混合反应液室温搅拌2小时。冷却后，将所得混合反应液加水稀释，并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(R)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄酯(300mg，收率：67.7％)，LC-MS m/z：608[M+H]+；At 0°C, sodium hydride (35.0 mg, 1.46 mmol) was added in batches to a solution of (R)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (206 mg, 0.876 mmol) in tetrahydrofuran (2 mL), and stirred at room temperature for 30 minutes. Then, a solution of tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (330 mg, 0.73 mmol) in tetrahydrofuran (2 mL) was added dropwise to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:pure water containing 0.1% formic acid=25%-65% elution) to give (R)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (300 mg, yield: 67.7%), LC-MS m/z: 608 [M+H] + ;
2)、(R)-3-((8-异丙基-4-((哌啶-4-基甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100159
2) Synthesis of (R)-3-((8-isopropyl-4-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100159
向溶有(R)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄酯(300mg，0.49mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2，-三氟乙酸(1mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：508.0[M+H]+；2,2,2,-trifluoroacetic acid (1 mL) was added dropwise to a solution of (R)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (300 mg, 0.49 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 508.0 [M+H] + ;
3)、(3R)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100160
3) Synthesis of benzyl (3R)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100160
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(111mg，0.59mmol)和三乙胺(149mg，1.48mmol)的四氢呋喃(2mL)溶液中，分批加入三光气(73mg，0.25mmol)。所得混合反应液0℃搅拌30分钟。然后将(R)-3-((8-异丙基-4-((哌啶-4-基甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1羧酸苄基酯(250mg，0.49mmol)加入到上述混合反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3R)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(200mg，收率：56.3％)，LC-MS m/z：721[M+H]+；Triphosgene (73 mg, 0.25 mmol) was added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (111 mg, 0.59 mmol) and triethylamine (149 mg, 1.48 mmol) in tetrahydrofuran (2 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 30 minutes. Then (R)-3-((8-isopropyl-4-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate benzyl ester (250 mg, 0.49 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give benzyl (3R)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate (200 mg, yield: 56.3%), LC-MS m/z: 721 [M+H] + ;
4)、(3R)-3-((8-异丙基-4-(((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100161
4) Synthesis of benzyl (3R)-3-((8-isopropyl-4-(((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100161
室温条件下，向溶有(3R)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(200mg，0.28mmol)的二氯甲烷(1.5mL)溶液中，滴加2，2，2-三氟乙酸(0.5mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：621[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.5 mL) was added dropwise to a solution of (3R)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (200 mg, 0.28 mmol) in dichloromethane (1.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 621[M+H] + ;
5)、(3R)-3-((4-(((1-(((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100162
5) Synthesis of benzyl (3R)-3-((4-(((1-(((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100162
室温条件下，向溶有(3R)-3-((8-异丙基-4-(((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(150mg，0.24mmol)和2-氟丙烯酸(26mg，0.29mmol)的二氯甲烷(2mL)溶液中，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(110mg，0.29mmol)和三乙胺(74mg，0.73mmol)。室温条件下，所得混合反应液室温搅拌2小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×80mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(3R)-3-((4-(((1-(((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(100mg，收率：59.7％)，LC-MS m/z：693[M+H]+；To a solution of (3R)-3-((8-isopropyl-4-(((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (150 mg, 0.24 mmol) and 2-fluoroacrylic acid (26 mg, 0.29 mmol) in dichloromethane (2 mL) at room temperature, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) and triethylamine (74 mg, 0.73 mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give (3R)-3-((4-(((1-(((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (100 mg, yield: 59.7%), LC-MS m/z: 693 [M+H] + ;
6)、4-(((8-异丙基-2-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100163
6) Synthesis of 4-(((8-isopropyl-2-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100163
将溶有(3R)-3-((4-(((1-(((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(30mg，0.043mmol)的2，2，2-三氟乙酸(2mL)溶加热50℃搅拌2小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈：含有0.1％甲酸的纯水＝25％-65％)纯得到4-(((8-异丙基-2-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(10mg，收率：41.3％)，LC-MS m/z：559[M+H]+；A solution of (3R)-3-((4-(((1-(((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (30 mg, 0.043 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 2 hours. The resulting mixed reaction liquid was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid:pure water containing 0.1% formic acid=25%-65%) to give 4-(((8-isopropyl-2-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (10 mg, yield: 41.3%), LC-MS m/z: 559 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，5.55-5.42(m，2H)，5.29-5.25(m，2H)，4.16-4.09(m，2H)，3.94-3.91(m，1H)，3.84-3.58(m，4H)，3.55-3.54(m，1H)，3.51-3.49(m，2H)，3.45-3.41(m，1H)，3.18-3.15(m，1H)，3.12-3.04(m，1H)，2.88-2.82(m，2H)，2.26-1.79(m，11H)，1.32(d，J＝7.2Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.87 (s, 1H), 5.55-5.42 (m, 2H), 5.29-5.25 (m, 2H), 4.16-4.09 (m, 2H), 3.94-3.91 (m, 1H), 3.84-3.58 (m, 4H), 3.55-3.54 (m, 1H), 3.51-3.49 (m, 2H), 3.45-3.41 (m, 1H), 3.18-3.15 (m, 1H) , 3.12-3.04(m, 1H), 2.88-2.82(m, 2H), 2.26-1.79(m, 11H), 1.32(d, J=7.2Hz, 6H).
实施例25、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物25)的合成：Example 25, Synthesis of (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (Compound 25):
1)、1-(叔丁氧羰基)吡咯烷-3-基4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2024077920-ftappb-I100164
1) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100164
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(302mg，1.61mmol)和三乙胺(326mg，3.23mmol)的二氯甲烷(4m L)溶液中，滴加三光气(160mg，0.54mmol)。所得混合反应液0℃搅拌1小时。然后将3-异丙基-N7-(哌啶-4-基甲基)-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(400mg，1.08mmol)加入上述混合反应液中。加料完毕，所得混合反应液0℃搅拌溶液12小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到1-(叔丁氧羰基)吡咯烷-3-基4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸酯(182mg，收率：28.9％)，LC-MS m/z：586[M+H]+；Triphosgene (160 mg, 0.54 mmol) was added dropwise to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (302 mg, 1.61 mmol) and triethylamine (326 mg, 3.23 mmol) in dichloromethane (4 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 1 hour. Then 3-isopropyl-N 7 -(piperidin-4-ylmethyl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (400 mg, 1.08 mmol) was added to the above mixed reaction solution. After the addition was completed, the resulting mixed reaction solution was stirred at 0°C for 12 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (182 mg, yield: 28.9%), LC-MS m/z: 586 [M+H] + ;
2)、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100165
2) Synthesis of 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100165
向溶有1-(叔丁氧羰基)吡咯烷-3-基4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸酯(182mg，0.31mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸吡咯烷-3-基酯(90mg，收率：59％)，LC-MS m/z：486[M+H]+；2,2,2-Trifluoroacetic acid (0.4 mL) was added dropwise to a solution of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (182 mg, 0.31 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (90 mg, yield: 59%), LC-MS m/z: 486 [M+H] + ;
3)、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100166
3) Synthesis of 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100166
将溶有4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸吡咯烷-3-基酯(30mg，0.06mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(12.4mg，0.07mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(36mg，0.09mmol)和N，N-二异丙基乙胺(24mg，0.19mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(23mg，收率：62％)，LC-MS m/z：597[M+H]+；A solution of 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (30 mg, 0.06 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (12.4 mg, 0.07 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36 mg, 0.09 mmol) and N,N-diisopropylethylamine (24 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (23 mg, yield: 62%), LC-MS m/z: 597 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.60(s，1H)，6.87-6.79(m，1H)，6.44(dd，J＝27.6，15.1Hz，1H)，5.24(d，J＝14.1Hz，2H)，4.16-4.05(m，3H)，3.98-3.95(m，2H)，3.88-3.80(m，1H)，3.77-3.63(m，3H)，3.56-3.52(m，3H)，3.18(dd，J＝13.0，6.6Hz，4H)，3.09-3.02(m，1H)，2.82(s，2H)，2.27(s，6H)，2.23-2.18(m，1H)，2.15-2.10(m，1H)，2.03(dd，J＝12.3，1.6Hz，2H)，1.96-1.89(m，1H)，1.82(d，J＝11.9Hz，2H)，1.58-1.48(m，2H)，1.28(d，J＝6.9Hz，6H)，1.22(dd，J＝12.5，3.9Hz，1H). 1 H NMR (400MHz, MeOD-d4) δ7.60 (s, 1H), 6.87-6.79 (m, 1H), 6.44 (dd, J=27.6, 15.1Hz, 1H), 5.24 (d, J=14.1Hz , 2H), 4.16-4.05(m, 3H), 3.98-3.95(m, 2H), 3.88-3.80(m, 1H), 3.77-3.63(m, 3H), 3.56-3.52(m, 3H), 3.18 (dd, J=13.0, 6.6Hz, 4H), 3.09-3.02(m, 1H), 2.82(s, 2H), 2.27(s, 6H), 2.23-2.18(m, 1H), 2.15-2.10(m, 1H), 2.03(dd, J＝ 12.3, 1.6Hz, 2H), 1.96-1.89 (m, 1H), 1.82 (d, J＝11.9Hz, 2H), 1.58-1.48 (m, 2H), 1.28 (d, J＝6.9Hz, 6H), 1.22(dd, J=12.5, 3.9Hz, 1H).
实施例26、4-(((8-异丙基-2-(((S)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物26)的合成：Example 26, Synthesis of 4-(((8-isopropyl-2-(((S)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 26):
1)、4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100167
1) Synthesis of tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100167
将溶有4-(((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(450mg，1.07mmol)和间氯过氧苯甲酸(923mg，5.35mmol)的二氯甲烷(5mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(400mg，收率：82.60％)，LC-MS m/z：453[M+H]+；A solution of tert-butyl 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (450 mg, 1.07 mmol) and m-chloroperbenzoic acid (923 mg, 5.35 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (400 mg, yield: 82.60%), LC-MS m/z: 453[M+H] + ;
2)、(S)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100168
2) Synthesis of (S)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100168
在00C条件下，向溶有(3S)-3-羟基哌啶-1-羧酸苄基酯(233mg，0.99mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入双(三甲基硅烷基)氨基钾(7.92mL，3.96mmol，0.5M的四氢呋喃溶液)和4-(((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸叔丁酯(450mg，0.99mmol)。所得混合反应液加热60℃搅拌4小时。冷却后，将混合反应液通过C18柱纯色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(S)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(200mg，收率：33.10％)，LC-MS m/z：608[M+H]+；At 0°C, potassium bis(trimethylsilyl)amide (7.92 mL, 3.96 mmol, 0.5 M tetrahydrofuran solution) and tert-butyl 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylate (450 mg, 0.99 mmol) were added to a solution of (3S)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (233 mg, 0.99 mmol) in N,N-dimethylformamide (5 mL). The resulting mixed reaction solution was heated at 60°C and stirred for 4 hours. After cooling, the mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain (S)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (200 mg, yield: 33.10%), LC-MS m/z: 608 [M+H] + ;
3)、(S)-3-((8-异丙基-4-((哌啶-4-基甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100169
3) Synthesis of (S)-3-((8-isopropyl-4-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100169
向溶有(S)-3-((4-(((1-(叔丁氧基羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(200mg，0.33mmol)的二氯甲烷(2mL)溶液中，加入2，2，2，-三氟乙酸(0.2mL)。所得混合反应液搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(S)-3-((8-异丙基-4-((哌啶-4-基甲基)氨基)吡唑并[1，5-a][1，3，5] 三嗪-2-基)氧基)哌啶-1羧酸苄基酯(100mg，收率：59.8％)，LC-MS m/z：508[M+H]+；To a solution of (S)-3-((4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (200 mg, 0.33 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroacetic acid (0.2 mL). The resulting mixed reaction liquid was stirred for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give (S)-3-((8-isopropyl-4-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (200 mg, 0.33 mmol). Benzyl triazine-2-yl)oxy)piperidine-1-carboxylate (100 mg, yield: 59.8%), LC-MS m/z: 508 [M+H] + ;
4)、(3S)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100170
4) Synthesis of benzyl (3S)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100170
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(39mg，0.21mmol)和三乙胺(42.5mg，0.42mmol)的四氢呋喃(1mL)溶液中，加入三光气(21mg，0.070mmol)。所得混合反应液室温搅拌1小时。然后在0℃条件下，将(S)-3-((8-异丙基-4-((哌啶-4-基甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1羧酸苄基酯(70mg，0.14mmol)加入上述混合反应液，0℃搅拌溶液3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3S)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(60mg，收率：60.4％)，LC-MS m/z：721[M+H]+；Triphosgene (21 mg, 0.070 mmol) was added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (39 mg, 0.21 mmol) and triethylamine (42.5 mg, 0.42 mmol) in tetrahydrofuran (1 mL) at 0°C. The resulting mixed reaction solution was stirred at room temperature for 1 hour. Then, (S)-3-((8-isopropyl-4-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate benzyl ester (70 mg, 0.14 mmol) was added to the mixed reaction solution at 0°C, and the solution was stirred at 0°C for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give benzyl (3S)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate (60 mg, yield: 60.4%), LC-MS m/z: 721 [M+H] + ;
5)、(3S)-3-((8-异丙基-4-(((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100171
5) Synthesis of benzyl (3S)-3-((8-isopropyl-4-(((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100171
室温条件下，向溶有(3S)-3-((4-(((1-(((1-(叔丁氧基羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(55mg，0.076mmol)的二氯甲烷(1mL)溶液中，滴加2，2，2-三氟乙酸(0.1mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3S)-3-((8-异丙基-4-(((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(45mg，收率：95.0％)，LC-MS m/z：621[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.1 mL) was added dropwise to a solution of (3S)-3-((4-(((1-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (55 mg, 0.076 mmol) in dichloromethane (1 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give benzyl (3S)-3-((8-isopropyl-4-(((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate (45 mg, yield: 95.0%), LC-MS m/z: 621 [M+H] + ;
6)、(3S)-3-((4-(((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100172
6) Synthesis of benzyl (3S)-3-((4-(((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100172
将溶有(3S)-3-((8-异丙基-4-(((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(50mg，0.081mmol)，2-氟丙-2-烯酸(11mg，0.12mmol)，1-甲基-1H-咪唑(27mg，0.32mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(45.5mg，0.16mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌4小时。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3S)-3-((4-(((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基) -8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(40mg，收率：71.7％)，LC-MS m/z：693[M+H]+；A solution of benzyl (3S)-3-((8-isopropyl-4-(((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate (50 mg, 0.081 mmol), 2-fluoroprop-2-enoic acid (11 mg, 0.12 mmol), 1-methyl-1H-imidazole (27 mg, 0.32 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (45.5 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 4 hours. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (3S)-3-((4-(((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino) -8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (40 mg, yield: 71.7%), LC-MS m/z: 693 [M+H] + ;
7)、4-(((8-异丙基-2-(((S)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100173
7) Synthesis of 4-(((8-isopropyl-2-(((S)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100173
将溶有(3S)-3-((4-(((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-2-基)氧基)哌啶-1-羧酸苄基酯(30mg，0.043mmol)的2，2，2三氟乙酸(0.5mL)溶液，加热50℃搅拌3小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((8-异丙基-2-(((S)-哌啶-3-基)氧基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(10mg，收率：41.3％)，LC-MS m/z：559[M+H]+；A solution of (3S)-3-((4-(((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2-yl)oxy)piperidine-1-carboxylic acid benzyl ester (30 mg, 0.043 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-(2-fluoroacryloyl)pyrrolidin-3-yl 4-(((8-isopropyl-2-(((S)-piperidin-3-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)piperidine-1-carboxylate (10 mg, yield: 41.3%), LC-MS m/z: 559 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.83-7.78(m，1H)，5.46(dd，J＝44，3.6Hz，1H)，5.28-5.20(m，2H)，5.15-5.09(m，1H)，4.11(s，2H)，3.94-3.86(m，1H)，3.83-3.53(m，4H)，3.47(d，J＝6.4Hz，2H)，3.28-3.22(m，1H)，3.09-3.01(m，1H)，3.00-2.88(m，2H)，2.87-2.77(m，3H)，2.24-2.04(m，4H)，2.01-1.71(m，6H)，1.69-1.59(m，1H)，1.29(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.83-7.78 (m, 1H), 5.46 (dd, J=44, 3.6Hz, 1H), 5.28-5.20 (m, 2H), 5.15-5.09 ( m, 1H), 4.11 (s, 2H), 3.94-3.86 (m, 1H), 3.83-3.53 (m, 4H), 3.47 (d, J=6.4Hz, 2 H), 3.28-3.22(m, 1H), 3.09-3.01(m, 1H), 3.00-2.88(m, 2H), 2.87-2.77(m, 3H), 2.24-2.04(m, 4H), 2.01- 1.71 (m, 6H), 1.69-1.59 (m, 1H), 1.29 (d, J=6.8Hz, 6H).
实施例27、(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物27)的合成：Example 27, Synthesis of (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 27):
1)、(1R，3s，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100174
1) Synthesis of tert-butyl (1R, 3s, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8 carboxylate
Figure PCTCN2024077920-ftappb-I100174
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(1.3g，5.37mmol)，(1R，3s，5S)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.46g，6.45mmol)和N，N-二异丙基乙胺(1.04g，8.06mmol)的异丙醇(15mL)溶液加热70℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-20％洗脱)纯化得到(1R，3s，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.44g，收率：62.1％)，LC-MS m/z：433[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.3 g, 5.37 mmol), (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.46 g, 6.45 mmol) and N,N-diisopropylethylamine (1.04 g, 8.06 mmol) in isopropanol (15 mL) was heated at 70°C and stirred overnight. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-20% elution) to give (1R, 3s, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.44 g, yield: 62.1%), LC-MS m/z: 433 [M+H] + ;
2)、(1R，3s，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100175
2) Synthesis of tert-butyl (1R, 3s, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8 carboxylate
Figure PCTCN2024077920-ftappb-I100175
将溶有(1R，3s，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.44g，3.33mmol)和间氯过氧苯甲酸(1.73g，10.02mmol)的二氯甲烷(18mL)溶液， 室温搅拌过夜。将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到(1R，3s，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.41g，收率：91.2％)，LC-MS m/z：465[M+H]+；A solution of (1R, 3s, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.44 g, 3.33 mmol) and m-chloroperbenzoic acid (1.73 g, 10.02 mmol) in dichloromethane (18 mL) was added. Stir at room temperature overnight. The resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-40% elution) to give (1R, 3s, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.41 g, yield: 91.2%), LC-MS m/z: 465[M+H] + ;
3)、(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯
Figure PCTCN2024077920-ftappb-I100176
3) (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure PCTCN2024077920-ftappb-I100176
将溶有(1R，3s，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.41g，3.04mmol)，四氢-2H-吡喃-4-胺(461mg，4.56mmol)和N，N-二异丙基乙胺(1.18g，9.12mmol)的异丙醇(15mL)溶液，加热90℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-50％洗脱)纯化得到(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.45g，收率：98.4％)，LC-MS m/z：486[M+H]+；A solution of (1R, 3s, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.41 g, 3.04 mmol), tetrahydro-2H-pyran-4-amine (461 mg, 4.56 mmol) and N,N-diisopropylethylamine (1.18 g, 9.12 mmol) in isopropanol (15 mL) was heated at 90°C and stirred overnight. After cooling, the resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.45 g, yield: 98.4%), LC-MS m/z: 486 [M+H] + ;
4)、N4-((1R，3s，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
Figure PCTCN2024077920-ftappb-I100177
4) Synthesis of N 4 -((1R, 3s, 5S)-8-azabicyclo[3.2.1]oct-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
Figure PCTCN2024077920-ftappb-I100177
室温条件下，向溶有(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.45g，2.99mmol)的二氯甲烷(15mL)溶液中，滴加2，2，2-三氟乙酸(5mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到N4-((1R，3s，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(1.10g，收率：95.6％)，LC-MS m/z：386[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (5 mL) was added dropwise to a solution of (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.45 g, 2.99 mmol) in dichloromethane (15 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give N 4 -((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (1.10 g, yield: 95.6%), LC-MS m/z: 386 [M+H] + ;
5)、(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100178
5) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100178
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(243mg，1.40mmol)和三乙胺(283mg，2.81mmol)的二氯甲烷(4mL)溶液中，加入三光气(111mg，0.37mmol)。所得混合反应液0℃搅拌1小时。将N4-((1R，3s，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(360mg，0.94mmol)加入到上述的混合反应液中。加完后，所得混合反应液0℃搅拌溶液12小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8- 羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(130mg，收率：23.8％)，LC-MS m/z：585[M+H]+；Triphosgene (111 mg, 0.37 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (243 mg, 1.40 mmol) and triethylamine (283 mg, 2.81 mmol) in dichloromethane (4 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 1 hour. N 4 -((1R, 3s, 5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (360 mg, 0.94 mmol) was added to the above mixed reaction solution. After the addition, the resulting mixed reaction solution was stirred at 0°C for 12 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-1,2-dihydro ... 1-(tert-Butyloxycarbonyl)azetidin-3-yl carboxylate (130 mg, yield: 23.8%), LC-MS m/z: 585 [M+H] + ;
6)、(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100179
6) Synthesis of (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100179
室温条件下，向溶有(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(130mg，0.223mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化到(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，收率：83.5％)，LC-MS m/z：485[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (130 mg, 0.223 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (90 mg, yield: 83.5%), LC-MS m/z: 485 [M+H] + ;
7)、(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100180
7) Synthesis of (1R, 3s, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100180
将溶有(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，0.18mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(36.0mg，0.28mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(106mg，0.28mmol)和N，N-二异丙基乙胺(72mg，0.56mmol)的N，N-二甲基甲酰胺(1.2mL)溶液室温搅拌2小时。将所得混合反应液通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1R，3s，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(64mg，收率：57.8％)，LC-MS m/z：596[M+H]+；A solution of (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (90 mg, 0.18 mmol), (E)-4-(dimethylamino)but-2-enoic acid (36.0 mg, 0.28 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol) in N,N-dimethylformamide (1.2 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1R,3s,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (64 mg, yield: 57.8%), LC-MS m/z: 596 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.64(s，1H)，6.85-6.74(m，1H)，6.19(d，J＝15.5Hz，1H)，5.26-5.19(m，1H)，4.66(d，J＝16.6Hz，2H)，4.39(d，J＝27.9Hz，3H)，4.08-3.96(m，4H)，3.57-3.50(m，2H)，3.15(d，J＝6.5Hz，2H)，3.03-2.96(m，1H)，2.27(s，6H)，2.11-1.99(m，6H)，1.92(d，J＝7.9Hz，2H)，1.80(t，J＝11.9Hz，2H)，1.66-1.55(m，2H)，1.26(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d4): δ7.64 (s, 1H), 6.85-6.74 (m, 1H), 6.19 (d, J=15.5Hz, 1H), 5.26-5.19 (m, 1H), 4.66 (d, J=16.6Hz, 2H), 4.39 (d, J=27.9Hz, 3H), 4.08-3.96 (m, 4H), 3.57 -3.50 (m, 2H), 3.15 (d, J=6.5Hz, 2H), 3.03-2.96 (m, 1H), 2.27 (s, 6H), 2.11-1.99 (m, 6H), 1.92 (d, J =7.9Hz, 2H), 1.80 (t, J = 11.9Hz, 2H), 1.66-1.55 (m, 2H), 1.26 (d, J = 6.9Hz, 6H).
实施例28、8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物28)的合成：Example 28, Synthesis of 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 28):
1)、8-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100181
1) Synthesis of 8-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100181
将溶有8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯(50mg，0.08mmol)，(E)-4-(二甲氨基)丁-2-烯酸(16mg，0.12mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(45mg，0.16mmol)和1-甲基-1H-咪唑(26mg，0.32mmol)的N，N-二甲基甲酰胺(3mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(41mg，收率：70％)，LC-MS m/z：729[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester (50 mg, 0.08 mmol), (E)-4-(dimethylamino)but-2-enoic acid (16 mg, 0.12 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (45 mg, 0.16 mmol) and 1-methyl-1H-imidazole (26 mg, 0.32 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 8-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (41 mg, yield: 70%), LC-MS m/z: 729 [M+H] + ;
2)、8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100182
2) Synthesis of 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100182
将溶有8-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(41mg，0.06mmol)的2，2，2-三氟乙酸(2mL)溶液，加热50℃搅拌5小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(18mg，收率：54％)，LC-MS m/z：595[M+H]+；A solution of 8-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (41 mg, 0.06 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50° C. and stirred for 5 hours. After cooling, the resulting The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (18 mg, yield: 54%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.79(s，1H)，6.83-6.75(m，1H)，6.17(d，J＝12.2Hz，1H)，5.62(s，1H)，5.21-5.17(m，2H)，4.64-4.54(m，1H)，4.38-4.34(m，1H)，4.26-4.22(m，1H)，4.02-3.98(m，1H)，3.82-3.76(m，2H)，3.72(s，1H)，3.48-3.45(m，1H)，3.22-3.19(m，1H)，3.14(d，J＝6.0Hz，2H)，3.10-3.06(m，1H)，2.89-2.85(m，2H)，2.79-2.75(m，1H)，2.50-2.46(m，3H)，2.26(s，6H)，2.09-2.06(m，1H)，1.99-1.95(m，2H)，1.89-1.80(m，2H)，1.71-1.68(m，2H)，1.63-1.58(m，1H)，1.34(s，3H)，1.32(s，3H). 1 H NMR (400MHz, MeOD) δ7.79 (s, 1H), 6.83-6.75 (m, 1H), 6.17 (d, J=12.2Hz, 1H), 5.62 (s, 1H), 5.21-5.17 (m , 2H), 4.64-4.54(m, 1H), 4.38-4.34(m, 1H), 4.26-4.22(m, 1H), 4.02-3.98(m, 1H), 3.82-3.76(m, 2H), 3.72 (s, 1H), 3.48-3.45 (m, 1H), 3.22-3. 19 (m, 1H), 3.14 (d, J=6.0Hz, 2H), 3.10-3.06 (m, 1H), 2.89-2.85 (m, 2H), 2.79-2.75 (m, 1H), 2.50-2.46 ( m, 3H), 2.26 (s, 6H), 2.09-2.06 (m, 1H), 1.99-1.95 (m, 2H), 1.89-1.80 (m, 2H), 1.71-1.68 (m, 2H), 1.63- 1.58(m,1H), 1.34(s,3H), 1.32(s,3H).
实施例29、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯或异构体(化合物29A和29B)的合成：Example 29, Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester or isomer (Compounds 29A and 29B):
1)、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100183
1) Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100183
将溶有3-羟基吡咯烷-1-羧酸叔丁酯(234mg，1.25mmol)和三乙胺(316mg，3.12mmol)的二氯甲烷(5mL)溶液中，0℃搅拌5分钟，然后将双(三氯甲基)碳酸酯(124mg，0.42mmol)加入到上述混合反应液，搅拌1小时。再将N4-(8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(400mg，1.04mmol)的二氯甲烷(5mL)溶液滴加到上述混合反应液中，室温搅拌16小时。将混合反应液减压浓缩并通过C18柱色谱(乙腈：含有0.5％NH4HCO3的纯水＝10～70％洗脱)纯化得到3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(300mg，收率：48％)，LC-MS m/z：599[M+H]+；A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (234 mg, 1.25 mmol) and triethylamine (316 mg, 3.12 mmol) in dichloromethane (5 mL) was stirred at 0°C for 5 minutes, and then bis(trichloromethyl) carbonate (124 mg, 0.42 mmol) was added to the mixed reaction solution and stirred for 1 hour. A solution of N 4 -(8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (400 mg, 1.04 mmol) in dichloromethane (5 mL) was added dropwise to the mixed reaction solution and stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by C18 column chromatography (acetonitrile: pure water containing 0.5% NH 4 HCO 3 = 10-70% elution) to give 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (300 mg, yield: 48%), LC-MS m/z: 599 [M+H] + ;
2)、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100184
2) Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100184
将溶有3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(400mg，0.67mmol)和2，2，2-三氟三氟乙酸(1mL)的二氯甲烷(3mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步，LC-MS m/z：499[M+H]+；A solution of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (400 mg, 0.67 mmol) and 2,2,2-trifluorotrifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 499 [M+H] + ;
3)、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯或异构体(化合物29A和29B)的合成
Figure PCTCN2024077920-ftappb-I100185
3) Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester or isomer (Compounds 29A and 29B)
Figure PCTCN2024077920-ftappb-I100185
将溶有3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(150mg，0.30mmol)，2-氟丙-2-烯酸(40mg，0.45mmol)，1-甲基-1H-咪唑(98.52mg，1.2mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(168mg，0.60mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈：含有0.5％NH4HCO3的纯水＝10～70％洗脱)纯化得到的得到两个异构体：BIOT-002-9067(化合物29A)(10mg，收率：6％)：LC-MS m/z：571[M+H]+；A solution of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (150 mg, 0.30 mmol), 2-fluoroprop-2-enoic acid (40 mg, 0.45 mmol), 1-methyl-1H-imidazole (98.52 mg, 1.2 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (168 mg, 0.60 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.5% NH 4 HCO 3 = 10-70% elution) to obtain two isomers: BIOT-002-9067 (Compound 29A) (10 mg, yield: 6%): LC-MS m/z: 571 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.64(s，1H)，5.47(dd，J＝47.2，3.4Hz，1H)，5.31(d，J＝8.0Hz，1H)，5.24(d，J＝16.6Hz，1H)，4.67(s，1H)，4.34(s，2H)，4.05(dd，J＝9.6，5.5Hz，1H)，3.98(d，J＝11.5Hz，2H)，3.95-3.88(m，1H)，3.71(dd，J＝64.1，13.6Hz，3H)，3.53(dd，J＝11.6，9.6Hz，2H)，2.99(dt，J＝13.8，6.8Hz，1H)，2.20(dd，J＝32.8， 10.3Hz，2H)，2.02(d，J＝9.0Hz，6H)，1.88(d，J＝7.3Hz，2H)，1.76(dd，J＝23.7，12.5Hz，2H)，1.60(td，J＝15.5，4.4Hz，2H)，1.26(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.64 (s, 1H), 5.47 (dd, J=47.2, 3.4Hz, 1H), 5.31 (d, J=8.0Hz, 1H), 5.24 (d, J =16.6Hz, 1H), 4.67 (s, 1H), 4.34 (s, 2H), 4.05 (dd, J = 9.6, 5.5 Hz, 1H), 3.98 (d, J=11.5Hz, 2H), 3.95-3.88 (m, 1H), 3.71 (dd, J=64.1, 13.6Hz, 3H), 3.53 (dd, J=11.6, 9.6Hz , 2H), 2.99 (dt, J=13.8, 6.8Hz, 1H), 2.20 (dd, J=32.8, 10.3Hz, 2H), 2.02 (d, J=9.0Hz, 6H), 1.88 (d, J=7.3Hz, 2H), 1.76 (dd, J=23.7, 12.5Hz, 2H), 1.60 (td, J= 15.5, 4.4Hz, 2H), 1.26 (d, J=6.9Hz, 6H).
BIOT-002-90208(化合物29B)(10mg，收率：6％)(10mg，收率：6％)：LC-MS m/z：571[M+H]+；BIOT-002-90208 (Compound 29B) (10 mg, yield: 6%) (10 mg, yield: 6%): LC-MS m/z: 571 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.67(s，1H)，5.56-5.41(m，1H)，5.27(d，J＝26.4Hz，2H)，4.30(s，3H)，4.04(s，1H)，3.97(d，J＝9.0Hz，3H)，3.75(s，2H)，3.64(d，J＝9.1Hz，1H)，3.59-3.49(m，2H)，3.07-2.96(m，1H)，2.23(s，3H)，2.10(s，6H)，2.03(d，J＝12.7Hz，3H)，1.59(d，J＝12.2Hz，2H)，1.27(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.67 (s, 1H), 5.56-5.41 (m, 1H), 5.27 (d, J=26.4Hz, 2H), 4.30 (s, 3H), 4.04 (s , 1H), 3.97 (d, J=9.0Hz, 3H), 3.75 (s, 2H), 3.64 (d, J=9.1Hz, 1H), 3.59-3.49 (m, 2H), 3.07-2.96 (m, 1H), 2.23 (s, 3H), 2.10 (s, 6H), 2.03 (d, J = 12.7Hz, 3H), 1.59 (d, J = 12.2Hz, 2H), 1.27 (d, J = 6.9Hz, 6H).
实施例30、(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物30)的合成：Example 30, Synthesis of (1s, 4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 30):
1)、(1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸的合成
Figure PCTCN2024077920-ftappb-I100186
1) Synthesis of (1s, 4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid
Figure PCTCN2024077920-ftappb-I100186
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(1.2g，4.96mmol)，(1s，4s)-4-氨基环己烷-1-甲酸(851mg，5.95mmol)和N，N-二异丙基乙胺(1.92g，14.88mmol)的异丙醇(20mL)溶液加热70℃搅拌过夜。冷却后，将混合反应液加水(100mL)稀释，并用乙酸乙酯(3 x 100mL)萃取。合并的有机相用饱和食盐水(1x 100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-40％洗脱)纯化得到(1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸(1.09g，收率：63％)，LC-MS：m/z：350[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.2 g, 4.96 mmol), (1s,4s)-4-aminocyclohexane-1-carboxylic acid (851 mg, 5.95 mmol) and N,N-diisopropylethylamine (1.92 g, 14.88 mmol) in isopropanol (20 mL) was heated at 70°C and stirred overnight. After cooling, the mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-40% elution) to give (1s, 4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid (1.09 g, yield: 63%), LC-MS: m/z: 350 [M+H] + ;
2)、3-(((1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯的合成
Figure PCTCN2024077920-ftappb-I100187
2) Synthesis of tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100187
将溶有(1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸(315mg，0.90mmol)，3-羟基吡咯烷-1-羧酸叔丁酯(338mg，1.80mmol)，N1-((乙基亚氨基)亚甲基)-N3，N3-二甲基丙烷-1，3-二胺盐酸盐(520mg，2.70mmol)和4-二甲氨基吡啶(221mg，1.81mmol)的二氯甲烷(5mL)溶液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯(292mg，收率：62％)，LC-MS m/z：519[M+H]+；A solution of (1s,4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid (315 mg, 0.90 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (338 mg, 1.80 mmol), N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride (520 mg, 2.70 mmol) and 4-dimethylaminopyridine (221 mg, 1.81 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (292 mg, yield: 62%), LC-MS m/z: 519 [M+H]+;
3)、3-(((1s，4s)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯的合成
Figure PCTCN2024077920-ftappb-I100188
3) Synthesis of tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100188
向溶有3-(((1s，4s)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯(292mg，0.56mmol)和3-氯过氧苯甲酸(195mg，1.12mmol)的二氯甲烷(5mL)溶液室温搅拌过夜。将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法 (乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到3-(((1s，4s)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯(280mg，收率：90％)，LC-MS m/z：551[M+H]+；A solution of tert-butyl 3-(((1s, 4s)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (292 mg, 0.56 mmol) and 3-chloroperbenzoic acid (195 mg, 1.12 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography The mixture was purified by elution with ethyl acetate: petroleum ether = 20-40% to give tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (280 mg, yield: 90%), LC-MS m/z: 551 [M+H] + ;
4)、3-(((1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100189
4) Synthesis of tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100189
将溶有3-(((1s，4s)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁基酯(280mg，0.51mmol)，四氢-2H-吡喃-4-胺(62mg，0.61mmol)和N，N-二异丙基乙胺(197mg，1.53mmol)的异丙醇(4mL)溶液加热90℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-50％洗脱)纯化得到3-(((1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(252mg，收率：86％)，LC-MS m/z：572[M+H]+；A solution of tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (280 mg, 0.51 mmol), tetrahydro-2H-pyran-4-amine (62 mg, 0.61 mmol) and N,N-diisopropylethylamine (197 mg, 1.53 mmol) in isopropanol (4 mL) was heated at 90°C and stirred overnight. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (252 mg, yield: 86%), LC-MS m/z: 572 [M+H] + ;
5)、(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100190
5) Synthesis of (1s, 4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100190
室温条件下，向溶有3-(((1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(252mg，0.44mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯(194mg，收率：93％)，LC-MS m/z：472[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of tert-butyl 3-(((1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (252 mg, 0.44 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (194 mg, yield: 93%), LC-MS m/z: 472 [M+H] + ;
6)、(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100191
6) Synthesis of (1s, 4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100191
将溶有(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯(50mg，0.11mmol)，2-氟丙烯酸(12mg，0.13mmol)，1-甲基-1H-咪唑(35mg，0.42mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(60mg，0.21mmol)的N，N-二甲基甲酰胺(5mL) 溶液加热60℃搅拌2小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1s，4s)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(36.8mg，收率：64％)，LC-MS m/z：544[M+H]+；(1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (50 mg, 0.11 mmol), 2-fluoroacrylic acid (12 mg, 0.13 mmol), 1-methyl-1H-imidazole (35 mg, 0.42 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (60 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (5 mL). The solution was heated at 60°C and stirred for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give (1s,4s)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (36.8 mg, yield: 64%), LC-MS m/z: 544 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.66(s，1H)，5.54-5.35(m，2H)，5.24(dt，J＝16.6，3.4Hz，1H)，4.17-4.11(m，1H)，4.07-4.01(m，1H)，3.99-3.90(m，3H)，3.82-3.71(m，2H)，3.70-3.62(m，1H)，3.53(td，J＝11.6，2.1Hz，2H)，3.00(p，J＝6.9Hz，1H)，2.62(s，1H)，2.24-2.11(m，2H)，2.08-1.97(m，4H)，1.88(s，2H)，1.76(d，J＝4.6Hz，4H)，1.63-1.53(m，2H)，1.27(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d4) δ7.66 (s, 1H), 5.54-5.35 (m, 2H), 5.24 (dt, J=16.6, 3.4Hz, 1H), 4.17-4.11 (m, 1H), 4.07-4.01(m, 1H), 3.99-3.90(m, 3H), 3.82-3.71(m, 2H), 3.70-3.62(m, 1H ), 3.53 (td, J=11.6, 2.1Hz, 2H), 3.00 (p, J=6.9Hz, 1H), 2.62 (s, 1H), 2.24-2.11 (m, 2H), 2.08-1.97 (m, 4H), 1.88 (s, 2H), 1.76 (d, J=4.6Hz, 4H), 1.63-1.53 (m, 2H), 1.27 (d, J=6.9Hz, 6H).
实施例31、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物31)的合成：Example 31, Synthesis of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 31):
1)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100192
1) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100192
将溶有N7-((8-氮杂双环[3.2.1]辛-3-基)甲基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(360mg，0.90mmol)，三乙胺(91mg，0.90mmol)和二(1H-1，2，4-三唑-1-基)甲酮(297mg，1.81mmol)的N，N-二甲基甲酰胺(5mL)溶液氩气保护下，室温搅拌1小时。然后3-羟基吡咯烷-1-羧酸叔丁酯(507mg，2.71mmol)和叔丁醇钾(2mL，1M的四氢呋喃溶液)的加入上述混合反应液、所得混合反应液加热50℃搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(260mg，收率：47.0％)，LC-MS m/z：612[M+H]+；A solution of N 7 -((8-azabicyclo[3.2.1]octan-3-yl)methyl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (360 mg, 0.90 mmol), triethylamine (91 mg, 0.90 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (297 mg, 1.81 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour under argon protection. Then tert-butyl 3-hydroxypyrrolidine-1-carboxylate (507 mg, 2.71 mmol) and potassium tert-butoxide (2 mL, 1 M tetrahydrofuran solution) were added to the above mixed reaction solution, and the obtained mixed reaction solution was heated at 50°C and stirred overnight. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (260 mg, yield: 47.0%), LC-MS m/z: 612 [M+H] + ;
2)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100193
2) Synthesis of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100193
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(260mg，0.43mmol)的二氯甲烷(3mL)和T2，2，2-三氟乙酸(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：512[M+H]+；A solution of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (260 mg, 0.43 mmol) in dichloromethane (3 mL) and T2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 512 [M+H] + ;
3)、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100194
3) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100194
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(100mg，0.20mmol)，2-氟丙烯酸(27mg，0.30mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(115mg，0.30mmol)和N，N-二甲基甲酰胺(78mg，0.60mmol)的N，N-二甲基甲酰胺(5mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(44mg，收率：38.6％)，LC-MS m/z：584[M+H]+；A solution of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.20 mmol), 2-fluoroacrylic acid (27 mg, 0.30 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and N,N-dimethylformamide (78 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (44 mg, yield: 38.6%), LC-MS m/z: 584 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.60(s，1H)，5.45(d，J＝47.2Hz，1H)，5.29-5.20(m，3H)，4.26(s，2H)，4.11-4.05(m，1H)，3.97(d，J＝11.6Hz，2H)，3.92-3.78(m，2H)，3.72-3-.62(m，2H)，3.60-3.52(m，2H)，3.20-3.11(m，2H)，3.09-3.01(m，1H)，2.35(s，1H)，2.23-2.10(m，2H)，2.07-1.94(m，4H)，1.75(d，J＝7.6Hz，4H)，1.60-1.40(m，4H)，1.29(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD) δ7.60 (s, 1H), 5.45 (d, J = 47.2Hz, 1H), 5.29-5.20 (m, 3H), 4.26 (s, 2H), 4.11-4.05 (m , 1H), 3.97 (d, J=11.6Hz, 2H), 3.92-3.78 (m, 2H), 3.72-3-.62 (m, 2H), 3.60-3.52(m, 2H), 3.20-3.11(m, 2H), 3.09-3.01(m, 1H), 2.35(s, 1H), 2.23-2.10(m, 2H), 2.07-1.94(m, 4H ), 1.75 (d, J=7.6Hz, 4H), 1.60-1.40 (m, 4H), 1.29 (d, J=6.8Hz, 6H).
实施例32、4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物32)的合成：
Figure PCTCN2024077920-ftappb-I100195
Example 32, Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (Compound 32):
Figure PCTCN2024077920-ftappb-I100195
将溶有4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸氮杂环丁烷-3-基酯(75mg，0.16mmol)，2-氟丙烯酸(18mg，0.20mmol)，1-甲基-1H-咪唑(53mg，0.65mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(90mg，0.32mmol)的N，N-二甲基甲酰胺(2.5mL)溶液加热60℃搅拌2小时。将混合反应液通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(46mg，收率：53％)。LC-MS m/z：544[M+H]+；A solution of azetidin-3-yl 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (75 mg, 0.16 mmol), 2-fluoroacrylic acid (18 mg, 0.20 mmol), 1-methyl-1H-imidazole (53 mg, 0.65 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (90 mg, 0.32 mmol) in N,N-dimethylformamide (2.5 mL) was heated at 60°C and stirred for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3·H2O = 5-95% elution) to obtain 4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (46 mg, yield: 53%). LC-MS m/z: 544 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.60(s，1H)，5.54(dd，J＝46.9，3.5Hz，1H)，5.27(d，J＝2.8Hz，1H)，5.23-5.18(m，1H)，5.17-5.12(m，1H)，4.78-4.68(m，1H)，4.43-4.32(m，2H)，4.16(s，2H)，4.12-4.02(m，2H)，3.97(dt，J＝11.6，3.6Hz，3H)，3.56(td，J＝11.5，2.1Hz，2H)，3.22(t，J＝6.2Hz，2H)，3.09-3.02(m，1H)，2.95-2.78(m，2H)，2.03(d，J＝12.4Hz，3H)，1.96-1.89(m，1H)，1.84(d，J＝13.0Hz，2H)，1.58-1.48(m，2H)，1.29(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.60 (s, 1H), 5.54 (dd, J=46.9, 3.5Hz, 1H), 5.27 (d, J=2.8Hz, 1H), 5.23-5.18 (m , 1H), 5.17-5.12(m, 1H), 4.78-4.68(m, 1H), 4.43-4.32(m, 2H), 4.16(s, 2H), 4.12-4.02(m, 2H), 3.97(dt , J=11. 6, 3.6Hz, 3H), 3.56 (td, J=11.5, 2.1Hz, 2H), 3.22 (t, J=6.2Hz, 2H), 3.09-3.02 (m, 1H), 2.95-2.78 (m, 2H ), 2.03 (d, J = 12.4Hz, 3H), 1.96-1.89 (m, 1H), 1.84 (d, J = 13.0Hz, 2H), 1.58-1.48 (m, 2H), 1.29 (d, J = 6.9Hz, 6H).
实施例33、1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基(1R，5S)-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(化合物33)的合成：Example 33, Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl(1R,5S)-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 33):
1)、(1R，5S)-3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100196
1) Synthesis of tert-butyl (1R, 5S)-3-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100196
将溶有(1R，5S)-3-(((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(300mg，0.69mmol)，二碳酸二叔丁酯(181mg，0.83mmol)，4-二甲基氨基吡啶(126mg，1.04mmol)和N，N-二异丙基乙胺(445mg，3.45mmol)的二氯甲烷(5mL)溶液室温搅拌4小时。LCMS检测反应完全。将混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到(1R，5S)-3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(350mg，收率：95％)，LC-MS m/z：534[M+H]+；A solution of (1R,5S)-3-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.69 mmol), di-tert-butyl dicarbonate (181 mg, 0.83 mmol), 4-dimethylaminopyridine (126 mg, 1.04 mmol) and N,N-diisopropylethylamine (445 mg, 3.45 mmol) in dichloromethane (5 mL) was stirred at room temperature for 4 hours. The reaction was complete by LCMS. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give (1R,5S)-3-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (350 mg, yield: 95%), LC-MS m/z: 534 [M+H] + ;
2)、(1R，5S)-3-(((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100197
2) Synthesis of tert-butyl (1R, 5S)-3-(((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100197
室温条件下，相溶有氢化钠(60mg，1.5mmol，质量分数：60％)的四氢呋喃(1mL)溶液中，加入溶有(1R，5S)-3-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(367mg，0.69mmol)和(R)-3-羟基哌啶-1-羧酸苄基酯(178mg，0.76mmol)的四氢呋喃(2mL)溶液。所得混合反应液室温搅拌3小时。LCMS检测反应完成。将所得混合反应液加水(20mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-30％洗脱)纯化得到(1R，5S)-3-(((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(210mg，收率：41.6％)，LC-MS m/z：733[M+H]+；At room temperature, a solution of (1R, 5S)-3-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (367 mg, 0.69 mmol) and (R)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (178 mg, 0.76 mmol) in tetrahydrofuran (2 mL) was added to a solution of sodium hydride (60 mg, 1.5 mmol, mass fraction: 60%) in tetrahydrofuran (1 mL). The resulting mixed reaction solution was stirred at room temperature for 3 hours. LCMS detected that the reaction was complete. The resulting mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30% elution) to give (1R,5S)-3-(((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (210 mg, yield: 41.6%), LC-MS m/z: 733 [M+H] + ;
3)、(3R)-3-((7-(((((1R，5S)-8-氮杂双环[3.2.1]辛-3-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100198
3) Synthesis of benzyl (3R)-3-((7-(((((1R,5S)-8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100198
将溶有(1R，5S)-3-(((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(208mg，0.28mmol)和2，2，2-三氟乙酸(0.4mL)的二氯甲烷(1.2mL)溶液，室温搅拌2小时。将混合反应液减压浓缩得到粗产物，直接 用于下一步骤，无需进一步纯化。LC-MS m/z：533[M+H]+。A solution of (1R, 5S)-3-(((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (208 mg, 0.28 mmol) and 2,2,2-trifluoroacetic acid (0.4 mL) in dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly Used in the next step without further purification. LC-MS m/z: 533 [M+H] + .
4)、(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100199
4) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100199
在室温条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(67mg，0.39mmol)的N，N-二甲基甲酰胺(1mL)溶液中，加入三乙胺(119mg，1.18mmol)。然后将二(三氯甲基)碳酸酯(115mg，0.39mmol)的N，N-二甲基甲酰胺(2mL)溶液加入到上述混合反应液中，所得混合反应液氮气保护下，室温搅拌1小时。然后将(3R)-3-((7-(((((1R，5S)-8-氮杂双环[3.2.1]辛-3-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(230mg，0.43mmol)的N，N-二甲基甲酰胺(1mL)溶液，加入到上述混合反应液中.所得混合反应液加热40℃搅拌16小时。LCMS检测反应完成。将混合反应液通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(61mg，收率：21.6％)，LC-MS m/z：732[M+H]+；At room temperature, triethylamine (119 mg, 1.18 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (67 mg, 0.39 mmol) in N,N-dimethylformamide (1 mL). Then, a solution of bis(trichloromethyl) carbonate (115 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL) was added to the mixed reaction solution, and the mixed reaction solution was stirred at room temperature for 1 hour under nitrogen protection. Then, a solution of (3R)-3-((7-(((((1R,5S)-8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (230 mg, 0.43 mmol) in N,N-dimethylformamide (1 mL) was added to the above mixed reaction solution. The obtained mixed reaction solution was heated at 40° C. and stirred for 16 hours. The reaction was completed by LCMS. The mixed reaction solution was added to the mixture. The resulting solution was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (61 mg, yield: 21.6%), LC-MS m/z: 732 [M+H] + ;
4)、(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100200
4) Synthesis of (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100200
将溶有(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(60mg，0.082mmol)和2，2，2-三氟乙酸(0.4mL)的二氯甲烷(1.2mL)溶液，室温搅拌2小时。LCMS检测反应完全。将混合反应液减压浓缩得到粗产物，直接用于下一步骤，无需进一步纯化。LC-MS m/z：632[M+H]+；A solution of (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (60 mg, 0.082 mmol) and 2,2,2-trifluoroacetic acid (0.4 mL) in dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 632[M+H] + ;
5)、(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100201
5) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl(1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100201
将溶有(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(32mg，0.050mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(10g.076mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(28mg，0.10mmol)和N-甲基咪唑(17mg，0.20mmol)的N，N-二甲基甲酰胺(2mL)溶液加热40℃搅拌16小时，LCMS检测反应液完全。残余物通过C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(10mg，收率：27％)，LC-MS m/z：743[M+H]+；A solution of (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidine-3-yl ester (32 mg, 0.050 mmol), (E)-4-(dimethylamino)but-2-enoic acid (10 g. 076 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (28 mg, 0.10 mmol) and N-methylimidazole (17 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL) was heated at 40° C. and stirred for 16 hours. The reaction solution was complete when LCMS detected. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (10 mg, yield: 27%), LC-MS m/z: 743 [M+H] + ;
6)、1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基(1R，5S)-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
Figure PCTCN2024077920-ftappb-I100202
6) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl(1R,5S)-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100202
将溶有(1R，5S)-3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(10mg，0.013mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。LCMS监测反应完全。将所得混合反应液减压浓缩。残余物通过制备HPLC纯化得到1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基(1R，5S)-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(5.07mg，收率：61.9％)，LC-MS m/z：609[M+H]+；A solution of (1R,5S)-3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (10 mg, 0.013 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The reaction was complete when monitored by LCMS. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl(1R,5S)-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (5.07 mg, yield: 61.9%), LC-MS m/z: 609 [M+H] + ;
1H NMR(400MHz，CD3OD-d4)：δ7.76(s，1H)，6.72(dt，J＝14.8，7.2Hz，1H)，6.48(d，J＝15.2Hz，1H)，5.50(s，1H)，5.24-5.16(m，1H)，4.64(s，1H)，4.36(dd，J＝27.6，21.6Hz，4H)，3.99(dd，J＝38.8，9.6Hz，3H)，3.48(ddd，J＝15.6，13.1，3.2Hz，2H)，3.32(s，1H)，3.23(d，J＝6.8Hz，2H)，3.19-3.04(m，2H)，2.89(s，6H)，2.44-2.29(m，1H)，2.19-1.90(m，6H)，1.89-1.69(m，5H)，1.55-1.42(m，2H)，1.31(d，J＝6.8Hz，6H). 1 H NMR (400MHz, CD 3 OD-d 4 ): δ7.76 (s, 1H), 6.72 (dt, J=14.8, 7.2Hz, 1H), 6.48 (d, J=15.2Hz, 1H), 5.50 (s, 1H), 5.24-5.16 (m, 1H), 4.64 (s, 1H), 4.36 (dd, J=27.6, 21.6Hz, 4H), 3.99 (dd, J=38.8, 9.6Hz, 3H), 3.48(ddd,J＝ 15.6, 13.1, 3.2Hz, 2H), 3.32 (s, 1H), 3.23 (d, J=6.8Hz, 2H), 3.19-3.04 (m, 2H), 2.89 (s, 6H), 2.44-2.29 (m , 1H), 2.19-1.90 (m, 6H), 1.89-1.69 (m, 5H), 1.55-1.42 (m, 2H), 1.31 (d, J=6.8Hz, 6H).
实施例34、8-((3-异丙基-5-(((S)-哌啶-3-基)氧基)吡唑[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物34)的合成： Example 34, Synthesis of 8-((3-isopropyl-5-(((S)-piperidin-3-yl)oxy)pyrazol[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]oct-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compound 34):
1)、8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基叔丁氧基羰基)氨基)甲基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100203
1) Synthesis of tert-butyl 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yltert-butoxycarbonyl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100203
将溶有8-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(160mg，0.30mmol)，(S)-3-羟基哌啶-1-甲酸苄基酯(84mg，0.36mmol)和氢化钠(11mg，0.45mmol)的四氢呋喃(3mL)溶液室温搅拌1小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基叔丁氧基羰基)氨基)甲基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(200mg，收率：91.0％)，LC-MS m/z：733[M+H]+；A solution of tert-butyl 8-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (160 mg, 0.30 mmol), (S)-3-hydroxypiperidine-1-carboxylate benzyl ester (84 mg, 0.36 mmol) and sodium hydride (11 mg, 0.45 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give tert-butyl 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yltert-butoxycarbonyl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (200 mg, yield: 91.0%), LC-MS m/z: 733 [M+H] + ;
2)、(S)-3-((7-(((3-氮杂双环[3.2.1]辛-8-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100204
2) Synthesis of benzyl (S)-3-((7-(((3-azabicyclo[3.2.1]oct-8-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100204
将溶有8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基叔丁氧基羰基)氨基)甲基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(200mg，0.27mmol)的二氯甲烷(10mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌16小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈：纯水＝0-95％洗脱)纯化得到(S)-3-((7-(((3-氮杂双环[3.2.1]辛-8-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸苄基酯(140mg，收率：96％)，LC-MS m/z：533[M+H]+；A solution of 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yltert-butyloxycarbonyl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (200 mg, 0.27 mmol) in dichloromethane (10 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=0-95% elution) to give (S)-benzyl 3-((7-(((3-azabicyclo[3.2.1]octan-8-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (140 mg, yield: 96%), LC-MS m/z: 533 [M+H] + ;
3)、8-(((5-(((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100205
3) Synthesis of 8-(((5-(((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100205
将溶有3-羟基吡咯烷-1-甲酸叔丁酯(21mg，0.11mmol)，三乙胺(33mg，0.33mmol)和1，1`-羰基二-(1，2，4-三唑)(36mg，0.22mmol)的N，N-二甲基甲酰胺(1mL)溶液氮气保护下，0℃搅拌搅拌0.5小时。 然后将混合物加入(S)-3-((7-(((3-氮杂双环[3.2.1]辛-8-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸苄基酯(60mg，0.11mmol)加入到上述混合反应液中。所得混合物室温搅拌16小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0-80％洗脱)纯化得到8-(((5-(((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(40mg，收率：48％)，LC-MS m/z：746[M+H]+；A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (21 mg, 0.11 mmol), triethylamine (33 mg, 0.33 mmol) and 1,1'-carbonylbis-(1,2,4-triazole) (36 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was stirred at 0°C for 0.5 hours under nitrogen protection. Then, (S)-3-((7-(((3-azabicyclo[3.2.1]oct-8-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (60 mg, 0.11 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=0-80% elution) to give 8-(((5-(((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (40 mg, yield: 48%), LC-MS m/z: 746 [M+H] + ;
4)、8-(((5-(((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂二环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100206
4) Synthesis of 8-(((5-(((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100206
将溶有8-(((5-(((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(40mg，0.05mmol)的二氯甲烷(1mL)和2，2，2-三氟乙酸(0.1mL)溶液室温搅拌16小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，无需进一步纯化。LC-MS m/z：646[M+H]+；A solution of 8-(((5-(((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (40 mg, 0.05 mmol) in dichloromethane (1 mL) and 2,2,2-trifluoroacetic acid (0.1 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 646[M+H] + ;
5)、8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂二环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100207
5) Synthesis of 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100207
将溶有8-(((5-(((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂二环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(40mg，0.06mmol)、(E)-4-(二甲基氨基)丁-2-烯酸(10mg，0.08mmol)，1-甲基-1H-咪唑(20mg，0.24mmol)和N、N，N′，N′-四甲基氯甲脒六氟磷酸盐(34mg，0.12mmol)。将混合反应液通过C18柱色谱法(乙腈∶纯水＝0-60％洗脱)纯化得到8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂二环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(30mg，收率：64％)，LC-MS m/z：757[M+H]+；8-(((5-(((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (40 mg, 0.06 mmol), (E)-4-(dimethylamino)but-2-enoic acid (10 mg, 0.08 mmol), 1-methyl-1H-imidazole (20 mg, 0.24 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (34 mg, 0.12 mmol) were dissolved. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water = 0-60% elution) to give 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]oct-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (30 mg, yield: 64%), LC-MS m/z: 757 [M+H] + ;
6)、8-((3-异丙基-5-(((S)-哌啶-3-基)氧基)吡唑[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100208
6) Synthesis of 8-((3-isopropyl-5-(((S)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100208
将溶有8-(((5-((S)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂二环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(30mg，0.04mmol)的2，2，2-三氟乙酸(1mL)溶液加热50℃搅拌16小时。冷却后，将混合反应液减压浓缩浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0-95％洗脱)纯化得到8-((3-异丙基-5-(((S)-哌啶-3-基)氧基)吡唑[1，5-a]嘧啶-7-基)氨基)甲基)-3-氮杂双环[3.2.1]辛-3-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(2mg，收率：8.0％)，LC-MS m/z：623[M+H]+；A solution of 8-(((5-((S)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (30 mg, 0.04 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was heated at 50° C. and stirred for 16 hours. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=0-95% elution) to give 8-((3-isopropyl-5-(((S)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-3-azabicyclo[3.2.1]oct-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (2 mg, yield: 8.0%), LC-MS m/z: 623 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.77(s，1H)，6.78-6.68(m，2H)，5.57(s，1H)，5.51(s，1H)，5.27(d，J＝12.0Hz，1H)，4.03-3.60(m，8H)，3.59-3.37(m，3H)，3.20(d，J＝7.6Hz，2H)，3.10(td，J＝13.6，7.2Hz，2H)，3.00-2.85(m，8H)，2.16(dd，J＝23.6，16.0Hz，7H)，1.99(t，J＝13.2Hz，1H)，1.86(s，3H)，1.59-1.43(m，2H)，1.32(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.77 (s, 1H), 6.78-6.68 (m, 2H), 5.57 (s, 1H), 5.51 (s, 1H), 5.27 (d, J=12.0 Hz, 1H), 4.03-3.60 (m, 8H), 3.59-3.37 (m, 3H), 3.20 (d, J=7.6Hz, 2H), 3.10 (td, J=13.6, 7.2Hz, 2H), 3.00-2.85 (m, 8H), 2.16 (dd, J=23.6, 16.0Hz, 7H), 1.99 (t, J=13.2Hz, 1H ), 1.86 (s, 3H), 1.59-1.43 (m, 2H), 1.32 (d, J=6.8Hz, 6H).
实施例35、(R)-4-(((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物35)的合成：Example 35, Synthesis of (R)-4-(((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)azetidine-3-yl ester (Compound 35):
1)、(R)-3-((7-(((1-((苄氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100209
1) Synthesis of tert-butyl (R)-3-((7-(((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100209
将(R)-(-)-1-[(S)-2-(二环己基膦基)二茂铁基]乙基二叔丁基膦(140mg，0.25mmol)和三(二亚苄基丙酮)二钯(230mg，0.25mmol)加入到盛有预先搅拌4-(((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸苄基酯(680mg，1.26mmol)和(R)-3-羟基哌啶-1-羧酸叔丁酯(632mg，3.14mmol)和碳酸铯(1.23g，3.77mmol)的甲苯(8mL)溶液的微波反应器。将反应器密封并微波加热140℃加热1小时。将混合反应液加盐水(10mL)和水(10mL)稀释，并用乙醚(3×20mL)萃取。合并的有机相用盐水和水(4×20mL，v∶v＝1∶1)洗涤，干燥，减压浓缩。残余物通过C18柱色谱法(乙腈∶含有0.1％甲酸的纯水＝50-85％洗脱)纯化得到(R)-3-((7-(((1-((苄氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸叔丁酯(800mg，收率：97％)，LC-MS m/z：707[M+H]+；(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (140 mg, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium (230 mg, 0.25 mmol) were added to a microwave reactor containing a pre-stirred solution of benzyl 4-(((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylate (680 mg, 1.26 mmol) and tert-butyl (R)-3-hydroxypiperidine-1-carboxylate (632 mg, 3.14 mmol) and cesium carbonate (1.23 g, 3.77 mmol) in toluene (8 mL). The reactor was sealed and microwaved at 140°C for 1 hour. The mixed reaction solution was diluted with brine (10 mL) and water (10 mL) and extracted with ether (3×20 mL). The combined organic phase was washed with brine and water (4×20 mL, v:v=1:1), dried, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 50-85% elution) to give (R)-3-((7-(((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (800 mg, yield: 97%), LC-MS m/z: 707 [M+H] + ;
2)、(R)-3-((7-((叔丁氧羰基)(哌啶-4-基甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100210
2) Synthesis of tert-butyl (R)-3-((7-((tert-butyloxycarbonyl)(piperidin-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100210
将溶有(R)-3-((7-(((1-((苄氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸叔丁酯(800mg，1.13mmol)和钯碳(480mg)的2，2，2-三氟乙醇(9mL)溶液，氢气(5atm)保护下，室温搅拌过夜。将混合反应液过滤，滤饼用甲醇(3×50mL)洗涤。收集滤液在真空下浓缩粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：573[M+H]+；A solution of (R)-tert-butyl 3-((7-(((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (800 mg, 1.13 mmol) and palladium on carbon (480 mg) in 2,2,2-trifluoroethanol (9 mL) was stirred overnight at room temperature under the protection of hydrogen (5 atm). The mixed reaction liquid was filtered and the filter cake was washed with methanol (3×50 mL). The filtrate was collected and concentrated under vacuum to obtain the crude product, which was used directly in the next step without further purification. LC-MS m/z: 573[M+H] + ;
3)、(R)-3-((7-(((1-(((1-((苄氧基)羰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100211
3) Synthesis of tert-butyl (R)-3-((7-(((1-(((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100211
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔苄酯(97mg，0.47mmol)和三乙胺(141mg，1.4mmol)的四氢呋喃(5mL)溶液中，加入双(三氯甲基)碳酸酯(68mg，0.23mmol)，0℃搅拌1小时，然后在0℃条件下，将(R)-3-((7-((叔丁氧羰基)(哌啶-4-基甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(400mg，0.70mmol)。所得混合反应液室温搅拌过夜。将所得混合反应液加水稀释，并用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(R)-3-((7-(((1-(((1-((苄氧基)羰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(160mg，收率：29％)。LC-MS m/z：806[M+H]+；At 0°C, bis(trichloromethyl)carbonate (68 mg, 0.23 mmol) was added to a solution of tert-benzyl 3-hydroxyazetidine-1-carboxylate (97 mg, 0.47 mmol) and triethylamine (141 mg, 1.4 mmol) in tetrahydrofuran (5 mL), and stirred at 0°C for 1 hour. Then, tert-butyl (R)-3-((7-((tert-butyloxycarbonyl)(piperidin-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (400 mg, 0.70 mmol) was added at 0°C. The resulting mixed reaction solution was stirred at room temperature overnight. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give (R)-3-((7-(((1-(((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (160 mg, yield: 29%). LC-MS m/z: 806 [M+H] + ;
4)、(R)-3-((7-(((1-((氮杂环丁烷-3-基氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100212
4) Synthesis of tert-butyl (R)-3-((7-(((1-((azetidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100212
将溶有(R)-3-((7-(((1-(((1-((苄氧基)羰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(160mg，0.20mmol)和钯碳(86mg)的甲醇(2mL)溶液，氢气氛围(5atm)下，室温搅拌过夜。将混合反应液过滤，滤饼用甲醇(3×30mL)洗涤。收集滤液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：672[M+H]+；A solution of (R)-3-((7-(((1-(((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.20 mmol) and palladium on carbon (86 mg) in methanol (2 mL) was stirred at room temperature overnight under a hydrogen atmosphere (5 atm). The mixed reaction solution was filtered and the filter cake was washed with methanol (3×30 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 672[M+H] + ;
5)、(R)-3-((7-((叔丁氧基羰基)((1-((((1-(2-氟丙烯酰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100213
5) Synthesis of tert-butyl (R)-3-((7-((tert-butoxycarbonyl)((1-((((1-(2-fluoroacryloyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100213
在室温条件下，向溶有(R)-3-((7-(((1-((氮杂环丁烷-3-基氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(125mg，0.19mmol)和2-氟丙烯酸(25mg，0.28mmol)的N，N-二甲基甲酰胺(1.5mL)溶液中，加入N，N，N′，N′-四甲基氯甲脒六氟磷(104mg，0.37mmol)和1-甲基-1H-咪唑(76mg，0.93mmol)。所得混合反应液室温搅拌5小时。将所得混合反应液加水稀释，并用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(R)-3-((7-((叔丁氧基羰基)((1-((((1-(2-氟丙烯酰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(45mg，收率：32.5％)，LC-MS m/z：744[M+H]+；At room temperature, N, N, N', N'-tetramethylchloroformamidine hexafluorophosphorus (104 mg, 0.37 mmol) and 1-methyl-1H-imidazole (76 mg, 0.93 mmol) were added to a solution of (R)-3-((7-(((1-((azetidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (125 mg, 0.19 mmol) and 2-fluoroacrylic acid (25 mg, 0.28 mmol) in N, N-dimethylformamide (1.5 mL). The resulting mixed reaction solution was stirred at room temperature for 5 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give (R)-3-((7-((tert-butoxycarbonyl)((1-((((1-(2-fluoroacryloyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (45 mg, yield: 32.5%), LC-MS m/z: 744 [M+H] + ;
6)、(R)-4-(((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100214
6) Synthesis of (R)-4-(((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100214
室温条件下，向溶有(R)-3-((7-((叔丁氧基羰基)((1-((((1-(2-氟丙烯酰基)氮杂环丁烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(45mg，0.060mmol)的二氯甲烷(0.8mL)溶液中，滴加2，2，2-三氟乙酸(0.2mL)。所得混合反应液室温搅拌2小时。将所得混合反应液加水稀释并用乙酸乙酯(3×30mL)萃取。合并有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到(R)-4-(((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，收率：60.8％)，LC-MS m/z：544[M+H]+；To a solution of (R)-tert-butyl 3-((7-((tert-butoxycarbonyl)((1-((((1-(2-fluoroacryloyl)azetidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (45 mg, 0.060 mmol) in dichloromethane (0.8 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.2 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and ethyl acetate ( 3×30mL). The combined organic phases were washed with saturated brine (1×10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give (R)-4-(((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, yield: 60.8%), LC-MS m/z: 544[M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.78(s，1H)，5.62-5.51(m，2H)，5.46(s，1H)，7.31(dd，J＝4.0Hz，J＝16Hz，1H)，5.19-5.16(m，1H)，4.79-4.73(m，1H)，4.44-4.37(m，2H)，4.19(s，2H)，4.03(d，J＝4.0Hz，1H)，3.42-3.41(m，2H)，3.30(s，1H)，3.24-3.21(m，1H)，3.13-3.08(m，2H)，2.94-2.38(m，3H)，2.06-1.82(m，9H)，1.34(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.78 (s, 1H), 5.62-5.51 (m, 2H), 5.46 (s, 1H), 7.31 (dd, J=4.0Hz, J=16Hz, 1H ), 5.19-5.16(m, 1H), 4.79-4.73(m, 1H), 4.44-4.37(m, 2H), 4.1 9(s, 2H), 4.03(d, J=4.0Hz, 1H), 3.42-3.41(m, 2H), 3.30(s, 1H), 3.24-3.21(m, 1H), 3.13-3.08(m, 2H), 2.94-2.38(m, 3H), 2.06-1.82(m, 9H), 1.34(d, J=8.0Hz, 6H).
实施例36、4-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物36)的合成：Example 36, Synthesis of 4-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 36):
1)、(3R)-3-((7-(((1-(((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100215
1) Synthesis of tert-butyl (3R)-3-((7-(((1-(((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100215
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸苄基酯(23.2mg，0.10mmol)和三乙胺(30mg，0.30mmol)的四氢呋喃(1mL)溶液中，分批加入双(三氯甲基)碳酸酯(15mg，0.05mmol)，室温搅拌1小时。然后将(R)-3-((7-((叔丁氧羰基)(哌啶-4-基甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(71mg，0.15mmol)加入上述混合反应液中，所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝65-85％洗脱)得到(3R)-3-((7-(((1-(((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a] 嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(55mg，收率：64％)，LC-MS m/z：820[M+H]+；At 0°C, bis(trichloromethyl)carbonate (15 mg, 0.05 mmol) was added in portions to a solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (23.2 mg, 0.10 mmol) and triethylamine (30 mg, 0.30 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hour. Then, tert-butyl (R)-3-((7-((tert-butyloxycarbonyl)(piperidin-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (71 mg, 0.15 mmol) was added to the mixed reaction solution, and the mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=65-85% elution) to give (3R)-3-((7-(((1-(((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] tert-Butyl pyrimidin-5-yl)oxy)piperidine-1-carboxylate (55 mg, yield: 64%), LC-MS m/z: 820 [M+H] + ;
2)、(3R)-3-((7-((叔丁氧羰基)((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100216
2) Synthesis of tert-butyl (3R)-3-((7-((tert-butyloxycarbonyl)((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100216
将溶有3R)-3-((7-(((1-(((1-((苄氧基)羰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)(叔丁氧基羰基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(55mg，0.067mmol)和钯(22mg)的2，2，2-三氟乙醇(1.5mL)溶液，氢气氛围下室温搅拌2小时。将所得混合反应液过滤，收集滤液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝30-45％洗脱)得到(3R)-3-((7-((叔丁氧羰基)((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(40mg，收率：87％)，LC-MS m/z：686[M+H]+；A solution of tert-butyl 3-((7-(((1-(((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (55 mg, 0.067 mmol) and palladium (22 mg) in 2,2,2-trifluoroethanol (1.5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The obtained mixed reaction liquid was filtered, and the collected filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 30-45% elution) to give (3R)-3-((7-((tert-butyloxycarbonyl)((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (40 mg, yield: 87%), LC-MS m/z: 686[M+H]+;
3)、(3R)-3-((7-((叔丁氧羰基)((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100217
3) Synthesis of tert-butyl (3R)-3-((7-((tert-butyloxycarbonyl)((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100217
将溶有3R)-3-((7-((叔丁氧羰基)((1-((吡咯烷-3-基氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(40mg，0.058mmol)和2-氟丙-2-烯酸(8mg，0.087mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(33mg，0.12mmol)和1-甲基-1H-咪唑(19mg，0.23mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌16小时。残余物通过C18柱色谱(乙腈∶纯水＝65-85％洗脱)纯化得到(3R)-3-((7-((叔丁氧羰基)((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(26mg，收率：58.8％)，LC-MS m/z：758[M+H]+； A solution of tert-butyl 3-((7-((tert-butoxycarbonyl)((1-((pyrrolidin-3-yloxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (40 mg, 0.058 mmol) and 2-fluoroprop-2-enoic acid (8 mg, 0.087 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (33 mg, 0.12 mmol) and 1-methyl-1H-imidazole (19 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (acetonitrile:purified water=65-85% elution) to give (3R)-tert-butyl 3-((7-((tert-butoxycarbonyl)((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (26 mg, yield: 58.8%), LC-MS m/z: 758 [M+H]+;
4)、4-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100218
4) Synthesis of 4-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100218
将溶有(3R)-3-((7-((叔丁氧羰基)((1-((1-(2-氟丙烯酰基)吡咯烷-3-基)氧基)羰基)哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸叔丁酯(26mg，0.034mmol)的二氯甲烷(0.9mL)和2，2，2-三氟乙酸(0.3mL)溶液，室温搅拌2小时，将所得混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝20-40％洗脱)得到4-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(11mg，收率：58％)，LC-MS m/z：558[M+H]+；A solution of (3R)-tert-butyl 3-((7-(tert-butoxycarbonyl)((1-((1-(2-fluoroacryloyl)pyrrolidin-3-yl)oxy)carbonyl)piperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (26 mg, 0.034 mmol) in dichloromethane (0.9 mL) and 2,2,2-trifluoroacetic acid (0.3 mL) was stirred at room temperature for 2 hours, and the resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=20-40% elution) to give 4-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (11 mg, yield: 58%), LC-MS m/z: 558 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.76(s，1H)，5.50-5.45(m，3H)，5.27-5.22(m，2H)，4.18-4.12(m，2H)，3.95-3.86(m，1H)，3.83-3.49(m，4H)，3.45-3.40(m，1H)，3.33-3.26(m，5H)，3.19-3.12(m，1H)，3.08(dd，J＝13.9，6.9Hz，1H)，2.82(s，2H)，2.25-2.06(m，4H)，2.05-1.89(m，2H)，1.86-1.81(m，3H)，1.32(d，J＝8.0Hz，6H).1H NMR (400MHz, MeOD): δ7.76 (s, 1H), 5.50-5.45 (m, 3H), 5.27-5.22 (m, 2H), 4.18-4.12 (m, 2H), 3.95-3.86 (m, 1H), 3.83-3.49(m, 4H), 3.45-3.40(m, 1H), 3.3 3-3.26 (m, 5H), 3.19-3.12 (m, 1H), 3.08 (dd, J=13.9, 6.9Hz, 1H), 2.82 (s, 2H), 2.25-2.06 (m, 4H), 2.05- 1.89 (m, 2H), 1.86-1.81 (m, 3H), 1.32 (d, J=8.0Hz, 6H).
实施例37、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯(化合物37)的合成：Example 37, Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl) ester (Compound 37):
1)、4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100219
1) Synthesis of tert-butyl 4-((tert-butyloxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100219
将溶有4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.5g，3.04mmol，三甲基-1，3，5，2，4，6-三噁三硼己环(579mg，4.56mmol)，四(三苯基膦)钯(0.35g，0.30mmol)的1.4-二氧六环(15mL)溶液，氮气保护下，加热100℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.2g，收率：83％)，LC-MS m/z：474[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.5 g, 3.04 mmol), trimethyl-1,3,5,2,4,6-trioxatriborin (579 mg, 4.56 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol) in 1.4-dioxane (15 mL) was heated at 100°C with stirring for 2 hours under nitrogen protection. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3 ·H 2 O pure water = 5-95% elution) to obtain tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.2 g, yield: 83%), LC-MS m/z: 474 [M+H] + ;
2)、3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100220
2) Synthesis of 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100220
向溶有4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.2g，2.54mmol)的二氯甲烷(9mL)溶液中，加入2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(500mg，收率：72％)，LC-MS m/z：274[M+H]+；2,2,2-Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.2 g, 2.54 mmol) in dichloromethane (9 mL). The resulting mixed reaction liquid was stirred at room temperature for 1 hour. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (500 mg, yield: 72%), LC-MS m/z: 274 [M+H] + ;
3)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲酯的合成
Figure PCTCN2024077920-ftappb-I100221
3) Synthesis of methyl 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)
Figure PCTCN2024077920-ftappb-I100221
在0℃条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(450mg，2.19mmol)和T三乙胺(74mg，0.73mmol)的二氯甲烷(4mL)溶液中，加入双(三氯甲基)碳酸酯(867mg，2.92mmol)。所得混合反应液0℃搅拌1小时。然后，在0℃条件下，3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(400mg，1.46mmol)加入上述的混合反应液中。加完后，所得混合反应液0℃搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲酯(250mg，收率：34％)，LC-MS m/z：505[M+H]+；At 0°C, bis(trichloromethyl)carbonate (867mg, 2.92mmol) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (450mg, 2.19mmol) and triethylamine (74mg, 0.73mmol) in dichloromethane (4mL). The resulting mixed reaction solution was stirred at 0°C for 1 hour. Then, 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (400mg, 1.46mmol) was added to the above mixed reaction solution at 0°C. After the addition, the resulting mixed reaction solution was stirred at 0°C for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (250 mg, yield: 34%), LC-MS m/z: 505 [M+H] + ;
4)、(3-氟氮杂环丁烷-3-基)4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲酯的合成
Figure PCTCN2024077920-ftappb-I100222
4) Synthesis of (3-fluoroazetidine-3-yl)-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester
Figure PCTCN2024077920-ftappb-I100222
向溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲酯(200mg，0.40mmol)的二氯甲烷(3mL)溶液中，加入2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：405[M+H]+；2,2,2-trifluoroacetic acid (1 mL) was added to a solution of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (200 mg, 0.40 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was reduced in pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 405 [M+H] + ;
5)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯的合成
Figure PCTCN2024077920-ftappb-I100223
5) Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl) ester
Figure PCTCN2024077920-ftappb-I100223
将溶有(3-氟氮杂环丁烷-3-基)4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲酯(50mg，0.12mmol)，2-氟丙-2-烯酸(16mg，0.18mmol)，1-甲基-1H-咪唑(39mg，0.48mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(67mg，0.24mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌1小时。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯(2mg，收率：3.40％)，LC-MS m/z：477[M+H]+；A solution of (3-fluoroazetidine-3-yl)-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester (50 mg, 0.12 mmol), 2-fluoroprop-2-enoic acid (16 mg, 0.18 mmol), 1-methyl-1H-imidazole (39 mg, 0.48 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (67 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give methyl (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl) 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (2 mg, yield: 3.40%), LC-MS m/z: 477 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.11(s，1H)，5.58(dd，J＝48.0，3.5Hz，1H)，5.23(dd，J＝16.0， 3.5Hz，1H)，4.70-4.53(m，2H)，4.47(d，J＝20.0Hz，2H)，4.34-4.21(m，1H)，4.20-4.07(m，3H)，3m，2H)，3.91-3.83(m，1H)，3.30-3.23(m，1H)，3.13-3.04(m，1H)，2.99-2.96(m，1H)，2.49(s，3H)，2.14-2.06(m，2H)，1.69-1.58(m，2H)，1.31(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.87 (s, 1H), 6.11 (s, 1H), 5.58 (dd, J=48.0, 3.5Hz, 1H), 5.23 (dd, J=16.0, 3.5Hz, 1H), 4.70-4.53 (m, 2H), 4.47 (d, J=20.0Hz, 2H), 4.34-4.21 (m, 1H), 4.20-4.07 (m, 3H), 3m, 2H), 3.91-3.83(m, 1H), 3.30-3.23(m, 1H), 3.13-3.04(m, 1H), 2.99-2.96(m, 1H), 2.49(s, 3H), 2.14-2.06(m, 2H ), 1.69-1.58 (m, 2H), 1.31 (d, J=8.0Hz, 6H).
实施例38、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯(化合物38)的合成：Example 38, Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester (Compound 38):
1)、4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100224
1) Synthesis of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100224
将溶有4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(500.0mg，1.23mmol)和2-氯过氧苯甲酸(1065mg，6.16mmol)的二氯甲烷(10mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：439[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (500.0 mg, 1.23 mmol) and 2-chloroperoxybenzoic acid (1065 mg, 6.16 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 439 [M+H] + ;
2)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100225
2) Synthesis of tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100225
在室温条件下，向溶有4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(500mg，1.14mmol)的四氢呋喃(5mL)溶液中，逐滴加入甲基溴化镁(2.3mL，3M的四氢呋喃溶液)。所得混合反应液室温搅拌过夜。在0℃条件下，加水(20mL)淬灭反应，并用二氯甲烷(3×50mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(400mg，收率：93.6％)，LC-MS m/z：375[M+H]+；At room temperature, methylmagnesium bromide (2.3 mL, 3M solution in tetrahydrofuran) was added dropwise to a solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (500 mg, 1.14 mmol) in tetrahydrofuran (5 mL). The resulting mixed reaction solution was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction at 0°C, and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (400 mg, yield: 93.6%), LC-MS m/z: 375 [M+H] + ;
3)、8-异丙基-2-甲基-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺的合成
Figure PCTCN2024077920-ftappb-I100226
3) Synthesis of 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine
Figure PCTCN2024077920-ftappb-I100226
向溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(400mg，1.07mmol)的二氯甲烷(9mL)溶液中，滴加2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：275[M+H]+；2,2,2-Trifluoroacetic acid (3 mL) was added dropwise to a solution of tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (400 mg, 1.07 mmol) in dichloromethane (9 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 275 [M+H] + ;
4)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯的合成
Figure PCTCN2024077920-ftappb-I100227
4) Synthesis of methyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (1-(tert-butyloxycarbonyl)pyrrolidin-2-yl)
Figure PCTCN2024077920-ftappb-I100227
在室温条件下，向溶有的2-(羟甲基)吡咯烷-1-甲酸叔丁酯(250mg，1.24mmol)和三乙胺(250mg，2.48mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入三光气(245mg，0.83mmol)。所得混合物反应液室温搅拌1小时。在室温条件下，将8-异丙基-2-甲基-N-(哌啶-4-基)吡唑[1，5-a][1，3，5]三嗪-4-胺(227mg，0.83mmol)加入到上述混合反应液中。所得混合反应液室温搅拌过夜。将混合反应液减压浓缩并通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯(330mg，收率：79.6％)，LC-MS m/z：502[M+H]+；Triphosgene (245 mg, 0.83 mmol) was added to a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.24 mmol) and triethylamine (250 mg, 2.48 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (227 mg, 0.83 mmol) was added to the above mixed reaction solution at room temperature. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1carboxylic acid (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl ester (330 mg, yield: 79.6%), LC-MS m/z: 502 [M+H] + ;
5)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯的合成
Figure PCTCN2024077920-ftappb-I100228
5) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester
Figure PCTCN2024077920-ftappb-I100228
室温条件下，向溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯(330mg，0.66mmol)的二氯甲烷(9mL)溶液滴加2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：402[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (3 mL) was added dropwise to a solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)pyrrolidin-2-yl)methyl ester (330 mg, 0.66 mmol) in dichloromethane (9 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 402 [M+H] + ;
6)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100229
6) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100229
将溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(200mg，0.50mmol)，2-氟丙烯酸(135mg，1.50mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(569mg，1.50mmol)和N，N-二异丙基乙胺(322mg，2.50mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-46％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯(65mg，收率：27.5％)，LC-MS m/z：474[M+H]+；A solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (200 mg, 0.50 mmol), 2-fluoroacrylic acid (135 mg, 1.50 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (569 mg, 1.50 mmol) and N,N-diisopropylethylamine (322 mg, 2.50 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-46% elution) to obtain 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester (65 mg, yield: 27.5%), LC-MS m/z: 474 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.90(s，1H)，5.39(d，J＝47.2Hz，1H)，5.23(dd，J＝16.7，3.4Hz，1H)，4.41-4.29(m，2H)，4.17(s，4H)，3.70(d，J＝20.0Hz，2H)，3.19(dt，J＝14.0，6.8Hz，1H)，3.03(s，1H)，2.47(s，3H)，2.04(d，J＝12.4Hz，4H)，1.95-1.87(m，2H)，1.73-1.58(m，3H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD) δ7.90 (s, 1H), 5.39 (d, J=47.2Hz, 1H), 5.23 (dd, J=16.7, 3.4Hz, 1H), 4.41-4.29 (m, 2H ), 4.17 (s, 4H), 3.70 (d, J = 20.0Hz, 2H), 3.19 (dt, J = 14.0, 6.8Hz, 1H), 3.03 (s, 1H), 2.47 (s, 3H), 2.04 (d, J=12.4Hz, 4H), 1.95-1.87 (m, 2H), 1.73-1.58 (m, 3H), 1.31 (s, 3H), 1.29 (s, 3H).
实施例39、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(化合物39)的合成：
Figure PCTCN2024077920-ftappb-I100230
Example 39, Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl ester (Compound 39):
Figure PCTCN2024077920-ftappb-I100230
将溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(200mg，0.50mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(195mg，1.50mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(569mg，1.50mmol)和N，N-二异丙基乙胺(322mg，2.50mmol)的N，N-二甲甲基甲酰胺(2mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-20％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(51mg，收率：20％)，LC-MS m/z：513[M+H]+；A solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (200 mg, 0.50 mmol), (E)-4-(dimethylamino)but-2-enoic acid (195 mg, 1.50 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (569 mg, 1.50 mmol) and N,N-diisopropylethylamine (322 mg, 2.50 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-20% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl ester (51 mg, yield: 20%), LC-MS m/z: 513 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.90(s，1H)，6.85-6.79(m，1H)，6.78-6.58(m，1H)，4.44-4.32(m，2H)，4.21-4.12(m，2H)，3.79-3.72(m，1H)，3.70-3.64(m，1H)，3.61-3.50(m，3H)，3.41(s，1H)，3.40(s，1H)，3.22-3.15(m，1H)，3.04(s，1H)，2.60(s，3H)，2.56(s，3H)，2.47(s，3H)，2.13-1.96(m，6H)，1.71-1.60(m，2H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.90 (s, 1H), 6.85-6.79 (m, 1H), 6.78-6.58 (m, 1H), 4.44-4.32 (m, 2H), 4.21-4.12 (m, 2H), 3.79-3.72 (m, 1H), 3.70-3.64 (m, 1H), 3.61-3.50 (m, 3H), 3.41(s, 1H), 3.40(s, 1H), 3.22-3.15(m, 1H), 3.04(s, 1H), 2.60(s, 3H), 2.56(s, 3H), 2.47(s , 3H), 2.13-1.96 (m, 6H), 1.71-1.60 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H).
实施例40、4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物40)的合成：Example 40, Synthesis of 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 40):
1)、4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100231
1) Synthesis of tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100231
将溶有5，7-二氯-3-(丙-2-基)吡唑并[1，5-a]嘧啶(2g，8.73mmol)，N，N-二异丙基乙胺(3.38g，26.19mmol)和4-氨基哌啶-1-甲酸叔丁酯(2.10g，10.48mmol)的异丙醇(15mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(石油醚∶乙酸乙酯＝0～21％)纯化得到4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(2.93g，收率：85.0％)，LC-MS m/z：394[M+H]+；A solution of 5,7-dichloro-3-(propan-2-yl)pyrazolo[1,5-a]pyrimidine (2 g, 8.73 mmol), N,N-diisopropylethylamine (3.38 g, 26.19 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.10 g, 10.48 mmol) in isopropanol (15 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-21%) to give tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (2.93 g, yield: 85.0%), LC-MS m/z: 394[M+H] + ;
2)、4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100232
2) Synthesis of tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100232
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1g，2.54mmol)，4-二甲基氨基吡啶(31mg，0.254mmol)，N，N-二异丙基乙胺(983mg，7.62mmol)和二碳酸二叔丁酯(1.02g，4.68mmol)的四氢呋喃(3mL)溶液，加热50℃搅拌3小时。所得混合反应液通过C18柱色谱法(乙腈∶含有NH4HCO3的纯水)纯化得到4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.1g，收率：87.5％)，LC-MS m/z：494[M+H]+；A solution of tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1 g, 2.54 mmol), 4-dimethylaminopyridine (31 mg, 0.254 mmol), N,N-diisopropylethylamine (983 mg, 7.62 mmol) and di-tert-butyl dicarbonate (1.02 g, 4.68 mmol) in tetrahydrofuran (3 mL) was heated at 50°C with stirring for 3 hours. The resulting mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing NH 4 HCO 3 ) to give tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.1 g, yield: 87.5%), LC-MS m/z: 494 [M+H] + ;
3)、(R)-3-((7-((叔丁氧羰基)(1-(叔丁氧羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100233
3) Synthesis of (R)-3-((7-((tert-butyloxycarbonyl)(1-(tert-butyloxycarbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100233
将溶有4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.1g，2.25mmol)，(R)-1-[(SP)-2-(二环己基膦)二茂铁基]乙基二叔丁基膦(151mg，0.272mmol)，碳酸铯(1.33g，4.08mmol)，三(二亚苄基丙酮)钯(125mg，0.136mmol)和(R)-3-羟基哌啶-1-羧酸苄基酯(804g，3.40mmol)的甲苯(2mL)溶液，微波加热140℃搅拌2小时。将混合反应液过滤并减压浓缩。残余物通过C18柱色谱法(乙腈∶含有NH4HCO3的纯水)纯化得到(R)-3-((7-((叔丁氧羰基)(1-(叔丁氧羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(957mg，收率：61.46％)，LC-MS m/z：693[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.1 g, 2.25 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (151 mg, 0.272 mmol), cesium carbonate (1.33 g, 4.08 mmol), tris(dibenzylideneacetone)palladium (125 mg, 0.136 mmol) and (R)-3-hydroxypiperidine-1-carboxylate benzyl ester (804 g, 3.40 mmol) in toluene (2 mL) was heated in a microwave at 140° C. for 2 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing NH 4 HCO 3 ) to give (R)-3-((7-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (957 mg, yield: 61.46%), LC-MS m/z: 693 [M+H] + ;
4)、(R)-4-((叔丁氧羰基)(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100234
4) Synthesis of tert-butyl (R)-4-((tert-butyloxycarbonyl)(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100234
将溶有(R)-3-((7-((叔丁氧羰基)(1-(叔丁氧羰基)哌啶-4-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(957mg，1.45mmol)和钯碳(478mg)的三氟乙醇(2mL)溶液在氢气(1atm)氛围下，加热50℃搅拌2小时。将所得混合反应液过滤，滤饼用二氯甲烷洗涤，收集滤液减压浓缩得到(R)-4-((叔丁氧羰基)(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(701mg，收率：90.92％)，LC-MS m/z：559[M+H]+；A solution of (R)-3-((7-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (957 mg, 1.45 mmol) and palladium carbon (478 mg) in trifluoroethanol (2 mL) was heated at 50° C. and stirred for 2 hours under a hydrogen (1 atm) atmosphere. The obtained mixed reaction liquid was filtered, the filter cake was washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure to give (R)-4-((tert-butoxycarbonyl)(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (701 mg, yield: 90.92%), LC-MS m/z: 559[M+H] + ;
5)、(R)-4-((叔丁氧羰基)(5-((1-(1-氟环丙烷-1-羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100235
5) Synthesis of tert-butyl (R)-4-((tert-butyloxycarbonyl)(5-((1-(1-fluorocyclopropane-1-carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100235
将溶有(R)-4-((叔丁氧羰基)(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(701mg，1.26mmol)，N，N-四甲基氯甲脒六氟磷酸盐(706mg，2.52mmol)，1-甲基-1H-咪唑(412mg，5.02mmol)和1-氟环丙烷-1-羧酸(197mg，1.89mmol)的N，N-二甲基甲酰胺(3mL)溶液，室温搅拌2小时。残余物通过C18柱色谱法(乙腈∶含有NH4HCO3的纯水)纯)纯化得到(R)-4-((叔丁氧羰基)(5-((1-(1-氟环丙烷-1-羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(640mg，收率：79％)，LC-MS m/z：645[M+H]+；A solution of (R)-tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (701 mg, 1.26 mmol), N,N-tetramethylchloroformamidine hexafluorophosphate (706 mg, 2.52 mmol), 1-methyl-1H-imidazole (412 mg, 5.02 mmol) and 1-fluorocyclopropane-1-carboxylic acid (197 mg, 1.89 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing NH 4 HCO 3 ) to give (R)-4-((tert-butyloxycarbonyl)(5-((1-(1-fluorocyclopropane-1-carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (640 mg, yield: 79%), LC-MS m/z: 645 [M+H] + ;
6)、(R)-4-((叔丁氧羰基)(5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100236
6) Synthesis of tert-butyl (R)-4-((tert-butyloxycarbonyl)(5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100236
将溶有(R)-4-((叔丁氧羰基)(5-((1-(1-氟环丙烷-1-羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(630mg，0.98mmol)的硼烷-四氢呋喃络合物(5mL)加热50℃搅拌16小时。在0℃条件下，用甲醇淬灭。所得混合反应液用水稀释并用乙酸乙酯萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(甲醇∶二氯甲烷＝0-5％洗脱)纯化得到(R)-4-((叔丁氧羰基)(5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(257mg，收率：41.7％)，A borane-tetrahydrofuran complex (5 mL) containing (R)-4-((tert-butyloxycarbonyl)(5-((1-(1-fluorocyclopropane-1-carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (630 mg, 0.98 mmol) was heated at 50°C and stirred for 16 hours. The mixture was quenched with methanol at 0°C. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give (R)-4-((tert-butoxycarbonyl)(5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (257 mg, yield: 41.7%).
LC-MS m/z：631[M+H]+；LC-MS m/z: 631 [M+H] + ;
7)、(R)-5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100237
7) Synthesis of (R)-5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100237
将溶有(R)-4-((叔丁氧羰基)(5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(257mg，0.41mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩得到(R)-5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(117mg，粗品))，直接用于下一步，无需进一步纯化，LC-MS m/z：431[M+H]+；A solution of (R)-4-((tert-butyloxycarbonyl)(5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (257 mg, 0.41 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give (R)-5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (117 mg, crude product), which was used directly in the next step without further purification. LC-MS m/z: 431 [M+H] + ;
8)、4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100238
8) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100238
将溶有(R)-5-((1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(110mg，0.26mmol)，碳酸双(三氯甲基)酯(38mg，0.128mmol)，三乙胺(78mg，0.767mmol)和3-羟基吡咯烷-1-羧酸叔丁酯(49mg，0.26mmol)的二氯甲烷(3mL)溶液，室温搅拌3小时。所得混合 反应液通过C18柱色谱法(乙腈和含有NH4HCO3的纯水)纯化得到4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(20mg，收率：12.15％)，LC-MS m/z：644[M+H]+；A solution of (R)-5-((1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (110 mg, 0.26 mmol), bis(trichloromethyl) carbonate (38 mg, 0.128 mmol), triethylamine (78 mg, 0.767 mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (49 mg, 0.26 mmol) in dichloromethane (3 mL) was stirred at room temperature for 3 hours. The resulting mixture was The reaction solution was purified by C18 column chromatography (acetonitrile and pure water containing NH 4 HCO 3 ) to give 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (20 mg, yield: 12.15%), LC-MS m/z: 644 [M+H] + ;
9)、4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100239
9) Synthesis of 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100239
将溶有4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(20mg，0.031mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液中，室温搅拌3小时。将所得混合反应液减压浓缩得到4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯(15mg，粗品)，无需进一步纯化即可直接用于下一步。LC-MS m/z：544[M+H]+；A solution of 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (20 mg, 0.031 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (15 mg, crude product), which was used directly in the next step without further purification. LC-MS m/z: 544[M+H] + ;
10)、4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100240
10) Synthesis of 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100240
将溶有4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-3-基酯(15mg，0.027mmol)，N，N-四甲基氯甲脒六氟磷酸盐(21mg，0.074mmol)，1-甲基-1H-咪唑(12mg，0.15mmol)和2-氟丙-2-烯酸(5mg，0.055mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱法(乙腈和含有NH4HCO3的纯水)纯化得到4-((5-(((R)-1-((1-氟环丙基)甲基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(2mg，收率：11.8％)，LC-MS m/z：616[M+H]+；A solution of 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-3-yl ester (15 mg, 0.027 mmol), N,N-tetramethylchloroformamidine hexafluorophosphate (21 mg, 0.074 mmol), 1-methyl-1H-imidazole (12 mg, 0.15 mmol) and 2-fluoroprop-2-enoic acid (5 mg, 0.055 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile and pure water containing NH 4 HCO 3 ) to give 4-((5-(((R)-1-((1-fluorocyclopropyl)methyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (2 mg, yield: 11.8%), LC-MS m/z: 616 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.78(s，1H)，5.64-5.40(m，2H)，5.25(dd，J＝16.6，3.5Hz，2H)，4.26-3.88(m，5H)，3.83-3.70(m，5H)，3.67-3.56(m，2H)，3.55-3.49(m，1H)，3.34(s，1H)，3.12-3.02(m，3H)，2.40-1.91(m，10H)，1.62(s，2H)，1.33(d，J＝1.4Hz，3H)，1.31(d，J＝1.4Hz，3H)，0.96(d，J＝9.4Hz，2H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.78 (s, 1H), 5.64-5.40 (m, 2H), 5.25 (dd, J=16.6, 3.5Hz, 2H), 4.26-3.88 (m, 5H), 3.83-3.70(m, 5H), 3.67-3.56(m, 2H), 3.55-3.49(m, 1H), 3.34(s, 1H), 3.12-3.02(m, 3H), 2.40-1.91( m, 10H), 1.62 (s, 2H), 1.33 (d, J = 1.4Hz, 3H), 1.31 (d, J = 1.4Hz, 3H), 0.96 (d, J = 9.4Hz, 2H).
实施例41、(R)-5-((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯(化合物41)的合成：Example 41, Synthesis of (R)-5-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidine-1-carboxylate 1-(but-2-ynyl)azetidine-3-yl ester (Compound 41):
1)、5-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100241
1) Synthesis of tert-butyl 5-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100241
将溶有5，7-二氯-3-(丙-2-基)吡唑并[1，5-a]嘧啶(600mg，2.61mmol)，5-氨基吖辛环-1-羧酸叔丁基酯(0.77g，3.39mmol)和N，N-二异丙基乙胺(437mg，3.39mmol)的异丙醇(3mL)加热70℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0～21％洗脱)纯化得到5-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯(1100mg，收率：99.73％)，LC-MS m/z：422[M+H]+；Isopropanol (3 mL) containing 5,7-dichloro-3-(propan-2-yl)pyrazolo[1,5-a]pyrimidine (600 mg, 2.61 mmol), 5-aminoazocine-1-carboxylic acid tert-butyl ester (0.77 g, 3.39 mmol) and N,N-diisopropylethylamine (437 mg, 3.39 mmol) was heated at 70°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-21% elution) to give 5-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylic acid tert-butyl ester (1100 mg, yield: 99.73%), LC-MS m/z: 422[M+H] + ;
2)、(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100242
2) Synthesis of tert-butyl (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100242
将溶有5-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯(600mg，1.42mmol)，(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(158mg，0.28mmol)，三(二亚苄基丙酮)二钯(130mg，0.14mmol)，碳酸铯(1.39g，4.272mmol)和(3R)-3-羟基哌啶-1-甲酸苄酯(0.42g，1.77mmol)的甲苯(2mL)，氩气保护下，微波加热140℃搅拌2小时。所得混合反应液减压浓缩。残留物通过C18柱色谱法(乙腈纯水＝0～95％洗脱)纯化得到(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯(350mg，收率：39.7％)，LC-MS m/z：621[M+H]+；5-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylic acid tert-butyl ester (600 mg, 1.42 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (158 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (130 mg, 0.14 mmol), cesium carbonate (1.39 g, 4.272 mmol) and (3R)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (0.42 g, 1.77 mmol) in toluene (2 mL) were heated in a microwave at 140° C. under argon protection for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile pure water = 0-95% elution) to give (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylic acid tert-butyl ester (350 mg, yield: 39.7%), LC-MS m/z: 621 [M+H] + ;
3)、(R)-3-((7-(吖辛环-5-基氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100243
3) Synthesis of (R)-3-((7-(azocine-5-ylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100243
将溶有(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸叔丁酯(350mg，0.56mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液，室温搅拌4小时。将所得混合反应液减压浓缩得到粗产物(290mg)，无需进一步纯化，可直接用于下一步，LC-MS m/z：521[M+H]+；A solution of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azocine-1-carboxylic acid tert-butyl ester (350 mg, 0.56 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give a crude product (290 mg), which was used directly in the next step without further purification. LC-MS m/z: 521 [M+H] + ;
4)、(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100244
4) Synthesis of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100244
将溶有(R)-3-((7-(吖辛环-5-基氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(290mg，0.56mmol)，碳酸双(三氯甲基)酯(83mg，0.28mmol)，三乙胺(170mg，1.67mmol)和3-羟基氮杂环丁烷-1-羧酸叔丁酯(97mg，0.56mmol)的二氯甲烷(2mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。通残余物通过C18柱色谱法(乙腈∶纯水＝0～95％洗脱)纯化(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(188mg，收率：46.9％)，LC-MS：m/z：720[M+H]+；A solution of (R)-3-((7-(azocine-5-ylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (290 mg, 0.56 mmol), bis(trichloromethyl) carbonate (83 mg, 0.28 mmol), triethylamine (170 mg, 1.67 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (97 mg, 0.56 mmol) in dichloromethane (2 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water=0-95% elution) to obtain (R)-1-(tert-butoxycarbonyl)azetidin-3-yl 5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylate (188 mg, yield: 46.9%), LC-MS: m/z: 720 [M+H] + ;
5)、(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100245
5) Synthesis of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylate
Figure PCTCN2024077920-ftappb-I100245
将溶有R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(188mg，0.26mmol)和2，2，2三氟乙酸(1mL)的二氯甲烷(3mL)溶液在，室温搅拌4小时。将所得混合反应液减压浓缩得到粗产物(130mg)，无需进一步纯化，可直接用于下一步，LC-MS m/z：620[M+H]+；A solution of R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidine-1-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (188 mg, 0.26 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to give a crude product (130 mg), which was used directly in the next step without further purification, LC-MS m/z: 620 [M+H] + ;
6)、(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100246
6) Synthesis of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylate 1-(but-2-ynyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100246
将溶有(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸氮杂环丁烷-3-基酯(130mg，0.48mmol)，2-(7-氮杂-1H-苯并三唑-1-基)-1，1，3，3-四甲基脲六氟磷酸盐(276mg，0.73mmol)，乙基二异丙胺(188mg，1.46mmol)和丁-2-炔酸(53mg，0.63mmol)的N，N-二甲基甲酰胺(3mL)溶液，室温搅拌4小时。将所得混合物减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0～95％洗脱)纯化得到(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯(120mg，收率：83.4％)，LC-MS m/z：686[M+H]+；A solution of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylate (130 mg, 0.48 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (276 mg, 0.73 mmol), ethyldiisopropylamine (188 mg, 1.46 mmol) and but-2-ynoic acid (53 mg, 0.63 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-95% elution) to give (R)-1-(but-2-ynyl)azetidin-3-yl 5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidin-1-carboxylate (120 mg, yield: 83.4%), LC-MS m/z: 686 [M+H] + ;
7)、(R)-5-((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100247
7) Synthesis of (R)-5-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidine-1-carboxylic acid 1-(but-2-ynyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100247
将溶有(R)-5-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)吖辛环-1-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯(120mg，0.17mmol)的2，2，2-三氟乙酸(2mL)溶液，加热50℃搅拌5小时。将所得混合反应液减压浓缩。残余物通过制备级高效液相色谱纯化得到(2.27mg，收率：2.4％)，LC-MS m/z：552[M+H]+；A solution of (R)-5-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)azetidine-1-carboxylic acid 1-(but-2-ynyl)azetidin-3-yl ester (120 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50° C. and stirred for 5 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (2.27 mg, yield: 2.4%), LC-MS m/z: 552[M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.78(d，J＝2.9Hz，1H)，5.51(s，1H)，5.27-5.16(m，1H)，4.59-4.53(m，1H)，4.37(dd，J＝10.9，5.9Hz，1H)，4.27-4.12(m，1H)，3.97(d，J＝11.5Hz，1H)，3.70(s，3H)，3.55(dd，J＝13.1，4.7Hz，1H)，3.43(dd，J＝13.1，2.5Hz，2H)，3.32(s，2H)，3.18-3.05(m，2H)，2.12(d，J＝3.9Hz，2H)，2.03-1.85(m，14H)，1.32(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d 4 ): δ7.78 (d, J=2.9Hz, 1H), 5.51 (s, 1H), 5.27-5.16 (m, 1H), 4.59-4.53 (m, 1H), 4.37 (dd, J=10.9, 5.9Hz, 1H), 4.27-4.12 (m, 1H), 3.97 (d, J=11.5Hz, 1H), 3.70 (s, 3 H), 3.55 (dd, J=13.1, 4.7Hz, 1H), 3.43 (dd, J=13.1, 2.5Hz, 2H), 3.32 (s, 2H), 3.18-3.05 (m, 2H), 2.12 (d , J=3.9Hz, 2H), 2.03-1.85 (m, 14H), 1.32 (d, J=6.9Hz, 6H).
实施例42、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(丁-2-炔基)-3-氟氮杂环丁烷-3-基)甲酯(化合物42)的合成：
Figure PCTCN2024077920-ftappb-I100248
Example 42, Synthesis of (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 42):
Figure PCTCN2024077920-ftappb-I100248
将溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.12mmol)，丁-2-炔酸(15mg，0.18mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(35mg，0.18mmol)和4-二甲基氨基吡啶(1.5mg，0.012mmol)的二氯甲烷(1mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到甲基4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(丁-2-炔基)-3-氟氮杂环丁烷-3-基)酯(1.19mg，收率：2.05％)，LC-MS m/z：471[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.12 mmol), but-2-ynoic acid (15 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and 4-dimethylaminopyridine (1.5 mg, 0.012 mmol) in dichloromethane (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1-(but-2-ynyl)-3-fluoroazetidin-3-yl) (1.19 mg, yield: 2.05%), LC-MS m/z: 471 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.89(s，1H)，6.14(s，1H)，4.53-4.30(m，5H)，4.28-4.08(m，4H)，3.94-3.86(m，1H)，3.21-3.10(m，2H)，2.51(s，3H)，2.18-2.08(m，2H)，2.04(s，3H)，1.72-1.60(m，2H)，1.40-1.30(m，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.89 (s, 1H), 6.14 (s, 1H), 4.53-4.30 (m, 5H), 4.28-4.08 (m, 4H), 3.94-3.86 ( m, 1H), 3.21-3.10 (m, 2H), 2.51 (s, 3H), 2.18-2.08 (m, 2H), 2.04 (s, 3H), 1.72-1.60 (m, 2H), 1.40-1.30 ( m, 6H).
实施例43、8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物43)的合成：Example 43, Synthesis of 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 43):
1)、8-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100249
1) Synthesis of tert-butyl 8-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100249
将溶有5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(1.00g，4.37mmol)，8-氨基-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(800mg，3.54mmol)和N，N-二异丙基乙胺(1.69g，13.11mmol)的异丙醇(15mL)溶液加热70℃下搅拌过夜。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-25％洗脱)纯化得到8-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1g，55％)，LC-MS m/z：420[M+H]+；A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (1.00 g, 4.37 mmol), 8-amino-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (800 mg, 3.54 mmol) and N,N-diisopropylethylamine (1.69 g, 13.11 mmol) in isopropanol (15 mL) was heated at 70°C and stirred overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give 8-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1 g, 55%), LC-MS m/z: 420[M+H] + ;
2)、8-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100250
2) Synthesis of tert-butyl 8-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100250
将溶有8-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1g，2.38mmol)，二碳酸二叔丁酯(779mg，3.57mmol)，N，N-二异丙基乙胺(921mg，7.14mmol)和4-二甲氨基吡啶(29mg，0.24mmol)的二氯甲烷(15mL)溶液室温搅拌过夜。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-20％洗脱)纯化得到8-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1g，收率：81％)，LC-MS m/z：520[M+H]+；A solution of 8-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1 g, 2.38 mmol), di-tert-butyl dicarbonate (779 mg, 3.57 mmol), N,N-diisopropylethylamine (921 mg, 7.14 mmol) and 4-dimethylaminopyridine (29 mg, 0.24 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20% elution) to give tert-butyl 8-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (1 g, yield: 81%), LC-MS m/z: 520 [M+H] + ;
3)、8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100251
3) Synthesis of tert-butyl 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100251
将溶有8-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的(1g，1.92mmol)，(R)-3-羟基哌啶-1-羧酸苄基酯(905mg，3.85mmol)，三(二亚苄基丙酮)二钯(174mg，0.19mmol)，(R)-1-[(SP)-2-(二环己基膦)二茂铁基]乙基二叔丁基膦(211mg，0.38mmol)和碳酸铯(1877mg，5.76mmol)的甲苯(20.0mL)溶液，氩气保护下，微波加热140℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-25％洗脱)纯化得到8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1100mg，收率：79.5％)，LC-MS m/z：719[M+H]+；A solution of tert-butyl 8-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (1 g, 1.92 mmol), (R)-3-hydroxypiperidine-1-carboxylate benzyl ester (905 mg, 3.85 mmol), tris(dibenzylideneacetone)dipalladium (174 mg, 0.19 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (211 mg, 0.38 mmol) and cesium carbonate (1877 mg, 5.76 mmol) in toluene (20.0 mL) was heated in a microwave at 140° C. under argon protection and stirred for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give tert-butyl 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (1100 mg, yield: 79.5%), LC-MS m/z: 719 [M+H] + ;
4)、(3R)-3-((7-((3-氮杂双环[3.2.1]辛-8-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100252
4) Synthesis of (3R)-3-((7-((3-azabicyclo[3.2.1]oct-8-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100252
将溶有8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1100mg，1.53mmol)二氯甲烷(10mL)溶液和2，2，2-三氟乙酸(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：519[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1100 mg, 1.53 mmol) in dichloromethane (10 mL) and a solution of 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 519[M+H] + ;
5)、8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100253
5) Synthesis of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100253
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(265mg，1.53mmol)，三乙胺(464mg，4.59mmol)和三光气(227mg，0.77mmol)的二氯甲烷(5mL)溶液，0℃搅拌1小时。然后将((3R)-3-((7-((3-氮杂双环[3.2.1]辛-8-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(794mg，1.53mmol)的二氯甲烷(2mL)溶液滴加上述混合反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(700mg，收率：63.8％)，LC-MS m/z：718[M+H]+；A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (265 mg, 1.53 mmol), triethylamine (464 mg, 4.59 mmol) and triphosgene (227 mg, 0.77 mmol) in dichloromethane (5 mL) was stirred at 0°C for 1 hour. Then, a solution of benzyl ((3R)-3-((7-((3-azabicyclo[3.2.1]oct-8-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (794 mg, 1.53 mmol) in dichloromethane (2 mL) was added dropwise to the mixed reaction liquid. The mixed reaction liquid was stirred at room temperature overnight. The mixed reaction liquid was concentrated under reduced pressure. The residue was filtered through a C18 column. Purification by chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) gave 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (700 mg, yield: 63.8%), LC-MS m/z: 718 [M+H] + ;
6)、8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100254
6) Synthesis of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100254
将溶有8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(700mg，0.97mmol)二氯甲烷(5mL)溶液和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯，可直接用于下一步。LC-MS m/z：618[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (700 mg, 0.97 mmol) in dichloromethane (5 mL) and a solution of 2,2,2-trifluoroacetic acid (0.5 mL) were stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 618[M+H] + ;
7)、8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100255
7) Synthesis of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100255
将溶有8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸氮杂环丁烷-3-基酯(50mg，0.08mmol)，2-氟丙烯酸(11mg，0.12mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(45mg，0.16mmol)和1-甲基-1H-咪唑(26mg，0.32mmol)的N，N-二甲基甲酰胺(3mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(40mg，收率：71.4％)，LC-MS m/z：690[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate azetidin-3-yl ester (50 mg, 0.08 mmol), 2-fluoroacrylic acid (11 mg, 0.12 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (45 mg, 0.16 mmol) and 1-methyl-1H-imidazole (26 mg, 0.32 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (40 mg, yield: 71.4%), LC-MS m/z: 690 [M+H] + ;
8)、8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100256
8) Synthesis of 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100256
将溶有8-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(40mg，0.06mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌5小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到8-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，收率：62.5％)，LC-MS m/z：556[M+H]+；A solution of 8-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (40 mg, 0.06 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50° C. and stirred for 5 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 8-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, yield: 62.5%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.79(s，1H)，5.62(s，1H)，5.60(d，J＝3.2Hz，1H)，5.48(d，J＝3.2Hz，1H)，5.22-5.25(m，1H)，5.20-5.15(m，2H)，4.44-4.39(m，2H)，4.10-4.01(m，1H)，3.80-3.72(m，14.7Hz，4H)，3.44-3.45(m，1H)，3.18-3.16(m，1H)，3.13-3.07(m，1H)，2.88-2.85(m，2H)，2.78-2.75(m，1H)，2.48-2.44(m，2H)，2.08-2.03(m，1H)，1.99-1.95(m，2H)，1.85-1.80(m，2H)，1.72-1.68(m，2H)，1.66-1.59(m，1H)，1.34(s，3H)，1.32(s，3H). 1 H NMR (400MHz, MeOD) δ7.79 (s, 1H), 5.62 (s, 1H), 5.60 (d, J=3.2Hz, 1H), 5.48 (d, J=3.2Hz, 1H), 5.22- 5.25(m, 1H), 5.20-5.15(m, 2H), 4.44-4.39(m, 2H), 4.10-4.01(m, 1H), 3.80-3.72(m, 14.7Hz, 4H), 3.44-3.45( m, 1H), 3 .18-3.16(m, 1H), 3.13-3.07(m, 1H), 2.88-2.85(m, 2H), 2.78-2.75(m, 1H), 2.48-2.44(m, 2H), 2.08-2.03( m, 1H), 1.99-1.95 (m, 2H), 1.85-1.80 (m, 2H), 1.72-1.68 (m, 2H), 1.66-1.59 (m, 1H), 1.34 (s, 3H), 1.32 ( s, 3H).
实施例44、3-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯及异构体(化合物44A和44B)的合成：Example 44. Synthesis of 3-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester and isomers (Compounds 44A and 44B):
1)、3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100257
1) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100257
将溶有3-羟基吡咯烷-1-羧酸叔丁酯(216mg，1.16mmol)，三乙胺(98mg，0.96mmol)和二(1H-1，2，4-三唑-1-基)甲酮(157mg，0.96mmol)的N，N-二甲基甲酰胺(5mL)溶液，氩气保护下，室温搅拌1小时。 然后将(3R)-3-((7-((8-氮杂双环[3.2.1]辛-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(500mg，0.96mmol)加入到上述混合反应液中，室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶H含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(500mg，收率：71％)，LC-MS m/z：732[M+H]+；A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (216 mg, 1.16 mmol), triethylamine (98 mg, 0.96 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (157 mg, 0.96 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour under argon protection. Then, (3R)-3-((7-((8-azabicyclo[3.2.1]oct-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (500 mg, 0.96 mmol) was added to the mixed reaction liquid, and stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: H2O containing 0.1% formic acid = 5-95% elution) to give 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (500 mg, yield: 71%), LC-MS m/z: 732 [M+H] + ;
2)、3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100258
2) Synthesis of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100258
将溶有3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(500mg，0.70mmol)的二氯甲烷(5mL)溶液和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌过夜温度。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：632[M+H]+；A solution of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl ester (500 mg, 0.70 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) were stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 632[M+H] + ;
3)、3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100259
3) Synthesis of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100259
将溶有3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(100mg，0.16mmol)，2-氟丙烯酸(22mg，0.24mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐(92mg，0.24mmol)和N，N-二异丙基乙胺(104mg，0.80mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(80mg，收率：72％)，LC-MS：m/z：704[M+H]+；A solution of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.16 mmol), 2-fluoroacrylic acid (22 mg, 0.24 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) and N,N-diisopropylethylamine (104 mg, 0.80 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (80 mg, yield: 72%), LC-MS: m/z: 704 [M+H] + ;
4)、3-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯及异构体(化合物44A和44B)的合成
Figure PCTCN2024077920-ftappb-I100260
4) Synthesis of 3-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester and isomers (Compounds 44A and 44B)
Figure PCTCN2024077920-ftappb-I100260
将溶有3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(80mg，0.11mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌3小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到得到两种异构体：A solution of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (80 mg, 0.11 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 3 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain two isomers:
BIOT-002-90105：Peak 1：2.065min；化合物44A(30mg，收率：46.1％)，LC-MS m/z：570[M+H]+；BIOT-002-90105: Peak 1: 2.065 min; Compound 44A (30 mg, yield: 46.1%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.72(s，1H)，5.58(s，1H)，5.54-5.40(m，1H)，5.33-5.28(m，1H)，5.27-5.21(m，1H)，5.20-5.15(m，1H)，4.34(s，2H)，4.13-4.04(m，1H)，3.97-3.89(m，1H)，3.87-3.68(m，3H)，3.67-3.57(m，1H)，3.36-3.34(m，1H)，3.20(d，J＝12.0Hz，1H)，3.14-3.03(m，1H)，2.90-2.82(m，2H)，2.80-2.72(m，1H)，2.29-2.16(m，2H)，2.14-2.04(m，5H)，1.96-1.91(m，2H)，1.82-1.73(m，2H)，1.65-1.57(m，1H)，1.32(s，3H)，1.30(s，3H). 1 H NMR (400MHz, MeOD) δ7.72 (s, 1H), 5.58 (s, 1H), 5.54-5.40 (m, 1H), 5.33-5.28 (m, 1H), 5.27-5.21 (m, 1H) , 5.20-5.15(m, 1H), 4.34(s, 2H), 4.13-4.04(m, 1H), 3.97-3.89(m, 1H), 3.87-3.68(m, 3H), 3.67-3.57(m, 1H), 3.36 -3.34 (m, 1H), 3.20 (d, J=12.0Hz, 1H), 3.14-3.03 (m, 1H), 2.90-2.82 (m, 2H), 2.80-2.72 (m, 1H), 2.29-2.16 (m, 2H), 2.14-2.04 (m, 5H), 1.96-1.91 (m, 2H), 1.82-1.73 (m, 2H), 1.65-1.57 (m, 1H), 1.32 (s, 3H), 1.30 (s,3H).
BIOT-002-90252：Peak 2：2.173min；化合物44B(12mg，收率：18.5％)，LC-MS m/z：570[M+H]+；BIOT-002-90252: Peak 2: 2.173 min; Compound 44B (12 mg, yield: 18.5%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.75(s，1H)，5.55-5.40(m，2H)，5.33-5.22(m，2H)，5.20-5.13(m，1H)，4.31(s，2H)，3.93(s，2H)，3.83-3.70(m，2H)，3.69-3.57(m，1H)，3.20(dd，J＝16.0，4.0Hz，1H)，3.14-3.04(m，1H)，2.90-2.81(m，2H)，2.79-2.71(m，1H)，2.39-2.29(m，1H)，2.28-2.19(m，2H)，2.18-2.04(m，6H)，1.99(s，1H)，1.97-1.92(m，1H)，1.91-1.75(m，2H)，1.66-1.55(m，1H)，1.33(s，3H)，1.31(s，3H). 1 H NMR (400MHz, MeOD) δ7.75 (s, 1H), 5.55-5.40 (m, 2H), 5.33-5.22 (m, 2H), 5.20-5.13 (m, 1H), 4.31 (s, 2H) , 3.93 (s, 2H), 3.83-3.70 (m, 2H), 3.69-3.57 (m, 1H), 3.20 (dd, J=16.0, 4.0Hz, 1H), 3.14-3.04 (m , 1H), 2.90-2.81(m, 2H), 2.79-2.71(m, 1H), 2.39-2.29(m, 1H), 2.28-2.19(m, 2H), 2.18-2.04(m, 6H), 1.99 (s, 1H), 1.97-1.92 (m, 1H), 1.91-1.75 (m, 2H), 1.66-1.55 (m, 1H), 1.33 (s, 3H), 1.31 (s, 3H).
实施例45、3-(((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物45)的合成：Example 45, Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 3-(((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 45):
1)、3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100261
1) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100261
将溶有3-(((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(32mg，0.051mmol)，2-氟丙烯酸(7mg，0.073mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(28mg，0.101mmol)和N-甲基咪唑(17mg，0.20mmol)的N，N-二甲基甲酰胺(2ml)溶液，加热40℃搅拌16小时。LCMS检测反应完成。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，收率：56.1％)，LC-MS m/z：704[M+H]+；3-(((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (32 mg, 0.051 mmol), 2-fluoroacrylic acid (7 mg, 0.073 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (28 mg, 0.101 mmol) and N-methylimidazole (17 mg, 0.20 mmol) were dissolved in N,N- The solution was heated to 40°C and stirred for 16 hours in dimethylformamide (2 ml). The reaction was completed by LCMS. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, yield: 56.1%), LC-MS m/z: 704 [M+H] + ;
2)、3-(((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100262
2) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 3-(((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100262
将溶有3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，0.02mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。LCMS检测反应完成。将混合反应液减浓缩。残余物通过制备级高效液相色谱纯化得到3-(((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(1.2mg，收率：7.4％)，LC-MS m/z：570[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, 0.02 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The reaction was completed by LCMS. The mixed reaction solution was concentrated. The residue was purified by preparative HPLC to give 1-(2-fluoroacryloyl)azetidin-3-yl 3-(((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.2 mg, yield: 7.4%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.77(s，1H)，5.61(d，J＝3.6Hz，0.5H)，5.49(d，J＝3.2Hz，1H)，5.24(d，J＝3.6Hz，0.5H)，5.20(d，J＝3.2Hz，1H)，4.74(s，1H)，4.33(d，J＝44.4Hz，5H)，4.04(s，1H)，3.58-3.38(m，4H)，3.24(d，J＝6.8Hz，2H)，3.19-3.03(m，3H)，2.43-2.32(m，1H)，2.17-1.96(m，6H)，1.85(dd，J＝9.6，4.4Hz，1H)，1.77(d，J＝3.6Hz，4H)，1.50(t，J＝11.6Hz，2H)，1.32(d，J＝6.8Hz，6H)，1.29(s，1H). 1 H NMR (400MHz, MeOD): δ7.77 (s, 1H), 5.61 (d, J=3.6Hz, 0.5H), 5.49 (d, J=3.2Hz, 1H), 5.24 (d, J=3.6 Hz, 0.5H), 5.20 (d, J=3.2Hz, 1H), 4.74 (s, 1H), 4.33 (d, J=44.4Hz, 5H), 4.04 (s, 1H), 3.58-3.38 (m, 4H), 3.24 (d, J=6.8Hz, 2H), 3.19-3.03 (m, 3H), 2.43-2.32 (m, 1H), 2.17-1.96 (m, 6H), 1.85 (dd, J=9.6, 4.4Hz, 1H), 1.77 (d, J=3.6Hz, 4H), 1.50 (t, J=11.6Hz, 2H), 1.32 (d, J=6.8Hz, 6H), 1.29 (s, 1H).
实施例46、3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物46)的合成：Example 46, Synthesis of 3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 46):
1)、3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100263
1) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100263
在室温条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(112mg，0.60mmol)的N，N-二甲基甲酰胺(2mL)溶液中，加入三乙胺(181mg，1.79mmol)和二(1H-1，2，4-三唑-1-基)甲酮(98mg，0.60mmol)，并氮气保护下，室温搅拌1小时。然后将溶有(3R)-3-((7-((((8-氮杂双环[3.2.1]辛-3-基)甲基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(230mg，0.43mmol)的N，N-二甲基甲酰胺(2mL)溶液加入到上述混合反应液中。所得混合反应液加热40℃搅拌16小时。LCMS检测反应完成。将所得混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(220mg，收率：68％)，LC-MS m/z：746[M+H]+；At room temperature, triethylamine (181 mg, 1.79 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (98 mg, 0.60 mmol) were added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (112 mg, 0.60 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 1 hour under nitrogen protection. Then, a solution of (3R)-3-((7-((((8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (230 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) was added to the above mixed reaction solution. The obtained mixed reaction solution was heated at 40°C and stirred for 16 hours. LCMS detected that the reaction was complete. The obtained mixed solution was purified by HPLC. The reaction mixture was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (220 mg, yield: 68%), LC-MS m/z: 746 [M+H] + ;
2)、3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100264
2) Synthesis of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100264
将溶有3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(210mg，0.28mmol)的2，2，2-三氟乙酸(0.4mL)和二氯甲烷(1.2mL)溶液室温搅拌2小时。将混合反应液减压浓缩得到粗产物，直接用于下一步骤，无需进一步纯化。LC-MS m/z：646[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (210 mg, 0.28 mmol) in 2,2,2-trifluoroacetic acid (0.4 mL) and dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 646[M+H] + ;
3)、3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100265
3) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100265
将溶有3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(50mg，0.067mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(43mg，0.16mmol)和1-甲基1H-咪唑(25mg，0.31mmol)的N，N-二甲基甲酰胺(2mL)溶液加热40℃搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(30mg，收率：54％)，LC-MS m/z：718[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (50 mg, 0.067 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (43 mg, 0.16 mmol) and 1-methyl 1H-imidazole (25 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) was heated at 40°C and stirred for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (30 mg, yield: 54%), LC-MS m/z: 718 [M+H] + ;
4)、3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100266
4) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl 3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100266
将溶有3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(25mg，0.034mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。将混合反应液减压浓缩。残余物通过制备级高效液相色谱制备纯化得到3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(2.5mg，收率：12％)，LC-MS m/z：584[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (25 mg, 0.034 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (2.5 mg, yield: 12%), LC-MS m/z: 584 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.76(s，1H)，5.51(s，1H)，5.37(d，J＝24.0Hz，1H)，5.24(d，J＝16.0Hz，2H)，4.26(s，2H)，3.64-3.54(m，8H)，3.26-3.04(m，4H)，2.37(s，1H)，2.23-2.14(m，3H)，1.99(s，3H)，1.93(s，1H)，1.87(s，1H)，1.78-1.72(m，4H)，1.47(s，1H)，1.32(d，J＝8.0Hz，6H)，1.29(s，2H). 1 H NMR (400MHz, MeOD): δ7.76 (s, 1H), 5.51 (s, 1H), 5.37 (d, J=24.0Hz, 1H), 5.24 (d, J=16.0Hz, 2H), 4.26 (s, 2H), 3.64-3.54 (m, 8H), 3.26-3.04 (m, 4H), 2.37 (s, 1H), 2.23-2.14 (m, 3H), 1.99 (s, 3H), 1.93 (s , 1H), 1.87 (s, 1H), 1.78-1.72 (m, 4H), 1.47 (s, 1H), 1.32 (d, J=8.0Hz, 6H), 1.29 (s, 2H).
实施例47、1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(化合物47)的合成：Example 47, Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 47):
1)、3-(((5-(((R)-1-((苄氧基)羰基))哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100267
1) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 3-(((5-(((R)-1-((benzyloxy)carbonyl))piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100267
将溶有3-(((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(50mg，0.078mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(19mg，0.12mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(43mg，0.155mmol)和1-甲基-1H-咪唑(25mg，0.31mmol)的N，N-二甲基甲酰胺(2mL)溶液加热40℃搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((5-(((R)-1-((苄氧基)羰基))哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(28mg，收率：48％)，LC-MS m/z：757.2[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (50 mg, 0.078 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (19 mg, 0.12 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (43 mg, 0.155 mmol) and 1-methyl-1H-imidazole (25 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) was heated at 40° C. and stirred for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl 3-(((5-(((R)-1-((benzyloxy)carbonyl))piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (28 mg, yield: 48%), LC-MS m/z: 757.2 [M+H] + ;
2)、1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯的合成
Figure PCTCN2024077920-ftappb-I100268
2) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100268
将溶有3-(((5-(((R)-1-((苄氧基)羰基))哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(30mg，0.039mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。将混合反应液减压浓缩。残余物通过制备级高效液相色谱纯化得到1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基-3-(((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸酯(4mg，收率：16％)，LC-MS m/z：623[M+H]+；A solution of 3-(((5-(((R)-1-((benzyloxy)carbonyl))piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (30 mg, 0.039 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl-3-(((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (4 mg, yield: 16%), LC-MS m/z: 623 [M+H] + ;
1H NMR(400MHz，CD3OD_SPE)δ7.76(d，J＝12.0Hz，1H)，6.75(dd，J＝16.0，8.0Hz，2H)，5.50(s，1H)，5.28(d，J＝12.0Hz，1H)，4.25(s，2H)，3.95(d，J＝8.0Hz，2H)，3.84(d，J＝8.0Hz，1H)，3.79-3.65(m，2H)，3.59-3.38(m，3H)，3.32(s，1H)，3.15-3.08(m，2H)，2.89(s，6H)，2.42-1.66(m，16H)，1.55-1.38(m，2H)，1.31(d，J＝8.0Hz，6H). 1 H NMR (400 MHz, CD 3 OD_SPE) δ7.76 (d, J=12.0Hz, 1H), 6.75 (dd, J=16.0, 8.0Hz, 2H), 5.50 (s, 1H), 5.28 (d, J=12.0Hz, 1H), 4.25 (s, 2H), 3.95 (d, J=8.0Hz, 2H), 3.84 (d, J=8.0Hz, 1H), 3.79-3.65(m, 2H), 3.59-3.38(m, 3H), 3.32(s, 1H), 3.15-3.08(m, 2H), 2.89(s, 6H), 2.42-1.66(m, 16H), 1.55-1.38(m, 2H), 1.31(d, J＝8.0Hz, 6H ).
实施例48、3-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯及异构体(化合物48A和48B)的合成：Example 48, Synthesis of 3-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester and isomers (Compounds 48A and 48B):
1)、3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100269
1) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100269
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(201mg，1.16mmol)，三乙胺(98mg，0.96mmol)和二(1H-1，2，4-三唑-1-基)甲酮(157mg，0.96mmol)的N，N-二甲基甲酰胺(5mL)溶液，氩气保护下，室温搅拌1小时。然后(3R)-3-((7-((8-氮杂双环[3.2.1]辛-3-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(500mg，0.96mmol)，并在室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(500mg，收率：72％)，LC-MS m/z：718[M+H]+；A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (201 mg, 1.16 mmol), triethylamine (98 mg, 0.96 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (157 mg, 0.96 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour under argon protection. Then (3R)-3-((7-((8-azabicyclo[3.2.1]oct-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate benzyl ester (500 mg, 0.96 mmol) was added and stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, yield: 72%), LC-MS m/z: 718 [M+H] + ;
2)、3-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100270
2) Synthesis of azetidin-3-yl 3-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100270
将溶有3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(500mg，0.69mmol)的二氯甲烷(5mL)溶液和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌过夜。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：618[M+H]+；A solution of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (500 mg, 0.69 mmol) in dichloromethane (5 mL) and a solution of 2,2,2-trifluoroacetic acid (0.5 mL) were stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 618[M+H] + ;
3)、3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100271
3) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100271
将溶有3-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(100mg，0.16mmol)，2-氟丙烯酸(22mg，0.24mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐(92mg，0.24mmol)和N，N-二异丙基乙胺(104mg，0.80mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(80mg，收率：72％)，LC-MS m/z：690[M+H]+；A solution of 3-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (100 mg, 0.16 mmol), 2-fluoroacrylic acid (22 mg, 0.24 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) and N,N-diisopropylethylamine (104 mg, 0.80 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (80 mg, yield: 72%), LC-MS m/z: 690 [M+H] + ;
4)、3-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯及异构体(化合物48A和48B)的合成
Figure PCTCN2024077920-ftappb-I100272
4) Synthesis of 3-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester and isomers (Compounds 48A and 48B)
Figure PCTCN2024077920-ftappb-I100272
将溶有3-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(85mg，0.11mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌3小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶H含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到两种异构体：A solution of 3-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (85 mg, 0.11 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50° C. and stirred for 3 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: H pure water containing 0.1% formic acid = 5-95% elution) to obtain two isomers:
BIOT-002-90116：峰1：2.065min；化合物48A(24mg，收率：35％)，LC-MS m/z：556[M+H]+；BIOT-002-90116: Peak 1: 2.065 min; Compound 48A (24 mg, yield: 35%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.72(s，1H)，5.61-5.48(m，2H)，5.24-5.22(m，1H)，5.20-5.18(m，1H)，4.79-4.73(m，1H)，4.46-4.38(m，3H)，4.37-4.32(m，1H)，4.1-4.05(m，2H)，3.37-3.34(m，1H)，3.20(dd，J＝16.0，4.0Hz，1H)，3.10-3.03(m，1H)，2.90-2.83(m，2H)，2.80-2.73(m，1H)，2.15-2.05(m，5H)，2.00-1.94(m，2H)，1.86-1.74(m，4H)，1.66-1.56(m，1H)，1.31(s，3H)，1.30(s，3H). 1 H NMR (400MHz, MeOD) δ7.72 (s, 1H), 5.61-5.48 (m, 2H), 5.24-5.22 (m, 1H), 5.20-5.18 (m, 1H), 4.79-4.73 (m, 1H), 4.46-4.38(m, 3H), 4.37-4.32(m, 1H), 4.1-4.05(m, 2H), 3.37-3.34(m, 1H), 3. 20(dd, J=16.0, 4.0Hz, 1H), 3.10-3.03(m, 1H), 2.90-2.83(m, 2H), 2.80-2.73(m, 1H), 2.15-2.05(m, 5H), 2.00-1.94(m, 2H), 1.86-1.74(m, 4H), 1.66-1.56(m, 1H), 1.31(s, 3H), 1.30(s, 3H).
BIOT-002-90253：峰2：2.192min；化合物48B(11.2mg，16％)，LC-MS m/z：556[M+H]+；BIOT-002-90253: Peak 2: 2.192 min; Compound 48B (11.2 mg, 16%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.76(s，1H)，5.62-5.48(m，1H)，5.43(s，1H)，5.24(d，J＝4.0Hz，1H)，5.20(d，J＝4.0Hz，1H)，4.79-4.73(m，1H)，4.45-4.38(m，3H)，4.34-4.29(m，1H)，4.10-4.01(m，1H)，3.94(t，J＝8.0Hz，1H)，3.28-3.18(m，1H)，3.12-3.05(m，2H)，2.90-2.83(m，2H)，2.80-2.74(m，1H)，2.36-2.29(m，2H)，2.17-2.07(m，5H)，2.03-1.97(m，2H)，1.93(s，1H)，1.88-1.78(m，1H)，1.66-1.57(m，1H)，1.33(s，3H)，1.31(s，3H). 1 H NMR (400MHz, MeOD) δ7.76 (s, 1H), 5.62-5.48 (m, 1H), 5.43 (s, 1H), 5.24 (d, J=4.0Hz, 1H), 5.20 (d, J =4.0Hz, 1H), 4.79-4.73(m, 1H), 4.45-4.38(m, 3H), 4.34-4.29(m, 1H), 4.10-4.01(m, 1H), 3.94(t, J=8.0 Hz, 1H), 3.28-3.18(m, 1H), 3.12-3.05(m, 2H), 2.90-2.83(m, 2H), 2.80-2.74(m, 1H), 2.36-2.29(m, 2H), 2.17-2.07(m , 5H), 2.03-1.97(m, 2H), 1.93(s, 1H), 1.88-1.78(m, 1H), 1.66-1.57(m, 1H), 1.33(s, 3H), 1.31(s, 3H ).
实施例49、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物49)的合成：Example 49, Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 49):
1)、(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸的合成
Figure PCTCN2024077920-ftappb-I100273
1) Synthesis of (1r, 4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid
Figure PCTCN2024077920-ftappb-I100273
在0℃条件下，向溶有(1r，4r)-4-氨基环己烷-1-羧酸(0.62g，4.35mmol)的N，N-二甲基甲酰胺(10mL)溶液，分批加入氢化钠(0.31g，13.05mmol)，0℃搅拌1小时，然后将5，7-二氯-3-(丙-2-基)吡唑并[1，5-a]嘧啶(1g，4.35mmol)加入上述反应液。所得混合反应液室温搅拌溶液3小时。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H 2O的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸(900mg，收率：61.5％)，LC-MS m/z：337[M+H]+；At 0°C, sodium hydride (0.31 g, 13.05 mmol) was added in batches to a solution of (1r, 4r)-4-aminocyclohexane-1-carboxylic acid (0.62 g, 4.35 mmol) in N,N-dimethylformamide (10 mL), stirred at 0°C for 1 hour, and then 5,7-dichloro-3-(propan-2-yl)pyrazolo[1,5-a]pyrimidine (1 g, 4.35 mmol) was added to the reaction solution. The resulting mixed reaction solution was stirred at room temperature for 3 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3·H2O = 5-95% elution) to give (1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid (900 mg, yield: 61.5%), LC-MS m/z: 337 [M+H] + ;
2)、3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100274
2) Synthesis of tert-butyl 3-(((1r, 4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100274
在0℃条件下，向溶有(1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸(600mg，1.78mmol)，3-羟基吡咯烷-1-羧酸叔丁酯(667mg，3.56mmol)和4-二甲氨基吡啶(43.5mg，0.36mmol)的二氯甲烷(6mL)溶液中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(409.5mg，2.14mmol)。所得混合反应液室温下搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(700mg，收率：77.7％)，LC-MS m/z：506[M+H]+；To a solution of (1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid (600 mg, 1.78 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (667 mg, 3.56 mmol) and 4-dimethylaminopyridine (43.5 mg, 0.36 mmol) in dichloromethane (6 mL) at 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (409.5 mg, 2.14 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 3-(((1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (700 mg, yield: 77.7%), LC-MS m/z: 506 [M+H] + ;
3)、3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100275
3) Synthesis of tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100275
将溶有3-(((1r，4r)-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(700mg，1.38mmol)，四氢-2H-吡喃-4-胺(153.6mg，1.52mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(116mg，0.14mmol)和碳酸铯(2248mg，6.90mmol)的1，4-二氧六环(7mL)溶液，氮气保护下，加热90℃搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(500mg，收率：63.5％)，LC-MS m/z：571[M+H]+；A solution of tert-butyl 3-(((1r,4r)-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (700 mg, 1.38 mmol), tetrahydro-2H-pyran-4-amine (153.6 mg, 1.52 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (116 mg, 0.14 mmol) and cesium carbonate (2248 mg, 6.90 mmol) in 1,4-dioxane (7 mL) was heated at 90° C. under nitrogen protection and stirred for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (500 mg, yield: 63.5%), LC-MS m/z: 571 [M+H] + ;
4)、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100276
4) Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100276
向溶有3-(((1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸叔丁酯(500mg，0.88mmol)的1，4-二氧六环(2mL)溶液，滴加盐酸/二氧六环(3mL，4M)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化即可直接用于下一步，LC-MS m/z：471[M+H]+；To a solution of tert-butyl 3-(((1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (500 mg, 0.88 mmol) in 1,4-dioxane (2 mL) was added dropwise hydrochloric acid/dioxane (3 mL, 4 M). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 471 [M+H] + ;
5)、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100277
5) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylate
Figure PCTCN2024077920-ftappb-I100277
将溶有(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯(100mg，0.21mmol)，(2E)-4-(二甲基氨基)丁-2-烯酸(40.7mg，0.32mmol)和2-乙氧基-1-乙氧碳酰基-1，2-二氢喹啉(52mg，0.21mmol)的二氯甲烷(1mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有(0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(20mg，收率：16.2％)，LC-MS m/z：582[M+H]+；A solution of (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.21 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (40.7 mg, 0.32 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (52 mg, 0.21 mmol) in dichloromethane (1 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing (0.1% NH 3 ·H 2 O=5-95% elution) to give (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (20 mg, yield: 16.2%), LC-MS m/z: 582 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.59(s，1H)，6.88-6.80(m，1H)，6.51-6.38(m，1H)，5.40-5.28(m，2H)，4.13-4.05(m，1H)，3.99-3.93(m，2H)，3.89-3.79(m，1H)，3.77-3.64(m，3H)，3.59-3.52(m，2H)，3.45-3.38(m，1H)，3.19-3.15(m，2H)，3.09-3.01(m，1H)，2.45-2.36(m，1H)，2.28(d，J＝4.0Hz，6H)，2.22-2.16(m，3H)，2.10-1.99(m，4H)，1.66-1.50(m，4H)，1.49-1.37(m，3H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.59 (s, 1H), 6.88-6.80 (m, 1H), 6.51-6.38 (m, 1H), 5.40-5.28 (m, 2H), 4.13-4.05 (m, 1H), 3.99-3.93 (m, 2H), 3.89-3.79 (m, 1H), 3.77-3.64 (m, 3H), 3.59-3.52 (m, 2H), 3.45 -3.38 (m, 1H), 3.19-3.15 (m, 2H), 3.09-3.01 (m, 1H), 2.45-2.36 (m, 1H), 2.28 (d, J=4.0Hz, 6H), 2.22-2.16 (m, 3H), 2.10-1.99 (m, 4H), 1.66-1.50 (m, 4H), 1.49-1.37 (m, 3H), 1.29 (s, 3H), 1.27 (s, 3H).
实施例50、(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基) 环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物50)的合成：Example 50, (1r, 4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino) Synthesis of cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 50):
1)、(1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸的合成
Figure PCTCN2024077920-ftappb-I100278
1) Synthesis of (1r, 4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid
Figure PCTCN2024077920-ftappb-I100278
将溶有4-氯-2-(甲基磺酰基)-8-(丙-2-基)吡唑并[1，5-a][1，3，5]三嗪(1g，4.12mmol)，(1r，4r)-4-氨基环己烷-1-羧酸(0.71g，4.94mmol)和N，N-二异丙基乙胺(1.60g，12.36mmol)的异丙醇(10mL)溶液加热80℃搅拌16小时。冷却后，将混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝5-95％洗脱)纯化得到(1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸(270mg，收率：19％)，LC-MS m/z：350[M+H]+；A solution of 4-chloro-2-(methylsulfonyl)-8-(propan-2-yl)pyrazolo[1,5-a][1,3,5]triazine (1 g, 4.12 mmol), (1r,4r)-4-aminocyclohexane-1-carboxylic acid (0.71 g, 4.94 mmol) and N,N-diisopropylethylamine (1.60 g, 12.36 mmol) in isopropanol (10 mL) was heated at 80°C and stirred for 16 hours. After cooling, the mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5-95% elution) to give (1r,4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid (270 mg, yield: 19%), LC-MS m/z: 350 [M+H] + ;
2)、3-(((1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100279
2) Synthesis of 3-(((1r,4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100279
在0℃条件下，向溶有(1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-甲酸(270mg，0.77mmol)，3-羟基吡咯烷-1-羧酸苄基酯(341mg，1.54mmol)和4-二甲氨基吡啶(188mg，1.54mmol)的二氯甲烷(5mL)溶液中，加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(443mg，2.31mmol)。所得混合反应液室温搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-(((1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(370mg，收率：86.7％)，LC-MS m/z：553[M+H]+；To a solution of (1r,4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid (270 mg, 0.77 mmol), 3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (341 mg, 1.54 mmol) and 4-dimethylaminopyridine (188 mg, 1.54 mmol) in dichloromethane (5 mL) at 0°C, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give benzyl 3-(((1r,4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (370 mg, yield: 86.7%), LC-MS m/z: 553 [M+H] + ;
3)、3-(((1r，4r)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100280
3) Synthesis of Benzyl 3-(((1r,4r)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100280
将溶有3-(((1r，4r)-4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(370mg，0.67mmol)和3-氯过氧苯甲酸(463mg，2.68mmol)的二氯甲烷(5mL)溶液室温搅拌24小时。所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到3-(((1r，4r)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(198mg，收率：50.6％)，LC-MS m/z：585[M+H]+； A solution of benzyl 3-(((1r,4r)-4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (370 mg, 0.67 mmol) and 3-chloroperbenzoic acid (463 mg, 2.68 mmol) in dichloromethane (5 mL) was stirred at room temperature for 24 hours. The resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-40% elution) to give benzyl 3-(((1r,4r)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (198 mg, yield: 50.6%), LC-MS m/z: 585 [M+H] + ;
4)、3-(((1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100281
4) Synthesis of 3-(((1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100281
将溶有3-(((1r，4r)-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(200mg，0.34mmol)，四氢-2H-吡喃-4-胺(86mg，0.85mmol)和N，N-二异丙基乙胺(176mg，1.36mmol)的异丙醇(5mL)溶液加热90℃搅拌16小时。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法纯化(乙酸乙酯∶石油醚＝10-50％洗脱)纯化得到3-(((1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(55mg，收率：26.5％)，LC-MS m/z：606[M+H]+；A solution of benzyl 3-(((1r,4r)-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (200 mg, 0.34 mmol), tetrahydro-2H-pyran-4-amine (86 mg, 0.85 mmol) and N,N-diisopropylethylamine (176 mg, 1.36 mmol) in isopropanol (5 mL) was heated at 90°C and stirred for 16 hours. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give benzyl 3-(((1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (55 mg, yield: 26.5%), LC-MS m/z: 606 [M+H] + ;
5)、(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100282
5) Synthesis of (1r, 4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100282
将溶有3-(((1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)环己烷-1-羰基)氧基)吡咯烷-1-羧酸苄基酯(55mg，0.091mmol)和钯碳(20mg)的甲醇(2mL)溶液氢气氛围下，室温搅拌2小时。将混合反应液过滤，滤饼用甲醇(3×20mL)洗涤。收集滤液减压浓缩得到(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸吡咯烷-3-基酯(93mg，粗品)，LC-MS m/z：472[M+H]+；A solution of benzyl 3-(((1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carbonyl)oxy)pyrrolidine-1-carboxylate (55 mg, 0.091 mmol) and palladium on carbon (20 mg) in methanol (2 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixed reaction liquid was filtered and the filter cake was washed with methanol (3×20 mL). The filtrate was collected and concentrated under reduced pressure to give (1r, 4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (93 mg, crude product), LC-MS m/z: 472 [M+H]+;
6)、(1r，4r)-4-((叔丁氧基羰基)(8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100283
6) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl(1r,4r)-4-((tert-butoxycarbonyl)(8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylate
Figure PCTCN2024077920-ftappb-I100283
将溶有吡(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸吡咯烷-3-基酯(100mg，0.21mmol)，2-氟丙-2-烯酸(23mg，0.25mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(118mg，0.42mmol)和1-甲基咪唑(69mg，0.84mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌16小时。将所得混合反应液减压浓缩得。残余物通过C18柱色谱法(乙腈∶含有0.1％NH4HCO3的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((叔丁氧基羰基)(8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(20mg：收率：15％)，LC-MS m/z：644[M+H]+； A solution of pyrrolidine-3-yl pyr(1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylate (100 mg, 0.21 mmol), 2-fluoroprop-2-enoic acid (23 mg, 0.25 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (118 mg, 0.42 mmol) and 1-methylimidazole (69 mg, 0.84 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 16 hours. The obtained mixed reaction solution was concentrated under reduced pressure to obtain. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 5-95% elution) to give (1r,4r)-4-((tert-butoxycarbonyl)(8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (20 mg: yield: 15%), LC-MS m/z: 644 [M+H] + ;
7)、(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100284
7) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl(1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylate
Figure PCTCN2024077920-ftappb-I100284
将溶有(1r，4r)-4-((叔丁氧基羰基)(8-异丙基-2-(四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(20mg，0.031mmol)和2，2，2-三氟乙酸(0.1mL)的二氯甲烷(0.3mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶含有0.1％NH4HCO3的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)环己烷-1-甲酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(10mg，收率：59％)，LC-MS m/z：544[M+H]+；A solution of (1r,4r)-4-((tert-butoxycarbonyl)(8-isopropyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (20 mg, 0.031 mmol) and 2,2,2-trifluoroacetic acid (0.1 mL) in dichloromethane (0.3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 5-95% elution) to give (1r,4r)-4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (10 mg, yield: 59%), LC-MS m/z: 544 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.64(s，1H)，5.48(dd，J＝47.2，3.5Hz，1H)，5.35(s，1H)，5.29-5.22(m，1H)，4.08-4.01(m，1H)，3.99-3.94(m，3H)，3.90(s，1H)，3.77(dd，J＝10.7，4.2Hz，1H)，3.71(t，J＝6.7Hz，1H)，3.63(dd，J＝16.1，7.6Hz，1H)，3.54(td，J＝11.5，1.9Hz，2H)，3.00(dt，J＝13.8，6.9Hz，1H)，2.38(dd，J＝11.4，8.7Hz，1H)，2.23-2.04(m，6H)，2.00(d，J＝12.7Hz，2H)，1.64-1.52(m，4H)，1.52-1.45(m，2H)，1.26(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d4) δ7.64 (s, 1H), 5.48 (dd, J=47.2, 3.5Hz, 1H), 5.35 (s, 1H), 5.29-5.22 (m, 1H), 4.08- 4.01 (m, 1H), 3.99-3.94 (m, 3H), 3.90 (s, 1H), 3.77 (dd, J=10.7, 4.2Hz, 1H), 3.71 (t, J=6.7Hz, 1H), 3.63 (dd , J=16.1, 7.6Hz, 1H), 3.54 (td, J=11.5, 1.9Hz, 2H), 3.00 (dt, J=13.8, 6.9Hz, 1H), 2.38 (dd, J=11.4, 8.7Hz, 1H), 2.23-2.04(m, 6H), 2.00(d, J＝12.7Hz, 2H), 1.64-1.52(m, 4H), 1.52-1.45(m, 2H), 1.26(d, J＝6.9Hz , 6H).
实施例51、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物51)的合成：Example 51, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 51):
1)、6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100285
1) Synthesis of tert-butyl 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100285
将溶有5，7-二氯-3-异丙基吡唑并[1，5-a]嘧啶(500mg，2.17mmol)，6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(516mg，2.6mmol)和N，N-二异丙基乙胺(841mg，6.51mmol)的异丙基(8mL)溶液加热80℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(800mg，收率：94％)，LC-MS m/z：392[M+H]+；A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (500 mg, 2.17 mmol), 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (516 mg, 2.6 mmol) and N,N-diisopropylethylamine (841 mg, 6.51 mmol) in isopropyl (8 mL) was heated at 80°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (800 mg, yield: 94%), LC-MS m/z: 392[M+H] + ;
2)、6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯合成
Figure PCTCN2024077920-ftappb-I100286
2) Synthesis of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100286
将溶有6-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(800mg，2.03mmol)，二碳酸二叔丁酯(665mg，3.05mmol)，4-二甲基氨基吡啶(24mg，0.20mmol)和三乙胺(617mg，6.09mmol)的二氯甲烷(5mL)溶液室温搅拌1小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-20％洗脱)纯化得到6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基) -3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(800mg，收率：80％)，LC-MS m/z：492[M+H]+；A solution of tert-butyl 6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (800 mg, 2.03 mmol), di-tert-butyl dicarbonate (665 mg, 3.05 mmol), 4-dimethylaminopyridine (24 mg, 0.20 mmol) and triethylamine (617 mg, 6.09 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20% elution) to obtain 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino) -tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (800 mg, yield: 80%), LC-MS m/z: 492 [M+H] + ;
3)、6-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100287
3) Synthesis of tert-butyl 6-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100287
将溶有6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(500mg，1.02mmol)，四氢-2H-吡喃-4-胺(308mg，3.04mmol)，(1，3-双(2，6-二异丙基苯基)咪唑亚基)(3-氯吡啶基)二氯化钯(II)(137mg，0.2mmol)和碳酸铯(994mg，3.04mmol)的1，4-二氧六环(5mL)溶液，氮气保护下，加热100℃搅拌2小时。冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到6-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(510mg，收率：90％)，LC-MS m/z：557[M+H]+；A solution of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.02 mmol), tetrahydro-2H-pyran-4-amine (308 mg, 3.04 mmol), (1,3-bis(2,6-diisopropylphenyl)imidazolylidene)(3-chloropyridyl)palladium(II)dichloride (137 mg, 0.2 mmol) and cesium carbonate (994 mg, 3.04 mmol) in 1,4-dioxane (5 mL) was heated at 100° C. and stirred for 2 hours under nitrogen protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give tert-butyl 6-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (510 mg, yield: 90%), LC-MS m/z: 557 [M+H] + ;
4)、N7-(3-氮杂双环[3.1.0]己烷-6-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺
Figure PCTCN2024077920-ftappb-I100288
4), N 7 -(3-azabicyclo[3.1.0]hexane-6-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine
Figure PCTCN2024077920-ftappb-I100288
将溶有6-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(500mg，0.90mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅拌1小时。将混合反应减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0-95％洗脱)纯化得到N7-(3-氮杂双环[3.1.0]己烷-6-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(150mg，收率：47％)，LC-MS m/z：357[M+H]+；A solution of tert-butyl 6-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 0.90 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-95% elution) to give N 7 -(3-azabicyclo[3.1.0]hexan-6-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (150 mg, yield: 47%), LC-MS m/z: 357 [M+H] + ;
5)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100289
5) Synthesis of 1-(tert-butoxycarbonyl)azetidin-3-yl 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100289
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(49mg，0.28mmol)，三乙胺(85mg，0.84mmol)和二(三氯甲基)碳酸酯(42mg，0.14mmol)的四氢呋喃(2mL)溶液0℃搅拌0.5小时。然后将NN7-(3-氮杂双环[3.1.0]己烷-6-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(150mg，0.42mmol)。所得混合反应液室温搅拌2小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0-80％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯(80mg，收率：51％)，LC-MS m/z：556[M+H]+；A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (49 mg, 0.28 mmol), triethylamine (85 mg, 0.84 mmol) and bis(trichloromethyl) carbonate (42 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was stirred at 0°C for 0.5 hours. Then, NN 7 -(3-azabicyclo[3.1.0]hexane-6-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (150 mg, 0.42 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-80% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (80 mg, yield: 51%), LC-MS m/z: 556 [M+H] + ;
6)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100290
6) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100290
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯(80mg，0.14mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)溶液室温搅拌1小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯＝0-95％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(60mg，收率：910％)，LC-MS m/z：456[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (80 mg, 0.14 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature for 1 minute. hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure = 0-95% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (60 mg, yield: 910%), LC-MS m/z: 456 [M+H] + ;
7)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100291
7) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100291
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(15mg，0.03mmol)，2-氟丙烯酸(4mg，0.05mmol)，1-甲基1H-咪唑(11mg，0.13mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(18mg，0.06mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱法(乙腈∶含有0.1％NH4HCO3的纯水＝0-60％)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(2mg，收率：12％)，LC-MS m/z：528[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (15 mg, 0.03 mmol), 2-fluoroacrylic acid (4 mg, 0.05 mmol), 1-methyl 1H-imidazole (11 mg, 0.13 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (18 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 0-60%) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (2 mg, yield: 12%), LC-MS m/z: 528 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.58(s，1H)，5.64-5.46(m，2H)，5.19-5.10(m，2H)，4.74(s，1H)，4.40(s，2H)，4.18-4.07(m，1H)，4.03(d，J＝11.2Hz，1H)，3.97(dd，J＝8.0，4.0Hz，2H)，3.87(d，J＝10.8Hz，1H)，3.79(d，J＝11.2Hz，1H)，3.66-3.61(m，1H)，3.60-3.56(m，2H)，3.54(s，1H)，3.05(dt，J＝13.6，6.9Hz，1H)，2.35(s，1H)，2.04(d，J＝10.4Hz，2H)，1.97(s，2H)，1.61-1.49(m，2H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.58 (s, 1H), 5.64-5.46 (m, 2H), 5.19-5.10 (m, 2H), 4.74 (s, 1H), 4.40 (s, 2H) ), 4.18-4.07 (m, 1H), 4.03 (d, J = 11.2Hz, 1H), 3.97 (dd, J = 8.0, 4.0Hz, 2H), 3.87 (d, J = 10.8Hz, 1H), 3 .79 (d, J=11.2Hz, 1H), 3.66-3.61 (m, 1H), 3.60-3.56 (m, 2H), 3.54 (s, 1H), 3.05 (dt, J=13.6, 6.9Hz, 1H ), 2.35 (s, 1H), 2.04 (d, J = 10.4Hz, 2H), 1.97 (s, 2H), 1.61-1.49 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H) .
实施例52、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物52)的合成：
Figure PCTCN2024077920-ftappb-I100292
Example 52, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 52):
Figure PCTCN2024077920-ftappb-I100292
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(50mg，0.11mmo)，(E)-4-(二甲氨基)丁-2-烯酸(21mg，0.16mmol)，1-甲基-1H-咪唑(36mg，0.44mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(61mg，0.22mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱法(乙腈∶含有0.1％的NH4HCO3的纯 水＝0-60％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(10mg，收率：16％)，LC-MS m/z：567[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (50 mg, 0.11 mmol), (E)-4-(dimethylamino)but-2-enoic acid (21 mg, 0.16 mmol), 1-methyl-1H-imidazole (36 mg, 0.44 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (61 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure NH 4 HCO 3 containing 0.1%). The product was purified by eluting with water (0-60%) to give (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 mg, yield: 16%), LC-MS m/z: 567 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.58(s，1H)，6.85-6.74(m，1H)，6.17(d，J＝12.0Hz，1H)，5.50(s，1H)，5.17(d，J＝3.6Hz，1H)，4.61(s，1H)，4.42-4.30(m，1H)，4.23(d，J＝10.0Hz，1H)，4.16-4.06(m，1H)，4.04-3.93(m，3H)，3.82(dd，J＝29.6，11.2Hz，2H)，3.63-3.51(m，4H)，3.14(d，J＝5.2Hz，2H)，3.05(dt，J＝13.6，6.9Hz，1H)，2.34(s，1H)，2.26(d，J＝2.4Hz，6H)，2.04(d，J＝10.8Hz，2H)，1.96(s，2H)，1.63-1.48(m，2H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.58 (s, 1H), 6.85-6.74 (m, 1H), 6.17 (d, J=12.0Hz, 1H), 5.50 (s, 1H), 5.17 ( d, J＝3.6Hz, 1H), 4.61 (s, 1H), 4.42-4.30 (m, 1H), 4.23 (d, J＝10.0Hz, 1H), 4.16-4.06 (m, 1H), 4.04-3.93 (m,3H),3.82 (dd, J=29.6, 11.2Hz, 2H), 3.63-3.51 (m, 4H), 3.14 (d, J=5.2Hz, 2H), 3.05 (dt, J=13.6, 6.9Hz, 1H), 2.34 ( s, 1H), 2.26 (d, J=2.4Hz, 6H), 2.04 (d, J=10.8Hz, 2H), 1.96 (s, 2H), 1.63-1.48 (m, 2H), 1.29 (s, 3H ), 1.27(s, 3H).
实施例53、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物53)的合成：Example 53, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 53):
1)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100293
1) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100293
将溶有3-羟基吡咯烷-1-甲酸叔丁酯(53mg，0.28mmol)，三乙胺(85mg，0.84mmol)和双(三氯甲基)碳酸酯(42mg，0.14mmol)的四氢呋喃(2mL)溶液中，0℃搅拌0.5h。然后将N7-(3-氮杂双环[3.1.0]己烷-6-基)-3-异丙基-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(150mg，0.42mmol)。所得混合反应液室温搅拌2小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(乙腈∶纯水＝0-80％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(100mg，收率：62％)，LC-MS m/z：570[M+H]+；A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (53 mg, 0.28 mmol), triethylamine (85 mg, 0.84 mmol) and bis(trichloromethyl) carbonate (42 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was stirred at 0°C for 0.5 h. Then N 7 -(3-azabicyclo[3.1.0]hexane-6-yl)-3-isopropyl-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (150 mg, 0.42 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-80% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (100 mg, yield: 62%), LC-MS m/z: 570 [M+H] + ;
2)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100294
2) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100294
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(100mg，0.18mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)溶液室温搅拌1小时。将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶纯水＝0-95％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸吡咯烷-3-基酯(80mg，收率：97％)，LC-MS m/z：470[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (100 mg, 0.18 mmol) in dichloromethane (3 mL) and a solution of 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature. 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-95% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid pyrrolidin-3-yl ester (80 mg, yield: 97%), LC-MS m/z: 470 [M+H] + ;
3)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100295
3) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100295
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸吡咯烷-3-基酯(40mg，0.08mmol)，2-氟丙烯酸(10mg，0.13mmol)，1-甲基-1H-咪唑(28mg，0.34mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(48mg，0.17mmol)的N，N-二甲进甲酰胺(2mL)溶液室温搅拌16小时。残余物通过C18柱色谱法(乙腈∶含有0.1％NH4HCO3的纯水＝0-60％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(5mg，收率：11％)，LC-MS m/z：542[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid pyrrolidin-3-yl ester (40 mg, 0.08 mmol), 2-fluoroacrylic acid (10 mg, 0.13 mmol), 1-methyl-1H-imidazole (28 mg, 0.34 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (48 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 0-60% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (5 mg, yield: 11%), LC-MS m/z: 542 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.57(s，1H)，5.59-5.38(m，2H)，5.28-5.23(m，2H)，4.11(t，J＝8.0Hz，1H)，3.97-3.92(m，3H)，3.81-3.67(m，4H)，3.67-3.44(m，5H)，3.09-3.01(m，1H)，2.31(s，1H)，2.24-2.20(m，1H)，2.13(s，1H)，2.08-2.03(m，2H)，1.94(d，J＝2.4Hz，2H)，1.58-1.52(m，2H)，1.29(s，3H)，1.27(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.57 (s, 1H), 5.59-5.38 (m, 2H), 5.28-5.23 (m, 2H), 4.11 (t, J=8.0Hz, 1H), 3.97-3.92(m, 3H), 3.81-3.67(m, 4H), 3.67-3.44(m, 5H ), 3.09-3.01(m, 1H), 2.31(s, 1H), 2.24-2.20(m, 1H), 2.13(s, 1H), 2.08-2.03(m, 2H), 1.94(d, J=2.4 Hz, 2H), 1.58-1.52 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H).
实施例54、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物54)的合成：
Figure PCTCN2024077920-ftappb-I100296
Example 54, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 54):
Figure PCTCN2024077920-ftappb-I100296
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸吡咯烷-3-基酯(40mg，0.08mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(17mg，0.13mmol)，1-甲基-1H-咪唑(28mg，0.34mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(48mg，0.17mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱法(乙腈∶含有0.1％NH4HCO3的纯水＝0-60％洗脱)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(5mg，收率：10％)，LC-MS m/z：581[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid pyrrolidin-3-yl ester (40 mg, 0.08 mmol), (E)-4-(dimethylamino)but-2-enoic acid (17 mg, 0.13 mmol), 1-methyl-1H-imidazole (28 mg, 0.34 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (48 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4 HCO 3 = 0-60% elution) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (5 mg, yield: 10%), LC-MS m/z: 581 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.57(s，1H)，6.90-6.78(m，1H)，6.52-6.35(m，1H)，5.47(s，1H)，5.26(d，J＝16.0Hz，1H)，4.16-4.06(m，1H)，3.97(d，J＝11.6Hz，2H)，3.89-3.64(m，6H)，3.60-3.52(m，4H)，3.18-3.12(m，2H)，3.08-3.03(m，1H)，2.33-2.32(m，1H)，2.31(s，6H)，2.29-2.24(m，1H)，2.14(s，1H)，2.04(d，J＝12.8Hz，2H)，1.94(s，2H)，1.58-1.52(m，2H)，1.28(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.57 (s, 1H), 6.90-6.78 (m, 1H), 6.52-6.35 (m, 1H), 5.47 (s, 1H), 5.26 (d, J ＝16.0Hz, 1H), 4.16-4.06(m, 1H), 3.97(d, J＝11.6Hz, 2H), 3.89-3.64(m, 6H), 3.60-3.52( m, 4H), 3.18-3.12(m, 2H), 3.08-3.03(m, 1H), 2.33-2.32(m, 1H), 2.31(s, 6H), 2.29-2.24(m, 1H), 2.14( s, 1H), 2.04 (d, J=12.8Hz, 2H), 1.94 (s, 2H), 1.58-1.52 (m, 2H), 1.28 (d, J=8.0Hz, 6H).
实施例55、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物55)的合成：Example 55, Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 55):
1)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100297
1) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100297
室温条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(195mg，1.04mmol)的二氯甲烷(2mL)溶液中，加入三乙胺(316mg，3.12mmol)，然后加入三光气(123mg，0.42mmol)，混合反应液0℃搅拌0.5小时。将3-异丙基-N7-(2-氮杂螺[3.3]庚烷-6-基)-N5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-5，7-二胺(385mg，1.04mmol)的二氯甲烷(2mL)加入到上述混合溶液。所得混合反应液室温搅拌16小时。LCMS监测反应完全，将所得混合反应液用饱和氯化铵溶液(10mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和食盐水(130mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩将。残余物通过C18柱色谱法(乙腈和水)纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(60mg，收率：9.9％)，LC-MS m/z：584[M+H]+；At room temperature, triethylamine (316 mg, 3.12 mmol) was added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (195 mg, 1.04 mmol) in dichloromethane (2 mL), and then triphosgene (123 mg, 0.42 mmol) was added, and the mixed reaction solution was stirred at 0°C for 0.5 hours. 3-Isopropyl- N 7 -(2-azaspiro[3.3]heptane-6-yl)-N 5 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (385 mg, 1.04 mmol) in dichloromethane (2 mL) was added to the above mixed solution. The obtained mixed reaction solution was stirred at room temperature for 16 hours. LCMS monitored the reaction to be complete, and the obtained mixed reaction solution was diluted with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (130 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile and water) to give 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (60 mg, yield: 9.9%), LC-MS m/z: 584 [M+H] + ;
2)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸吡咯烷-3-基酯合成
Figure PCTCN2024077920-ftappb-I100298
2) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100298
将6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(60mg，0.10mmol)的2，2，2-三氟乙酸(0.4mL)的二氯甲烷(1.2mL)溶液室温搅拌2小时。LCMS监测反应反应完全。将所得混合反液减压浓缩得到粗产品，直接用于下一步骤，无需进一步纯化，LC-MS m/z：484[M+H]+；A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (60 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (0.4 mL) in dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. The reaction was complete as monitored by LCMS. The resulting mixed liquid was concentrated under reduced pressure to give a crude product, which was used directly in the next step without further purification, LC-MS m/z: 484[M+H] + ;
3)、6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100299
3) Synthesis of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100299
将溶有6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-A]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸吡咯烷-3-基酯(122mg，0.25mmol)，2-氟丙烯酸(34mg，0.375mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(140mg，0.5mmol)和N-甲基咪唑(82mg，1.0mmol)的N，N-二甲基甲酰胺(2mL)溶液，所得混合反应液加热40℃搅拌16小时。LCMS监测反应完成。将混合反应液通过制备级高效液相色谱纯化得到6-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(3.17mg，收率：2.3％)，LC-MS m/z：556[M+H]+； A solution of 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-A]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid pyrrolidin-3-yl ester (122 mg, 0.25 mmol), 2-fluoroacrylic acid (34 mg, 0.375 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (140 mg, 0.5 mmol) and N-methylimidazole (82 mg, 1.0 mmol) in N,N-dimethylformamide (2 mL) was dissolved, and the resulting mixed reaction solution was heated at 40° C. and stirred for 16 hours. The reaction was monitored by LCMS to be complete. The mixed reaction solution was purified by preparative HPLC to obtain 6-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (3.17 mg, yield: 2.3%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.59(s，1H)，5.47(dd，1H)，5.25(d，2H)，5.15(s，1H)，4.07(d，J＝12Hz，3H)，4.01-3.85(m，6H)，3.82-3.51(m，5H)，3.04(dt，1H)，2.75(dd，2H)，2.34-1.96(m，6H)，1.60-1.45(m，2H)，1.28(d，J＝8Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.59 (s, 1H), 5.47 (dd, 1H), 5.25 (d, 2H), 5.15 (s, 1H), 4.07 (d, J=12Hz, 3H ), 4.01-3.85(m, 6H), 3.82-3.51(m, 5H), 3.04(dt, 1H), 2.75(dd, 2H), 2.34-1.96(m, 6H), 1.60-1.45(m, 2H) ), 1.28 (d, J=8Hz, 6H).
实施例56、(E)-6-(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑[1，5-a]嘧啶-7-基)氨基]-2-氮杂螺[3.3]庚烷-2-羧酸1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物56)的合成：
Figure PCTCN2024077920-ftappb-I100300
Example 56, Synthesis of (E)-6-(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compound 56):
Figure PCTCN2024077920-ftappb-I100300
将溶有6-((3-异丙基-5-(四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基]-2-氮杂螺[3.3]庚烷-2-羧酸吡咯烷-3-基酯(100mg，0.207mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(62mg，0.375mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(116mg，0.414mmol)和N-甲基咪唑(68mg，0.828mmol)的N，N-二甲基甲酰胺(2mL)溶液加热40℃搅拌16小时。LCMS检测反应完成。将混合反应液通过制备高效液相色谱纯化得到(3.0mg，收率：2.4％)，LC-MS m/z：595[M+H]+；A solution of 6-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.207 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (62 mg, 0.375 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (116 mg, 0.414 mmol) and N-methylimidazole (68 mg, 0.828 mmol) in N,N-dimethylformamide (2 mL) was heated at 40° C. and stirred for 16 hours. The reaction was completed by LCMS. The mixed reaction solution was purified by preparative high performance liquid chromatography to obtain (3.0 mg, yield: 2.4%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.59(s，1H)，6.88-6.78(m，1H)，6.44(dd，J＝29.6，15.2Hz，1H)，5.29-5.11(m，2H)，4.13-4.03(m，3H)，3.96(d，J＝5.6Hz，5H)，3.87-3.44(m，6H)，3.23-3.13(m，2H)，3.04(dt，J＝13.8，6.8Hz，1H)，2.80-2.68(m，2H)，2.34-1.96(m，12H)，1.60-1.45(m，2H)，1.28(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD): δ7.59 (s, 1H), 6.88-6.78 (m, 1H), 6.44 (dd, J=29.6, 15.2Hz, 1H), 5.29-5.11 (m, 2H), 4.13-4.03 (m, 3H), 3.96 (d, J=5.6Hz, 5H), 3.87-3.44 (m, 6H), 3.23-3.13 (m, 2H), 3.04 (dt, J=13.8, 6.8Hz, 1H), 2.80-2.68(m, 2H), 2.34-1.96(m, 12H), 1.60-1.45(m, 2H), 1.28(d, J=6.8Hz, 6H).
实施例57、6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物57)的合成：Example 57, Synthesis of 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 57):
1)、6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100301
1) Synthesis of tert-butyl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100301
将溶有6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(600mg，1.22mmol)，(R)-3-羟基哌啶-1-羧酸苄基酯(717mg，3.05mmol)，三(二亚苄基丙酮)钯(112mg，0.122mmol)，碳酸铯(1193mg，3.66mmol)和(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(135mg，0.244)的甲苯(10mL)溶液加热140℃搅拌1小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(480mg，收率：57％)，LC-MS m/z：691[M+H]+；A solution of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 1.22 mmol), benzyl (R)-3-hydroxypiperidine-1-carboxylate (717 mg, 3.05 mmol), tris(dibenzylideneacetone)palladium (112 mg, 0.122 mmol), cesium carbonate (1193 mg, 3.66 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (135 mg, 0.244) dissolved in toluene (10 mL) was heated at 140° C. and stirred for 1 hour. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give tert-butyl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (480 mg, yield: 57%), LC-MS m/z: 691 [M+H] + ;
2)、(3R)-3-((7-((3-氮杂双环[3.1.0]己烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100302
2) Synthesis of (3R)-3-((7-((3-azabicyclo[3.1.0]hexane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100302
将溶有6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(480mg，0.7mmol)的二氯甲烷(3mL)溶液和2，2，2-三氟乙酸(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(3R)-3-((7-((3-氮杂双环[3.1.0]己烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(200mg，收率：58％)，LC-MS m/z：491[M+H]+； A solution of tert-butyl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (480 mg, 0.7 mmol) in dichloromethane (3 mL) and a solution of 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give benzyl (3R)-3-((7-((3-azabicyclo[3.1.0]hexan-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (200 mg, yield: 58%), LC-MS m/z: 491 [M+H] + ;
3)、6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100303
3) Synthesis of 1-(tert-butoxycarbonyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100303
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(37mg，0.21mmol)和三乙胺(124mg，1.23mmol)的四氢呋喃(1mL)溶液中，加入三光气(63mg，0.21mmol)。所得混合反应液室温搅拌1小时。然后将(3R)-3-((7-((3-氮杂双环[3.1.0]己烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸酯(200mg，0.41mmol)。加完后，0℃搅拌溶液3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯(100mg，收率：68％)，LC-MS m/z：690[M+H]+；Triphosgene (63 mg, 0.21 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (37 mg, 0.21 mmol) and triethylamine (124 mg, 1.23 mmol) in tetrahydrofuran (1 mL) at 0°C. The resulting mixed reaction solution was stirred at room temperature for 1 hour. Then (3R)-3-((7-((3-azabicyclo[3.1.0]hexane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (200 mg, 0.41 mmol) was added. After the addition, the solution was stirred at 0°C for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-(tert-butoxycarbonyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, yield: 68%), LC-MS m/z: 690 [M+H] + ;
4)、6-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100304
4) Synthesis of 6-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100304
室温条件下，向溶有6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧基羰基)氮杂环丁烷-3-基酯(100mg，0.15mmol)的e二氯甲烷(0.9mL)溶液中，滴加2，2，2-三氟乙酸(0.3mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯化＝5-95％洗脱)纯化得到6-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(80mg，收率：94％)，LC-MS m/z：590[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise to a solution of 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (100 mg, 0.15 mmol) in dichloromethane (0.9 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: purification containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 6-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (80 mg, yield: 94%), LC-MS m/z: 590 [M+H] + ;
5)、6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100305
5) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100305
将溶有6-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(40mg，0.07mmol)，2-氟丙烯酸(7.56mg，0.084mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(39mg，0.14mmol)和1-甲基-1H-咪唑(23mg，0.28mmol)的N，N-二甲基甲酰胺(0.5mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-90％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，收率：44.6％)，LC-MS m/z：662[M+H]+； A solution of 6-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (40 mg, 0.07 mmol), 2-fluoroacrylic acid (7.56 mg, 0.084 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) and 1-methyl-1H-imidazole (23 mg, 0.28 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-90% elution) to give 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, yield: 44.6%), LC-MS m/z: 662 [M+H] + ;
6)、6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100306
6) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100306
将溶有6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(20mg，0.03mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(5mg，收率：31％)，LC-MS m/z：528[M+H]+；A solution of 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (20 mg, 0.03 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 1-(2-fluoroacryloyl)azetidin-3-yl 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 mg, yield: 31%), LC-MS m/z: 528 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.75(s，1H)，5.67(s，1H)，5.61(d，J＝3.5Hz，1H)，5.49(d，J＝3.5Hz，1H)，5.21(d，J＝16.1Hz，2H)，4.76(s，1H)，4.49(d，J＝69.7Hz，2H)，4.05(s，1H)，3.83(dd，J＝33.1，11.1Hz，2H)，3.60(dd，J＝22.9，11.0Hz，2H)，3.54-3.37(m，3H)，3.26(s，1H)，3.17-3.04(m，2H)，2.44(s，1H)，2.19-2.07(m，2H)，2.01(d，J＝8.2Hz，2H)，1.83(dd，J＝9.5，4.5Hz，1H)，1.31(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ7.75 (s, 1H), 5.67 (s, 1H), 5.61 (d, J=3.5Hz, 1H), 5.49 (d, J=3.5Hz, 1H), 5.21 ( d, J=16.1Hz, 2H), 4.76 (s, 1H), 4.49 (d, J=69.7Hz, 2H), 4.05 (s, 1H), 3.83 (dd, J=33.1, 11.1Hz, 2H), 3.60 (dd, J=22.9, 11.0Hz, 2H), 3.54-3.37 (m, 3H), 3.26 (s, 1H), 3.17-3.04 (m, 2H), 2.44 (s, 1H), 2.19 -2.07 (m, 2H), 2.01 (d, J=8.2Hz, 2H), 1.83 (dd, J=9.5, 4.5Hz, 1H), 1.31 (d, J=6.9Hz, 6H).
实施例58、6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物58)的合成：Example 58, Synthesis of 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 58):
1)、1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸酯
Figure PCTCN2024077920-ftappb-I100307
1), 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100307
将溶有6-((5-((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(40mg，0.07mmol)，(E)-4-(二甲氨基)丁-2-烯酸(11mg，0.084mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(40mg，0.14mmol)和1-甲基-1H-咪唑(23mg，0.28mmol)的N，N-二甲基甲酰胺(0.5mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-90％洗脱)纯化得到1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸酯(20mg，收率：42％)，LC-MS m/z：701[M+H]+；A solution of 6-((5-((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (40 mg, 0.07 mmol), (E)-4-(dimethylamino)but-2-enoic acid (11 mg, 0.084 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (40 mg, 0.14 mmol) and 1-methyl-1H-imidazole (23 mg, 0.28 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-90% elution) to give 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, yield: 42%), LC-MS m/z: 701 [M+H] + ;
2)、6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100308
2) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100308
向溶有1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基6-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸酯(20mg，0.03mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌2小时。冷却后。将所得混合反应液减压浓缩。残余物通过C18 柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-90％洗脱)纯化得到6-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(5mg，收率：31％)，LC-MS m/z：567[M+H]+；A solution of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 0.03 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50°C and stirred for 2 hours. After cooling. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 Column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-90% elution) was used to obtain 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 mg, yield: 31%), LC-MS m/z: 567 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.76(s，1H)，6.73(dt，J＝14.7，7.2Hz，1H)，6.48(d，J＝15.2Hz，1H)，5.67(s，1H)，5.53(s，1H)，5.19(d，J＝3.9Hz，1H)，4.65(s，1H)，4.44-4.26(m，2H)，4.04(dd，J＝11.6，4.0Hz，1H)，3.94(d，J＝7.1Hz，2H)，3.88-3.76(m，2H)，3.70-3.48(m，4H)，3.45-3.40(m，1H)，3.10(dt，J＝13.8，8.5Hz，2H)，2.90(s，6H)，2.43(s，1H)，2.14(s，2H)，2.01(d，J＝14.3Hz，3H)，1.90-1.81(m，1H)，1.31(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ7.76 (s, 1H), 6.73 (dt, J=14.7, 7.2Hz, 1H), 6.48 (d, J=15.2Hz, 1H), 5.67 (s, 1H), 5.53 (s, 1H), 5.19 (d, J=3.9Hz, 1H), 4.65 (s, 1H), 4.44-4.26 (m, 2H), 4.04 (dd, J=11.6, 4.0Hz, 1H), 3.94 (d, J=7.1Hz, 2H), 3.88-3.76 (m, 2H), 3.70-3.48 (m, 4H), 3.45-3.40 (m, 1H), 3.10 (dt, J=13.8, 8.5Hz, 2H), 2.90 (s, 6H), 2.43 (s, 1H), 2.14 (s, 2H), 2.01 (d, J = 14.3Hz, 3H), 1.90-1.81 (m, 1H), 1.31 (d, J = 6.9Hz, 6H).
实施例59、6-((5-(((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物59)的合成：Example 59, Synthesis of 6-((5-(((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 59):
1)、6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯
Figure PCTCN2024077920-ftappb-I100309
1), 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester
Figure PCTCN2024077920-ftappb-I100309
在0℃条件下，向溶有(R)-5-羟基-2，2-二甲基哌啶-1-羧酸苄基酯(200mg，0.76mmol)的四氢呋喃(5mL)溶液中，加入氢化钠(61mg，1.52mmol，质量分数60％)，所得混合反应液0℃搅拌0.5小时。然后将溶有6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(400mg，0.81mmol)的四氢呋喃(1mL)溶液，所得混合反应液室温搅拌3小时。LCMS检测反应液完全。将混合反应液加水(20mL)稀释并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和食盐水(1×30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-20％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(164mg，收率：30％)，LC-MS m/z：719[M+H]+；At 0°C, sodium hydride (61 mg, 1.52 mmol, mass fraction 60%) was added to a solution of (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid benzyl ester (200 mg, 0.76 mmol) in tetrahydrofuran (5 mL), and the resulting mixed reaction solution was stirred at 0°C for 0.5 hours. Then, a solution of 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (400 mg, 0.81 mmol) in tetrahydrofuran (1 mL) was dissolved, and the resulting mixed reaction solution was stirred at room temperature for 3 hours. LCMS detected that the reaction solution was complete. The mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20% elution) to give tert-butyl 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (164 mg, yield: 30%), LC-MS m/z: 719 [M+H] + ;
2)、(5R)-5-((7-((3-氮杂双环[3.1.0]己烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)-2，2-二甲基哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100310
2) Synthesis of (5R)-5-((7-((3-azabicyclo[3.1.0]hexane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100310
在室温下，向溶有6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(160mg，0.22mmol)的二氯甲烷(3mL)溶液中，加入2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌2小时。LCMS检测反应完全。将所得混合反应液减压浓缩得到粗产品，直接用于下一步骤，无需进一步纯化。LC-MS m/z：519[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 0.22 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 519[M+H] + ;
3)、6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100311
3) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100311
在室温条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(53mg，0.307mmol)的N，N-二甲基甲酰胺(2mL)溶液中，加入三乙胺(93mg，0.92mmol)。然后将溶有三光气(91mg，0.307mmol)的N，N-二甲基甲酰胺(2mL)溶液滴加上述混合反应液中。所得混合反应液室温搅拌1小时。再将将(5R)-5-((7-((3-氮杂双环[3.1.0]己烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)-2，2-二甲基哌啶-1-羧酸苄基酯(175mg，0.338mmol)的N，N-二甲基甲酰胺(2mL)溶液滴加到上述混合反应液。所得混合反应液加热40℃搅拌16小时。LCMS检测反应液完成。将混合反应液通过C18柱色谱纯化(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(58mg，收率：26.5％)，LC-MS m/z：718[M+H]+；At room temperature, triethylamine (93 mg, 0.92 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (53 mg, 0.307 mmol) in N, N-dimethylformamide (2 mL). Then, a solution of triphosgene (91 mg, 0.307 mmol) in N, N-dimethylformamide (2 mL) was added dropwise to the mixed reaction solution. The mixed reaction solution was stirred at room temperature for 1 hour. Then, a solution of (5R)-5-((7-((3-azabicyclo[3.1.0]hexane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid benzyl ester (175 mg, 0.338 mmol) in N, N-dimethylformamide (2 mL) was added dropwise to the mixed reaction solution. The mixed reaction solution was heated at 40°C and stirred for 16 hours. The reaction solution was completed by LCMS. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (58 mg, yield: 26.5%), LC-MS m/z: 718 [M+H] + ;
4)、6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100312
4) Synthesis of 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100312
将溶有6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(50mg，0.069mmol)的2，2，2-三氟乙酸(0.4mL)和二氯甲烷(1.2mL)溶液室温搅拌2小时。LCMS检测反应液完全。将所得混合反应液减压浓缩得到将残余物，直接用于下一步骤，无需进一步纯化。LC-MS m/z：618[M+H]+；A solution of 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (50 mg, 0.069 mmol) in 2,2,2-trifluoroacetic acid (0.4 mL) and dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. LCMS detected that the reaction solution was complete. The obtained mixed reaction solution was concentrated under reduced pressure to obtain the residue, which was directly used in the next step without further purification. LC-MS m/z: 618[M+H] + ;
5)、6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100313
5) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100313
将溶有6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(30mg，0.048mmol)，2-氟丙烯酸(7mg，0.073mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(27mg，0.097mmol)和N-甲基咪唑(16mg，0.19mmol)的N，N-二甲基甲酰胺(2mL)加热40℃搅拌16小时。LCMS检测反应液完全。将混合反应液通过C18柱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(15mg，收率：44.8％)，LC-MS m/z：690[M+H]+；A solution of 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (30 mg, 0.048 mmol), 2-fluoroacrylic acid (7 mg, 0.073 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (27 mg, 0.097 mmol) and N-methylimidazole (16 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was heated at 40° C. and stirred for 16 hours. The reaction solution was complete by LCMS. The mixed reaction solution was purified by C18 column (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (15 mg, yield: 44.8%), LC-MS m/z: 690 [M+H] + ;
6)、6-((5-(((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100314
6) Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 6-((5-(((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100314
将溶有6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(15mg，0.022mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。LCMS检测反应完成。将所得混合反应液减压浓缩。残余物通过制备级高效液相色谱纯化6-((5-(((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(1.64mg，收率：13.6％)，LC-MS m/z：556[M+H]+；A solution of 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (15 mg, 0.022 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The reaction was completed by LCMS. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 1-(2-fluoroacryloyl)azetidin-3-yl 6-((5-(((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.64 mg, yield: 13.6%), LC-MS m/z: 556 [M+H] + ;
1H NMR(400MHz，MeOD)：δ7.72(s，1H)，5.64(s，1H)，5.62-5.47(m，1H)，5.19(s，3H)，4.59(s，8H)，4.41(s，2H)，4.07(s，1H)，3.89(d，J＝11.4Hz，1H)，3.79(d，J＝10.8Hz，1H)，3.64(s，1H)，3.57(s，2H)，3.10-3.04(m，1H)，2.44(s，1H)，2.01(s，2H)，1.31(d，J＝6.8Hz，6H)，1.24(d，J＝7.2Hz，6H). 1 H NMR (400MHz, MeOD): δ7.72 (s, 1H), 5.64 (s, 1H), 5.62-5.47 (m, 1H), 5.19 (s, 3H), 4.59 (s, 8H), 4.41 ( s, 2H), 4.07 (s, 1H), 3.89 (d, J=11.4Hz, 1H), 3.79 (d, J=10.8Hz, 1H), 3.64 (s, 1H), 3.57 (s, 2H), 3.10-3.04 (m, 1H), 2.44 (s, 1H), 2.01 (s, 2H), 1.31 (d, J=6.8Hz, 6H), 1.24 (d, J=7.2Hz, 6H).
实施例60、6-((5-((((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物60)的合成：Example 60, Synthesis of 6-((5-((((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 60):
1)、6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100315
1) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100315
将溶有6-((5-((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸氮杂环丁烷-3-基酯(40mg，0.065mmol)(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(16mg，0.097mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(36mg，0.13mmol)和N-甲基咪唑(21mg，0.26mmol)的N，N-二甲基甲酰胺(2mL)溶液，加热40℃搅拌16小时。LCMS检测反应液完全。将混合反应液通过C18柱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(20mg，收率：42.3％)，LC-MS m/z：729[M+H]+；A solution of 6-((5-((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate azetidin-3-yl ester (40 mg, 0.065 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (16 mg, 0.097 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) and N-methylimidazole (21 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL) was heated at 40° C. and stirred for 16 hours. The reaction solution was complete by LCMS. The mixed reaction solution was purified by C18 column (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (20 mg, yield: 42.3%), LC-MS m/z: 729 [M+H] + ;
2)、6-((5-((((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100316
2) Synthesis of 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-((((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100316
将溶有6-((5-(((R)-1-((苄氧基)羰基)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(15mg，0.02mmol)的2，2，2-三氟乙酸(0.5mL)溶液加热50℃搅拌3小时。LCMS检测反应完成。将混合反应液减压浓缩。残余物通过制备级高效液相色谱纯化得到6-((5-((((R)-6，6-二甲基哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(4mg，收率：32.7％)，LC-MS m/z：595[M+H]+；A solution of 6-((5-(((R)-1-((benzyloxy)carbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (15 mg, 0.02 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) was heated at 50° C. and stirred for 3 hours. The reaction was completed by LCMS. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl 6-((5-((((R)-6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4 mg, yield: 32.7%), LC-MS m/z: 595 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.76(s，1H)，6.72(dd，J＝14.8，7.4Hz，1H)，6.48(d，J＝15.4Hz，1H)，5.67(s，1H)，5.49(s，1H)，5.19(s，1H)，4.65(s，1H)，4.39(s，1H)，4.29(d，J＝11.2Hz，1H)，4.04(d，J＝11.6Hz，1H)，3.94(d，J＝7.2Hz，2H)，3.83(dd，J＝22.4，11.2Hz，2H)，3.61(dd，J＝19.8，11.6Hz，3H)，3.53-3.43(m，1H)，3.10(dd，J＝14.0，7.2Hz，1H)，2.89(s，6H)，2.43(s，1H)，2.18-1.93(m，6H)，1.72(d，J＝13.6Hz，2H)，1.47(d，J＝7.2Hz，6H)，1.31(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD) δ7.76 (s, 1H), 6.72 (dd, J=14.8, 7.4Hz, 1H), 6.48 (d, J=15.4Hz, 1H), 5.67 (s, 1H), 5.49 (s, 1H), 5.19 (s, 1H), 4.65 (s, 1H), 4.39 (s, 1H), 4.29 (d, J = 11.2Hz, 1H), 4.04 (d, J = 11.6Hz, 1H) ), 3.94 (d, J=7.2Hz, 2H), 3 .83 (dd, J=22.4, 11.2Hz, 2H), 3.61 (dd, J=19.8, 11.6Hz, 3H), 3.53-3.43 (m, 1H), 3.10 (dd, J=14.0, 7.2Hz, 1H ), 2.89 (s, 6H), 2.43 (s, 1H), 2.18-1.93 (m, 6H), 1.72 (d, J = 13.6Hz, 2H), 1.47 (d, J = 7.2Hz, 6H), 1.31 (d, J=6.8Hz, 6H).
实施例61、(R)-6-((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物61)的合成：Example 61, Synthesis of (R)-6-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (Compound 61):
1)、(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100317
1) Synthesis of tert-butyl (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate
Figure PCTCN2024077920-ftappb-I100317
将溶有6-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(500mg，0.99mmol)，(R)-3-羟基哌啶-1-羧酸苄基酯(279mg，1.19mmol)，三(二亚苄基丙酮)钯(92mg，0.10mmol)，(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(110mg，0.20mmol)和碳酸铯(968mg，2.97mmol)的甲苯(15.0mL)溶液，氩气保护微波加热140℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚0-25％洗脱)纯化得到(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(490mg，收率：70％)，LC-MS m/z：705[M+H]+；A solution of tert-butyl 6-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 0.99 mmol), (R)-3-hydroxypiperidine-1-carboxylate benzyl ester (279 mg, 1.19 mmol), tris(dibenzylideneacetone)palladium (92 mg, 0.10 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (110 mg, 0.20 mmol) and cesium carbonate (968 mg, 2.97 mmol) in toluene (15.0 mL) was heated at 140° C. for 2 hours under argon protection in a microwave. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-25% elution) to give (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (490 mg, yield: 70%), LC-MS m/z: 705 [M+H] + ;
2)、(R)-3-((7-((2-氮杂螺[3.3]庚烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100318
2) Synthesis of (R)-3-((7-((2-azaspiro[3.3]heptane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester
Figure PCTCN2024077920-ftappb-I100318
室温条件下，向溶有(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(490mg，0.70mmol)的二氯甲烷(10mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌4小时。将所得混合反应液减压浓缩得到 粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：505[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise to a solution of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (490 mg, 0.70 mmol) in dichloromethane (10 mL). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain The crude product was used directly in the next step without further purification. LC-MS m/z: 505 [M+H] + ;
3)、(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100319
3) Synthesis of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100319
将溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(56mg，0.32mmol)，三乙胺(33mg，0.32mmol)和二(1H-1，2，4-三唑-1-基)甲酮(53mg，0.32mmol)的N，N-二甲基甲酰胺(5mL)溶液，氩气保护下，室温搅拌1小时。然后将苄基(R)-3-((7-((2-氮杂螺[3.3]庚烷-6-基)氨基)-3-异丙基吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(176mg，0.35mmol)加入上述混合反应液中，在所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0。1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(120mg，收率：53％)，LC-MS m/z：704[M+H]+；A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (56 mg, 0.32 mmol), triethylamine (33 mg, 0.32 mmol) and di(1H-1,2,4-triazole-1-yl)methanone (53 mg, 0.32 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour under argon protection. Then benzyl (R)-3-((7-((2-azaspiro[3.3]heptane-6-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (176 mg, 0.35 mmol) was added to the mixed reaction solution, and the mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (120 mg, yield: 53%), LC-MS m/z: 704 [M+H] + ;
4)、(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100320
4) Synthesis of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100320
将溶有R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(120mg，0.17mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(0.3mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：604[M+H]+；A solution of R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (120 mg, 0.17 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (0.3 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to a crude product, which was used directly in the next step without further purification. LC-MS m/z: 604[M+H] + ;
5)、(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100321
5) Synthesis of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100321
将溶有溶有(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯(103mg，0.17mmol)，2-氟丙烯酸(23mg，0.26mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(95mg，0.34mmol)和1-甲基-1H-咪唑(56mg，0.68mmol)的N，N-二 甲基甲酰胺(3mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶0.1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(70mg，收率：61.％)，LC-MS m/z：676[M+H]+；(R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester (103 mg, 0.17 mmol), 2-fluoroacrylic acid (23 mg, 0.26 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (95 mg, 0.34 mmol) and 1-methyl-1H-imidazole (56 mg, 0.68 mmol) were dissolved in N,N-dichloroformamide. The methylformamide (3 mL) solution was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: 0.1% formic acid in pure water = 5-95% elution) to obtain (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (70 mg, yield: 61.%), LC-MS m/z: 676 [M+H] + ;
6)、(R)-6-((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100322
6) Synthesis of (R)-6-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100322
将溶有(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(70mg，0.10mmol)的2，2，2-三氟乙酸(3mL)溶液加热50℃搅拌5小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶0.1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-6-((3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(41mg，收率：73％)，LC-MS m/z：542[M+H]+；A solution of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (70 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was heated at 50° C. and stirred for 5 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% formic acid in pure water = 5-95% elution) to give (R)-6-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (41 mg, yield: 73%), LC-MS m/z: 542 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.77(s，1H)，5.54(dd，J＝46.8，3.6Hz，2H)，5.46(s，1H)，5.21(dd，J＝16.0，3.6Hz，1H)，5.17-5.09(m，1H)，4.76-4.70(m，1H)，4.40-4.32(m，2H)，4.20-3.97(m，6H)，3.56-3.49(m，1H)，3.45-3.40(m，1H)，3.15-3.06(m，2H)，2.81-2.76(m，2H)，2.40-2.31(m，2H)，2.16-2.07(m，2H)，2.04-1.96(m，1H)，1.93(s，1H)，1.89-1.78(m，1H)，1.32(s，3H)，1.31(s，3H). 1 H NMR (400MHz, MeOD) δ7.77 (s, 1H), 5.54 (dd, J=46.8, 3.6Hz, 2H), 5.46 (s, 1H), 5.21 (dd, J=16.0, 3.6Hz, 1H ), 5.17-5.09(m, 1H), 4.76-4.70(m, 1H), 4.40-4.32(m, 2H), 4.20-3.97(m, 6H), 3.56 -3.49(m, 1H), 3.45-3.40(m, 1H), 3.15-3.06(m, 2H), 2.81-2.76(m, 2H), 2.40-2.31(m, 2H), 2.16-2.07(m, 2H), 2.04-1.96(m, 1H), 1.93(s, 1H), 1.89-1.78(m, 1H), 1.32(s, 3H), 1.31(s, 3H).
实施例62、((R)-6-(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸E)-1-(4-(二甲基氨基)丁-2-烯基)氮杂环丁烷-3-基酯(化合物62)的合成：Example 62, Synthesis of ((R)-6-(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester (Compound 62):
1)、(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100323
1) Synthesis of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100323
将溶有(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸氮杂环丁烷-3-基酯(103mg，0.17mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(34mg，0.26mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(95mg，0.34mmol)和1-甲基1H-咪唑(56mg，0.68mmol)的N，N-二甲基甲酰胺(3mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(75mg，收率：61％)，LC-MS m/z：715[M+H]+；A solution of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate azetidin-3-yl ester (103 mg, 0.17 mmol), (E)-4-(dimethylamino)but-2-enoic acid (34 mg, 0.26 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (95 mg, 0.34 mmol) and 1-methyl 1H-imidazole (56 mg, 0.68 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (E)-1-(4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (75 mg, yield: 61%), LC-MS m/z: 715 [M+H] + ;
2)、((R)-6-(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸E)-1-(4-(二甲基氨基)丁-2-烯基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100324
2) Synthesis of ((R)-6-(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100324
将溶有(R)-6-((5-((1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸(E)-1-(4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(75mg，0.10mmol)的2，2，2-三氟乙酸(3mL)溶液加热50℃搅拌5小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到((R)-6-(3-异丙基-5-(哌啶-3-基氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸E)-1-(4-(二甲基氨基)丁-2-烯基)氮杂环丁烷-3-基酯(41mg，收率：67％)，LC-MS m/z：581[M+H]+；A solution of (R)-6-((5-((1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (75 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (3 mL) was heated at 50° C. and stirred for 5 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give ((R)-6-(3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid E)-1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl ester (41 mg, yield: 67%), LC-MS m/z: 581 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.77(s，1H)，6.83-6.72(m，1H)，6.22(d，J＝15.6Hz，1H)，5.46(d，J＝9.6Hz，2H)，5.15(s，1H)，4.62-4.56(m，1H)，4.38-4.31(m，1H)，4.25-3.93(m，8H)，3.55-3.48(m，1H)，3.44-3.39(m，1H)，3.14-3.04(m，2H)，2.81-2.74(m，2H)，2.42-2.36(m，9H)，2.17-1.79(m，5H)，1.32(s，3H)，1.31(s，3H). 1 H NMR (400MHz, MeOD) δ7.77 (s, 1H), 6.83-6.72 (m, 1H), 6.22 (d, J = 15.6Hz, 1H), 5.46 (d, J = 9.6Hz, 2H), 5.15 (s, 1H), 4.62-4.56 (m, 1H), 4.38-4.31 (m, 1H), 4.25 -3.93(m, 8H), 3.55-3.48(m, 1H), 3.44-3.39(m, 1H), 3.14-3.04(m, 2H), 2.81-2.74(m, 2H), 2.42-2.36(m, 9H), 2.17-1.79(m, 5H), 1.32(s, 3H), 1.31(s, 3H).
实施例63、(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物63)的合成：
Figure PCTCN2024077920-ftappb-I100325
Example 63, Synthesis of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 63):
Figure PCTCN2024077920-ftappb-I100325
将溶有(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸吡咯烷-3-基酯(25mg，0.053mmol)，2-氟丙-2-烯酸(8mg，0.08mmol)，1-甲基-1H-咪唑(8.70mg，0.11mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(59.5mg，0.21mmol)的N，N-二甲基甲基甲酰胺(0.5mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH 3·H2O的纯水＝5-95％洗脱)纯化得到(1r，4r)-4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)环己烷-1-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(1mg，收率：3.5％)，LC-MS m/z：543[M+H]+；A solution of (1r, 4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid pyrrolidin-3-yl ester (25 mg, 0.053 mmol), 2-fluoroprop-2-enoic acid (8 mg, 0.08 mmol), 1-methyl-1H-imidazole (8.70 mg, 0.11 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (59.5 mg, 0.21 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2 O = 5-95% elution) to give (1r,4r)-4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclohexane-1-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (1 mg, yield: 3.5%), LC-MS m/z: 543 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.59(s，1H)，5.48(dd，J＝48.0，3.5Hz，1H)，5.38-5.32(m，1H)，5.30(s，1H)，5.29-5.22(m，1H)，4.13-4.05(m，1H)，4.00-3.94(m，2H)，3.93-3.87(m，1H)，3.80-3.74(m，1H)，3.74-3.68(m，1H)，3.67-3.60(m，1H)，3.56(d，J＝2.0Hz，1H)，3.50-3.46(m，1H)，3.44-3.40(m，1H)，3.40-3.37(m，1H)，3.10-3.01(m，1H)，2.46-2.37(m，1H)，2.24-2.15(m，3H)，2.13-2.03(m，3H)，2.02(s，1H)，1.65-1.38(m，6H)，1.28(d，J＝7.2Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.59 (s, 1H), 5.48 (dd, J=48.0, 3.5Hz, 1H), 5.38-5.32 (m, 1H), 5.30 (s, 1H) , 5.29-5.22(m, 1H), 4.13-4.05(m, 1H), 4.00-3.94(m, 2H), 3.93-3.87(m, 1H), 3.80-3.74(m, 1H), 3.74-3.68( m, 1H), 3.67-3.60 (m, 1H) , 3.56 (d, J=2.0Hz, 1H), 3.50-3.46 (m, 1H), 3.44-3.40 (m, 1H), 3.40-3.37 (m, 1H), 3.10-3.01 (m, 1H), 2.46 -2.37(m, 1H), 2.24-2.15(m, 3H), 2.13-2.03(m, 3H), 2.02(s, 1H), 1.65-1.38(m, 6H), 1.28(d, J=7.2Hz , 6H).
实施例64、5-((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物64A和64B)的合成：Example 64. Synthesis of 5-((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compounds 64A and 64B):
1)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100326
1) Synthesis of tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100326
在0℃条件下，向溶有(R)-3-羟基哌啶-1-甲酸苄基酯(1.09g，4.62mmol)的四氢呋喃(10mL)溶液中，分批加入氢化钠(185mg，7.71mmol)，所得混合反应液室温搅拌30分钟。然后，5-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2g，3.85mmol)的四氢呋喃(10mL)溶液，滴加入上述混合反应液中。所得混合反应液室温搅拌2小时。冷却后，将混合反应液加水稀释，并用乙酸乙酯(3x 200mL)萃取。合并的有机相用饱和食盐水(1x 50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2.2g，收率：79.5％)，LC-MS m/z：719[M+H]+；At 0°C, sodium hydride (185 mg, 7.71 mmol) was added in batches to a solution of (R)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (1.09 g, 4.62 mmol) in tetrahydrofuran (10 mL), and the resulting mixed reaction solution was stirred at room temperature for 30 minutes. Then, a solution of 5-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2 g, 3.85 mmol) in tetrahydrofuran (10 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.2 g, yield: 79.5%), LC-MS m/z: 719 [M+H] + ;
2)、(3R)-3-((3-异丙基-7-(八氢环戊[c]吡咯-5-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100327
2) Synthesis of benzyl (3R)-3-((3-isopropyl-7-(octahydrocyclopentyl[c]pyrrol-5-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100327
在室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2.2g，3.06mmol)的二氯甲烷(12mL)溶液中，滴加2，2，2-三氟乙酸(4mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤，无需进一步纯化。LC-MS m/z：619[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (4 mL) was added dropwise to a solution of tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.2 g, 3.06 mmol) in dichloromethane (12 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 619[M+H] + ;
3)、5-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100328
3) Synthesis of 1-(tert-butoxycarbonyl)pyrrolidin-3-yl 5-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100328
在0oC条件下，向溶有3-羟基吡咯烷-1-甲酸叔丁酯(736mg，3.94mmol)和三乙胺(994mg，9.85mmol)的四氢呋喃(15mL)溶液中，分批加入三光气(487mg，1.64mmol)。所得混合反应液0℃搅拌30分钟。在室温下，将(3R)-3-((3-异丙基-7-(八氢环戊[c]吡咯-5-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-甲酸苄基酯(1.7g，3.28mmol)分批加入到上述混合反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到5-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(1300mg，收率：54.2％)，LC-MS m/z：732[M+H]+；Triphosgene (487 mg, 1.64 mmol) was added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (736 mg, 3.94 mmol) and triethylamine (994 mg, 9.85 mmol) in tetrahydrofuran (15 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 30 minutes. At room temperature, (3R)-3-((3-isopropyl-7-(octahydrocyclopentyl[c]pyrrol-5-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (1.7 g, 3.28 mmol) was added in batches to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to give 5-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (1300 mg, yield: 54.2%), LC-MS m/z: 732 [M+H] + ;
4)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100329
4) Synthesis of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100329
在室温条件下，向溶有5-((5-((((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧基羰基)吡咯烷-3-基酯(1.3g，1.78mmol)的二氯甲烷(10mL)溶液中，滴加2，2，2-三氟乙酸(2mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：632[M+H]+； To a solution of 5-((5-((((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (1.3 g, 1.78 mmol) in dichloromethane (10 mL) was added dropwise 2,2,2-trifluoroacetic acid (2 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 632 [M+H] + ;
5)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊基[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100330
5) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100330
室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯(230mg，0.365mmol)和2-氟丙烯酸(39mg，0.44mmol)的二氯甲烷(2mL)溶液中，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(166mg，0.44mmol)和N，N-二异丙基乙胺(141mg，1.09mmol)。所得混合反应液室温搅拌2小时。将混合反应液加水水稀释，并用乙酸乙酯(3x 80mL)萃取。合并的有机相用饱和食盐水(1x 20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊基[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(150mg，收率：58.5％)，LC-MS m/z：704[M+H]+；To a solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester (230 mg, 0.365 mmol) and 2-fluoroacrylic acid (39 mg, 0.44 mmol) in dichloromethane (2 mL) at room temperature was added 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) and N,N-diisopropylethylamine (141 mg, 1.09 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3 x 80 mL). The combined organic phase was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (150 mg, yield: 58.5%), LC-MS m/z: 704 [M+H] + ;
6)、5-((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物64A和64B)的合成
Figure PCTCN2024077920-ftappb-I100331
6) Synthesis of 5-((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compounds 64A and 64B)
Figure PCTCN2024077920-ftappb-I100331
将溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊基[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(150mg，0.21mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌2小时。将混合反应液用水稀释，并用乙酸乙酯(3x 50mL)萃取。合并的有机相用饱和食盐水(1x 10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到两个异构体：A solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (150 mg, 0.21 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 2 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3x 50 mL). The combined organic phase was washed with saturated brine (1x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain two isomers:
BIOT-002-90194：峰1：1.279min；化合物64A，LC-MS m/z：570[M+H]+；(7mg，收率：6％)，BIOT-002-90194: Peak 1: 1.279 min; Compound 64A, LC-MS m/z: 570 [M+H] + ; (7 mg, yield: 6%),
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，5.54-5.24(m，2H)，5.29-5.24(m，2H)，4.12-4.05(m，1H)，3.95-3.91(m，1H)，3.85-3.74(m，3H)，3.62-3.56(m，4H)，3.47-3.41(m，3H)，3.45-3.41(m，1H)，3.19-3.08(m，2H)，2.82(s，2H)，2.51(s，2H)，2.24-2.14(m，4H)，2.05-1.98(m，1H)，1.89-1.85(m，1H)，1.66-1.60(m，2H)，1.34(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 5.54-5.24 (m, 2H), 5.29-5.24 (m, 2H), 4.12-4.05 (m, 1H), 3.95-3.91 (m, 1H), 3.85-3.74 (m, 3H), 3.62-3.56 (m, 4H), 3.47-3.41 (m, 3H), 3.45-3.41(m, 1H), 3.19-3.08(m, 2H), 2.82(s, 2H), 2.51(s, 2H), 2.24-2.14(m, 4H), 2.05-1.98(m, 1H), 1.89-1.85 (m, 1H), 1.66-1.60 (m, 2H), 1.34 (d, J=6.8Hz, 6H).
BIOT-002-90306：峰2：1.295min，化合物64B，LC-MS m/z：570[M+H]+；(7mg，收率：6％)，BIOT-002-90306: Peak 2: 1.295 min, compound 64B, LC-MS m/z: 570 [M+H] + ; (7 mg, yield: 6%),
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，5.55-5.28(t，J＝4.4Hz，3H)，5.28(s，2H)，4.12-4.05(m，1H)，3.95-3.91(m，1H)，3.85-3.74(m，3H)，3.62-3.56(m，4H)，3.47-3.41(m，3H)，3.45-3.41(m，1H)，3.37-3.32(m，1H)，3.19-3.08(m，2H)，2.82(s，3H)，2.51(s，2H)，2.24-2.14(m，4H)，2.05-1.98(m，1H)，1.89-1.85(m，1H)，1.66-1.60(m，2H)，1.34(d，J＝6.8Hz，6H)， 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 5.55-5.28 (t, J=4.4Hz, 3H), 5.28 (s, 2H), 4.12-4.05 (m, 1H), 3.95-3.91 (m, 1H), 3.85-3.74 (m, 3H), 3.62-3.56 (m, 4H), 3.47-3.41 (m, 3H), 3.4 5-3.41(m, 1H), 3.37-3.32(m, 1H), 3.19-3.08(m, 2H), 2.82(s, 3H), 2.51(s, 2H), 2.24-2.14(m, 4H), 2.05-1.98(m, 1H), 1.89-1.85(m, 1H), 1.66-1.60(m, 2H), 1.34(d, J=6.8Hz, 6H),
实施例65、5-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物65A和65B)的合成：Example 65. Synthesis of 5-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compounds 65A and 65B):
1)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100332
1) Synthesis of 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100332
在室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯(230mg，0.37mmol)和(E)-4-(二甲基氨基)和丁-2-烯酸(74mg，0.57mmol)的二氯甲烷(2mL)溶液中，加入N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(200mg，0.71mmol)合1-甲基-1H-咪唑(116mg，1.42mmol)。所得混合反应液室温搅拌2小时。将混合反应液加水稀释，并用乙酸乙酯(3x 80mL)萃取。合并的有机相用饱和食盐水(1x 20mL)洗涤，无水硫酸钠干燥，过滤后，减压浓缩。残余物通过C18柱色谱法(0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(160mg，收率：60％)，LC-MS m/z：743[M+H]+；To a solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester (230 mg, 0.37 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (74 mg, 0.57 mmol) in dichloromethane (2 mL) was added N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (200 mg, 0.71 mmol) and 1-methyl-1H-imidazole (116 mg, 1.42 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 80 mL). The combined organic phase was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (0.1% formic acid in acetonitrile: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (160 mg, yield: 60%), LC-MS m/z: 743 [M+H] + ;
2)、5-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物65A和65B)的合成
Figure PCTCN2024077920-ftappb-I100333
2) Synthesis of 5-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compounds 65A and 65B)
Figure PCTCN2024077920-ftappb-I100333
将溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-((E)-4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(160mg，0.22mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌2小时。将混合反应液加水稀释，并用乙酸乙酯(3x 50mL)萃取。合并的有机相层用饱和食盐水(1x 10mL)洗涤，用无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到两个异构体：A solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (160 mg, 0.22 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 2 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3x 50 mL). The combined organic phase layer was washed with saturated brine (1x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain two isomers:
BIOT-002-90195：峰1：1.418min，化合物65A，LC-MS m/z：609[M+H]+；(10mg，收率：7.6％)，BIOT-002-90195: Peak 1: 1.418 min, compound 65A, LC-MS m/z: 609 [M+H] + ; (10 mg, yield: 7.6%),
1H NMR(400MHz，MeOD-d4)：δ7.75(s，1H)，6.89-6.80(m，1H)，6.51-6.40(m，1H)，5.54(s，1H)，5.31-5.17(m，2H)，4.09-4.05(t，J＝8Hz，1H)，3.89-3.83(m，1H)，3.78-3.68(m，2H)，3.59-3.55(m，2H)，3.46-3.40(m，2H)，3.25-3.07(m，5H)，2.90-2.85(m，2H)，2.80(s，3H)，2.51(s，2H)，2.29-2.22(m，7H)，2.16-2.07(m，2H)，1.92-1.78(m，2H)，1.59(s，3H)，1.33(d，J＝4Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.75 (s, 1H), 6.89-6.80 (m, 1H), 6.51-6.40 (m, 1H), 5.54 (s, 1H), 5.31-5.17 (m , 2H), 4.09-4.05 (t, J=8Hz, 1H), 3.89-3.83 (m, 1H), 3.78-3.68 (m, 2H), 3.59-3.5 5(m, 2H), 3.46-3.40(m, 2H), 3.25-3.07(m, 5H), 2.90-2.85(m, 2H), 2.80(s, 3H), 2.51(s, 2H), 2.29- 2.22 (m, 7H), 2.16-2.07 (m, 2H), 1.92-1.78 (m, 2H), 1.59 (s, 3H), 1.33 (d, J=4Hz, 6H).
IOT-002-90307：峰1：1.448min，化合物65B，LC-MS m/z：609[M+H]+；(10mg，收率：7.6％)，IOT-002-90307: Peak 1: 1.448 min, compound 65B, LC-MS m/z: 609 [M+H] + ; (10 mg, yield: 7.6%),
1H NMR(400MHz，MeOD-d4)：δ7.75(s，1H)，6.89-6.80(m，1H)，6.51-6.40(m，1H)，5.51(s，1H)，5.31-5.17(m，2H)，4.21(s，1H)，3.91-3.69(m，3H)，3.66-3.50(m，3H)，3.25-3.07(m，6H)，2.96-2.88(m，4H)，2.81(s，1H)，2.30(s，7H)，2.17-2.05(m，6H)，1.87(s，2H)，1.65(s，1H)，1.33(d，J＝4Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.75 (s, 1H), 6.89-6.80 (m, 1H), 6.51-6.40 (m, 1H), 5.51 (s, 1H), 5.31-5.17 (m , 2H), 4.21(s, 1H), 3.91-3.69(m, 3H), 3.66-3.50(m, 3H), 3.25-3.07(m, 6H), 2.96-2.88(m, 4H), 2.81(s , 1H), 2.30 (s, 7H), 2.17-2.05 (m, 6H), 1.87 (s, 2H), 1.65 (s, 1H), 1.33 (d, J=4Hz, 6H).
实施例66、5-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯(化合物66)的合成：Example 66, Synthesis of 5-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(but-2-ynyl)pyrrolidin-3-yl ester (Compound 66):
1)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100334
1) Synthesis of 1-(but-2-ynyl)pyrrolidin-3-yl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100334
室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯(200mg，0.317mmol)和丁-2-炔酸(32mg，0.380mmol)的二氯甲烷(2mL)溶液中，加入N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(134mg，0.475mmol)和1-甲基-1H-吡咯(36mg，0.44mmol)。所得混合反应液室温搅拌2小时。将所得混合反应液加水(80mL)稀释，并用乙酸乙酯(3×80mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯(90mg，收率：40.7％)，LC-MS m/z：698[M+H]+；At room temperature, N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (134 mg, 0.475 mmol) and 1-methyl-1H-pyrrole (36 mg, 0.44 mmol) were added to a solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester (200 mg, 0.317 mmol) and but-2-ynoic acid (32 mg, 0.380 mmol) in dichloromethane (2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(but-2-ynyl)pyrrolidin-3-yl ester (90 mg, yield: 40.7%), LC-MS m/z: 698 [M+H] + ;
2)、5-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100335
2) Synthesis of 1-(but-2-ynyl)pyrrolidin-3-yl 5-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100335
将溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯(90mg，0.129mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌2小时。所得混合反应液加水(50mL)稀释，并用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过的C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((3-异丙基-5-(((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(丁-2-炔基)吡咯烷-3-基酯或非对应异构体(10mg，收率：13.8％)，LC-MS m/z：564[M+H]+；A solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(but-2-ynyl)pyrrolidin-3-yl ester (90 mg, 0.129 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 2 hours. The resulting mixed reaction liquid was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-((3-isopropyl-5-(((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(but-2-ynyl)pyrrolidin-3-yl ester or diastereoisomer (10 mg, yield: 13.8%), LC-MS m/z: 564 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，5.53(s，1H)，5.26(s，1H)，4.13-4.05(m，1H)，3.85-3.56(m，7H)，3.49-3.43(m，4H)，3.37(s，1H)，3.19-3.07(m，2H)，2.82(s，2H)，2.51(s，2H)，2.22-2.13(m，4H)，2.05-1.99(m，4H)，1.88-1.85(m，1H)，1.62(s，2H)，1.34(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 5.53 (s, 1H), 5.26 (s, 1H), 4.13-4.05 (m, 1H), 3.85-3.56 (m, 7H ), 3.49-3.43(m, 4H), 3.37(s, 1H), 3.19-3.07(m, 2H), 2.82(s, 2H), 2.51(s, 2H), 2.22-2.13(m, 4H), 2.05-1.99 (m, 4H), 1.88-1.85 (m, 1H), 1.62 (s, 2H), 1.34 (d, J=6.8Hz, 6H).
实施例67、(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(化合物67)的合成：Example 67, Synthesis of (1R, 3r, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (Compound 67):
1)、(1R，3r，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100336
1) Synthesis of tert-butyl (1R, 3r, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8 carboxylate
Figure PCTCN2024077920-ftappb-I100336
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(1.3g，5.37mmol)，(1R，3r，5S)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.46g，6.45mmol)和N，N-二异丙基乙胺(1.04g，8.06mmol)的异丙醇(15mL)溶液加热70℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×200 mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-20％洗脱)纯化得到(1R，3r，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.44g，收率：62.1％)，LC-MS m/z：433[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.3 g, 5.37 mmol), (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.46 g, 6.45 mmol) and N,N-diisopropylethylamine (1.04 g, 8.06 mmol) in isopropanol (15 mL) was heated at 70°C and stirred overnight. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and ethyl acetate (3×200 mL) for extraction. The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-20% elution) to give (1R, 3r, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.44 g, yield: 62.1%), LC-MS m/z: 433[M+H] + ;
2)、(1R，3r，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100337
2) Synthesis of tert-butyl (1R, 3r, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8 carboxylate
Figure PCTCN2024077920-ftappb-I100337
将溶有(1R，3r，5S)-3-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.44g，3.33mmol)和间氯过氧苯甲酸(1.73g，10.02mmol)的二氯甲烷(18mL)溶液，室温搅拌过夜。将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到(1R，3r，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.41g，收率：91.2％)，LC-MS m/z：465[M+H]+；A solution of (1R, 3r, 5S)-3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.44 g, 3.33 mmol) and m-chloroperbenzoic acid (1.73 g, 10.02 mmol) in dichloromethane (18 mL) was stirred at room temperature overnight. The resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-40% elution) to give (1R, 3r, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.41 g, yield: 91.2%), LC-MS m/z: 465 [M+H] + ;
3)(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯
Figure PCTCN2024077920-ftappb-I100338
3) (1R, 3r, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure PCTCN2024077920-ftappb-I100338
将溶有(1R，3r，5S)-3-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8羧酸叔丁酯(1.41g，3.04mmol)，四氢-2H-吡喃-4-胺(461mg，4.56mmol)和N，N-二异丙基乙胺(1.18g，9.12mmol)的异丙醇(15mL)溶液，加热90℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-50％洗脱)纯化得到(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.45g，收率：98.4％)，LC-MS m/z：486[M+H]+；A solution of (1R, 3r, 5S)-3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8carboxylic acid tert-butyl ester (1.41 g, 3.04 mmol), tetrahydro-2H-pyran-4-amine (461 mg, 4.56 mmol) and N,N-diisopropylethylamine (1.18 g, 9.12 mmol) in isopropanol (15 mL) was heated at 90°C and stirred overnight. After cooling, the resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.45 g, yield: 98.4%), LC-MS m/z: 486 [M+H] + ;
4)、N4-((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
Figure PCTCN2024077920-ftappb-I100339
4) Synthesis of N 4 -((1R, 3r, 5S)-8-azabicyclo[3.2.1]oct-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
Figure PCTCN2024077920-ftappb-I100339
室温条件下，向溶有(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.45g，2.99mmol)的二氯甲烷(15mL)溶液中，滴加2，2，2-三氟乙酸(5mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到N4-((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(1.10g，收率：95.6％)，LC-MS m/z：386[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (5 mL) was added dropwise to a solution of (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.45 g, 2.99 mmol) in dichloromethane (15 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give N 4 -((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (1.10 g, yield: 95.6%), LC-MS m/z: 386 [M+H] + ;
5)、(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100340
5) Synthesis of 1-(tert-butyloxycarbonyl)azetidin-3-yl (1R, 3r, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2024077920-ftappb-I100340
在0℃条件下，向溶有3-羟基氮杂环丁烷-1-羧酸叔丁酯(243mg，1.40mmol)和三乙胺(283mg，2.81mmol)的二氯甲烷(4mL)溶液中，加入三光气(111mg，0.37mmol)。所得混合反应液0℃搅拌1小时。将N4-((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(360mg，0.94mmol)加入到上述的混合反应液中。加完后，所得混合反应液0℃搅拌溶液12小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(130mg，收率：23.8％)，LC-MS m/z：585[M+H]+；Triphosgene (111 mg, 0.37 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (243 mg, 1.40 mmol) and triethylamine (283 mg, 2.81 mmol) in dichloromethane (4 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 1 hour. N 4 -((1R, 3r, 5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-isopropyl-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (360 mg, 0.94 mmol) was added to the above mixed reaction solution. After the addition, the resulting mixed reaction solution was stirred at 0°C for 12 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butoxycarbonyl)azetidin-3-yl ester (130 mg, yield: 23.8%), LC-MS m/z: 585 [M+H] + ;
6)、(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100341
6) Synthesis of (1R, 3r, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100341
室温条件下，向溶有(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(叔丁氧羰基)氮杂环丁烷-3-基酯(130mg，0.223mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化到(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，收率：83.5％)，LC-MS m/z：485[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(tert-butyloxycarbonyl)azetidin-3-yl ester (130 mg, 0.223 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (90 mg, yield: 83.5%), LC-MS m/z: 485 [M+H] + ;
7)、(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100342
7) Synthesis of (1R, 3r, 5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100342
将溶有(1R，3r，5S)-3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，0.18mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(36.0mg，0.28mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(106mg，0.28mmol)和N，N-二异丙基乙胺(72mg，0.56mmol)的N，N-二甲基甲酰胺(1.2mL)溶液室温搅拌2小时。将所得混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1R，3r，5S)-3-((8- 异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)氮杂环丁烷-3-基酯(64mg，收率：57.8％)，LC-MS m/z：596[M+H]+；A solution of (1R,3r,5S)-3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidine-3-yl ester (90 mg, 0.18 mmol), (E)-4-(dimethylamino)but-2-enoic acid (36.0 mg, 0.28 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol) in N,N-dimethylformamide (1.2 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain (1R, 3r, 5S)-3-((8- Isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)azetidin-3-yl ester (64 mg, yield: 57.8%), LC-MS m/z: 596 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.64(s，1H)，6.85-6.74(m，1H)，6.19(d，J＝15.5Hz，1H)，5.26-5.19(m，1H)，4.66(d，J＝16.6Hz，2H)，4.39(d，J＝27.9Hz，3H)，4.08-3.96(m，4H)，3.57-3.50(m，2H)，3.15(d，J＝6.5Hz，2H)，3.03-2.96(m，1H)，2.31(s，2H)，2.27(s，6H)，2.11-1.98(m，8H)，，1.63-1.56(m，2H)，1.26(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.64 (s, 1H), 6.85-6.74 (m, 1H), 6.19 (d, J=15.5Hz, 1H), 5.26-5.19 (m, 1H), 4.66 (d, J=16.6Hz, 2H), 4.39 (d, J=27.9Hz, 3H), 4.08-3.96 (m, 4H), 3.57-3.50 (m, 2H), 3.15 (d, J=6.5Hz, 2H), 3.03-2.96 (m, 1H), 2.31 (s, 2H), 2.27 (s, 6H), 2.11-1.98(m, 8H),, 1.63-1.56(m, 2H), 1.26(d, J=6.9Hz, 6H).
实施例68、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(化合物68)的合成：
Figure PCTCN2024077920-ftappb-I100343
Example 68, Synthesis of 1-(2-fluoroacryloyl)azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 68):
Figure PCTCN2024077920-ftappb-I100343
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(100mg，0.20mmol)，2-氟丙烯酸(27mg，0.30mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐(115mg，0.30mmol)和N，N-二异丙基乙胺(78mg，0.60mmol)的N，N-二甲基甲酰胺(5mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯(38mg，收率：33.3％)，LC-MS m/z：570[M+H]+；A solution of azetidin-3-yl 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.20 mmol), 2-fluoroacrylic acid (27 mg, 0.30 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester (38 mg, yield: 33.3%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.61(s，1H)，5.55(d，J＝50.0Hz，1H)，5.26(s，1H)，5.21(d，J＝16.8Hz，2H)，4.74(s，1H)，4.39(s，3H)，4.29(s，1H)，4.11-4.02(m，2H)，3.97(d，J＝11.2Hz，2H)，3.60-3.52(m，2H)，3.17(d，J＝6.4Hz，2H)，3.09-3.00(m，1H)，2.41-2.30(m，1H)，2.09-1.97(m，4H)，1.78(s，4H)，1.59-1.45(m，4H)，1.29(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD) δ7.61 (s, 1H), 5.55 (d, J=50.0Hz, 1H), 5.26 (s, 1H), 5.21 (d, J=16.8Hz, 2H), 4.74 ( s, 1H), 4.39 (s, 3H), 4.29 (s, 1H), 4.11-4.02 (m, 2H), 3.97 (d, J=1 1.2Hz, 2H), 3.60-3.52(m, 2H), 3.17(d, J=6.4Hz, 2H), 3.09-3.00(m, 1H), 2.41-2.30(m, 1H), 2.09-1.97(m , 4H), 1.78 (s, 4H), 1.59-1.45 (m, 4H), 1.29 (d, J=6.8Hz, 6H).
实施例69、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯及异构体(化合物69)的合成：
Figure PCTCN2024077920-ftappb-I100344
Example 69, Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester and isomers (Compound 69):
Figure PCTCN2024077920-ftappb-I100344
室温条件下，向溶有3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(150mg，0.30mmol)和(2E)-4-(二甲基氨基)丁-2-烯酸(58mg，0.45mmol)的N，N-e二甲基甲酰胺(2mL)溶液中，加入中的溶液(2mL)中加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(171mg，0.45mmol)和乙基二异丙胺(155mg，1.2mmol)。所得混合反应液室温搅拌16小时。将混反应液通过C18柱色谱法(乙腈∶含有0.5％甲酸的纯水＝10～70％洗脱)纯化得到的两个异构体：At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and ethyldiisopropylamine (155 mg, 1.2 mmol) were added to a solution of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (150 mg, 0.30 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (58 mg, 0.45 mmol) in N,N-e dimethylformamide (2 mL). The resulting mixed reaction solution was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.5% formic acid = 10-70% elution) to obtain two isomers:
BIOT-002-90286：化合物69A(10mg，收率：5.4％)，LC-MS m/z：610[M+H]+；BIOT-002-90286: Compound 69A (10 mg, yield: 5.4%), LC-MS m/z: 610 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.84(s，1H)，6.75(d，J＝17.9Hz，2H)，5.34(d，J＝12.4Hz，1H)，4.35(s，2H)，4.15(s，1H)，4.01(d，J＝11.0Hz，2H)，3.95(d，J＝3.8Hz，2H)，3.92-3.65(m，4H)，3.53(t，J＝11.1Hz，3H)，3.04(s，1H)，2.90(s，6H)，2.25(d，J＝31.6Hz，2H)，2.13-1.97(m，6H)，1.86(d，J＝6.2Hz，4H)，1.72(d，J＝10.9Hz，2H)，1.27(d，J＝6.8Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ) δ7.84 (s, 1H), 6.75 (d, J=17.9Hz, 2H), 5.34 (d, J=12.4Hz, 1H), 4.35 (s, 2H) , 4.15 (s, 1H), 4.01 (d, J = 11.0Hz, 2H), 3.95 (d, J = 3.8Hz, 2H), 3.92-3.65 (m, 4H), 3.5 3(t, J=11.1Hz, 3H), 3.04(s, 1H), 2.90(s, 6H), 2.25(d, J=31.6Hz, 2H), 2.13-1.97(m, 6H), 1.86(d , J=6.2Hz, 4H), 1.72 (d, J=10.9Hz, 2H), 1.27 (d, J=6.8Hz, 6H).
BIOT-002-90287：化合物69B(10mg，收率：5.4％)，LC-MS m/z：610[M+H]+； BIOT-002-90287: Compound 69B (10 mg, yield: 5.4%), LC-MS m/z: 610 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.90(s，1H)，6.77(dd，J＝18.1，11.7Hz，2H)，5.33(d，J＝17.0Hz，1H)，4.33(d，J＝25.1Hz，3H)，4.17(s，1H)，3.96(s，5H)，3.76(dd，J＝22.0，10.4Hz，3H)，3.54(d，J＝9.0Hz，3H)，3.07(s，1H)，2.91(s，6H)，2.24(d，J＝31.1Hz，5H)，2.07(s，5H)，1.99(d，J＝12.5Hz，2H)，1.71(d，J＝9.0Hz，2H)，1.28(t，J＝7.2Hz，6H).1H NMR (400MHz, MeOD-d 4 ): δ7.90 (s, 1H), 6.77 (dd, J=18.1, 11.7Hz, 2H), 5.33 (d, J=17.0Hz, 1H), 4.33 (d, J=25.1Hz, 3H), 4.17 (s, 1H), 3.96 (s, 5H), 3.76 (dd, J=22.0, 10.4Hz, 3H), 3 .54(d, J=9.0Hz, 3H), 3.07(s, 1H), 2.91(s, 6H), 2.24(d, J=31.1Hz, 5H), 2.07(s, 5H), 1.99(d, J=12.5Hz, 2H), 1.71 (d, J=9.0Hz, 2H), 1.28 (t, J=7.2Hz, 6H).
实施例70、8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物70)的合成：Example 70, Synthesis of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (Compound 70):
1)、8-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100345
1) Synthesis of tert-butyl 8-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100345
将溶有8-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(750mg，1.79mmol)，乙基二异丙胺(1.15g，8.95mmol)，4-二甲基氨基吡啶(328mg，2.69mmol)和二碳酸二叔丁酯(468mg，2.15mmol)的四氢呋喃(3mL)溶液加热50℃搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶水＝0～95％洗脱)纯化得到8-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(663mg，收率：71.4％)，LC-MS m/z：520[M+H]+；A solution of tert-butyl 8-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (750 mg, 1.79 mmol), ethyldiisopropylamine (1.15 g, 8.95 mmol), 4-dimethylaminopyridine (328 mg, 2.69 mmol) and di-tert-butyl dicarbonate (468 mg, 2.15 mmol) in tetrahydrofuran (3 mL) was heated at 50° C. and stirred for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to give tert-butyl 8-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (663 mg, yield: 71.4%), LC-MS m/z: 520 [M+H] + ;
2)、8-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100346
2) Synthesis of tert-butyl 8-((tert-butyloxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate
Figure PCTCN2024077920-ftappb-I100346
将溶有8-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(663mg，1.27mmol)，1，1′-双(二苯基膦基膦基)二氯化钯(92mg，0.127mmol)，碳酸铯(1.89mg，5.79mmol)，环丙基三氟硼酸钾(429mg，2.90mmol)的1，4-二氧六环(2mL)和水(0.5mL)，氮气保护下，微波加热110℃，搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱法(水和乙腈洗脱)纯化得到8-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(532mg，收率：79.3％)，LC-MS m/z：526[M+H]+；8-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (663 mg, 1.27 mmol), 1,1′-bis(diphenylphosphinophosphino)palladium dichloride (92 mg, 0.127 mmol), cesium carbonate (1.89 mg, 5.79 mmol), potassium cyclopropyltrifluoroborate (429 mg, 2.90 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) were heated in a microwave at 110° C. under nitrogen protection and stirred for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (eluted with water and acetonitrile) to give tert-butyl 8-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (532 mg, yield: 79.3%), LC-MS m/z: 526 [M+H] + ;
3)、N-(3-氮杂双环[3.2.1]辛-8-基)-5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100347
3) Synthesis of N-(3-azabicyclo[3.2.1]oct-8-yl)-5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100347
将溶有8-((叔丁氧羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(532mg，1.01mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液物室温搅拌4小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步，LC-MS m/z：326[M+H]+；A solution of 8-((tert-butyloxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (532 mg, 1.01 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 326 [M+H] + ;
4)、8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100348
4) Synthesis of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100348
将溶有N-(3-氮杂双环[3.2.1]辛-8-基)-5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-胺(305mg，0.938mmol)，碳酸三氯甲基酯(140mg，0.47mmol)，三乙胺(290mg，2.82mmol)和3-羟基吡咯烷-1-羧酸叔丁酯(0.18g，0.94mmol)的二氯甲烷(2mL)溶液，室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶水＝0～95％洗脱)纯化得到8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(195mg，收率：38.5％)，LC-MS m/z：539[M+H]+；A solution of N-(3-azabicyclo[3.2.1]octan-8-yl)-5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (305 mg, 0.938 mmol), trichloromethyl carbonate (140 mg, 0.47 mmol), triethylamine (290 mg, 2.82 mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.18 g, 0.94 mmol) in dichloromethane (2 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to give 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (195 mg, yield: 38.5%), LC-MS m/z: 539 [M+H] + ;
5)、8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100349
5) Synthesis of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100349
将溶有8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(195mg，0.36mmol)的2，2，2-三氟乙酸(1mL，0.36mmol)和D二氯甲烷(3mL)溶液，室温搅拌4小时。将混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步，LC-MS m/z：439[M+H]+；A solution of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl ester (195 mg, 0.36 mmol) in 2,2,2-trifluoroacetic acid (1 mL, 0.36 mmol) and D dichloromethane (3 mL) was stirred at room temperature for 4 hours. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 439 [M+H] + ;
6)、8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100350
6) Synthesis of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100350
将溶有8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(70mg，0.16mmol)，N，N，N，N，N-四甲基氯甲脒六氟磷酸(90mg，0.32mmol)，1-甲基-1H-咪唑(53mg，0.64mmol)和2-氟丙-2-烯酸(22mg，0.24mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶水＝0～95％洗脱)纯化得到8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(3.12mg，收率：3.8％)，LC-MS m/z：511[M+H]+；A solution of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (70 mg, 0.16 mmol), N,N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (90 mg, 0.32 mmol), 1-methyl-1H-imidazole (53 mg, 0.64 mmol) and 2-fluoroprop-2-enoic acid (22 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to give 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (3.12 mg, yield: 3.8%), LC-MS m/z: 511 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ：8.18(s，1H)，5.99(s，1H)，5.46(d，J＝46.5Hz，1H)，5.25(d，J＝19.6Hz，2H)，4.11(s，1H)，3.90(s，1H)，3.84-3.47(m，6H)，3.32(s，1H)，3.27-3.26(m，1H)，3.21(dd，J＝14.5，7.2Hz，3H)，2.48(d，J＝19.6Hz，2H)，2.30-2.21(m，2H)，2.00(s，2H)，1.41(d，J＝8.1Hz，2H)，1.36(d，J＝6.7Hz，6H)，1.31(s，2H). 1 H NMR (400 MHz, MeOD-d 4 )δ: 8.18 (s, 1H), 5.99 (s, 1H), 5.46 (d, J=46.5Hz, 1H), 5.25 (d, J=19.6Hz, 2H), 4.11 (s, 1H), 3.90 (s, 1H), 3.84-3.47 (m, 6H), 3.32 (s, 1H), 3.27-3.26 (m , 1H), 3.21 (dd, J=14.5, 7.2Hz, 3H), 2.48 (d, J=19.6Hz, 2H), 2.30-2.21 (m, 2H), 2.00 (s, 2H), 1.41 (d, J=8.1Hz, 2H), 1.36 (d, J=6.7Hz, 6H), 1.31 (s, 2H).
实施例71、8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸(E)-1-(4-(二甲基氨基)丁-2-烯基)吡咯烷-3-基酯(化合物71)的合成：
Figure PCTCN2024077920-ftappb-I100351
Example 71, Synthesis of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid (E)-1-(4-(dimethylamino)but-2-enyl)pyrrolidin-3-yl ester (Compound 71):
Figure PCTCN2024077920-ftappb-I100351
将溶有8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(70mg，0.16mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(90mg，0.32mmol)，1-甲基-1H-咪唑(53mg，0.64mmol)和(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(39mg，0.24mmol)N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶水＝0～95％洗脱)纯化得到(2.53mg，收率：2.9％)，LC-MS m/z：550[M+H]+；A solution of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (70 mg, 0.16 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (90 mg, 0.32 mmol), 1-methyl-1H-imidazole (53 mg, 0.64 mmol) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (39 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to obtain (2.53 mg, yield: 2.9%), LC-MS m/z: 550 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ：8.13(d，J＝5.9Hz，1H)，6.74(dd，J＝18.9，7.3Hz，2H)，5.99(s，1H)，5.30(d，J＝15.1Hz，1H)，4.09(s，1H)，3.95(d，J＝6.2Hz，2H)，3.88-3.47(m，7H)，3.34(s，1H)，3.28-3.23(m，2H)，2.90(s，6H)，2.70(s，1H)，2.49(d，J＝21.7Hz，2H)，2.27-2.22(m，2H)，2.16(s，1H)，2.00(s，2H)，1.69(d，J＝9.0Hz，2H)，1.36(s，6H)，1.29-1.26(m，2H). 1 H NMR (400MHz, MeOD-d 4 ): δ: 8.13 (d, J=5.9Hz, 1H), 6.74 (dd, J=18.9, 7.3Hz, 2H), 5.99 (s, 1H), 5.30 (d , J=15.1Hz, 1H), 4.09 (s, 1H), 3.95 (d, J=6.2Hz, 2H), 3.88-3.47 (m, 7H), 3.34 (s, 1H), 3.2 8-3.23 (m, 2H), 2.90 (s, 6H), 2.70 (s, 1H), 2.49 (d, J=21.7Hz, 2H), 2.27-2.22 (m, 2H), 2.16 (s, 1H) , 2.00 (s, 2H), 1.69 (d, J=9.0Hz, 2H), 1.36 (s, 6H), 1.29-1.26 (m, 2H).
实施例72、1-(丁-2-炔基酰基)吡咯烷-3-基-8-((5-环丙基-3-异丙基吡唑[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸酯(化合物72)的合成：
Figure PCTCN2024077920-ftappb-I100352
Example 72, Synthesis of 1-(but-2-ynyl acyl)pyrrolidin-3-yl-8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (Compound 72):
Figure PCTCN2024077920-ftappb-I100352
8-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸吡咯烷-3-基酯(70mg，0.16mmol)，N、N，N，N-四甲基氯甲脒六氟磷酸盐(90mg，0.32mmol)，1-甲基-1H-咪唑(53mg，0.64mmol)和丁-2-炔酸(20mg，0.24mmol)的N，N-二甲基甲酰胺(2mL)溶液的室温搅拌2小时。将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶水＝0～95％洗脱)纯化得到1-(丁-2-炔基酰基)吡咯烷-3-基-8-((5-环丙基-3-异丙基吡唑[1，5-a]嘧啶-7-基)氨基)-3-氮杂双环[3.2.1]辛烷-3-羧酸酯(3.56mg，收率：4.4％)，LC-MS m/z：505[M+H]+；A solution of 8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylic acid pyrrolidin-3-yl ester (70 mg, 0.16 mmol), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (90 mg, 0.32 mmol), 1-methyl-1H-imidazole (53 mg, 0.64 mmol) and but-2-ynoic acid (20 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to give 1-(but-2-ynyl acyl)pyrrolidin-3-yl-8-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (3.56 mg, yield: 4.4%), LC-MS m/z: 505 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ：8.18(s，1H)，5.99(s，1H)，5.27(s，1H)，4.12(s，1H)，3.85(dd，J＝33.6，14.2Hz，3H)，3.76-3.67(m，2H)，3.59(dd，J＝23.4，16.4Hz，2H)，3.45(dd，J＝24.0，22.4Hz，1H)，3.29-3.24(m，2H)，2.50(d，J＝17.8Hz，2H)，2.31-2.20(m，2H)，2.04-2.02(m，3H)，2.01(s，2H)，1.69(d，J＝7.4Hz，2H)，1.43-1.38(m，2H)，1.36(d，J＝6.9Hz，6H)，1.33-1.29(m，2H). 1 H NMR (400MHz, MeOD-d 4 ) δ: 8.18 (s, 1H), 5.99 (s, 1H), 5.27 (s, 1H), 4.12 (s, 1H), 3.85 (dd, J=33.6, 14.2 Hz, 3H), 3.76-3.67 (m, 2H), 3.59 (dd, J=23.4, 16.4Hz, 2H), 3.45 (dd, J=24.0, 22.4Hz, 1H), 3.29 -3.24 (m, 2H), 2.50 (d, J=17.8Hz, 2H), 2.31-2.20 (m, 2H), 2.04-2.02 (m, 3H), 2.01 (s, 2H), 1.69 (d, J =7.4Hz, 2H), 1.43-1.38 (m, 2H), 1.36 (d, J = 6.9Hz, 6H), 1.33-1.29 (m, 2H).
实施例73、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(丁-2-炔基)氮杂环丁烷-3-基酯及异构体(化合物73A和73B)的合成：
Figure PCTCN2024077920-ftappb-I100353
Example 73, Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(but-2-ynyl)azetidin-3-yl ester and isomers (Compounds 73A and 73B):
Figure PCTCN2024077920-ftappb-I100353
将溶有3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，0.18mmol)，丁-2-炔酸(24mg，0.28mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(106mg，0.28mmol)和N，N-二异丙基乙胺(72mg 0.56mmol)的N，N-二甲基甲酰胺(1.2mL)溶液室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O＝5-95％洗脱)纯化得到两个异构体：A solution of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (90 mg, 0.18 mmol), but-2-ynoic acid (24 mg, 0.28 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg 0.56 mmol) in N,N-dimethylformamide (1.2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3 ·H 2 O=5-95% elution) to obtain two isomers:
BIOT-002-90334：化合物73A(25mg，收率：24.5％)，LC-MS m/z：551[M+H]+；BIOT-002-90334: Compound 73A (25 mg, yield: 24.5%), LC-MS m/z: 551 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.64(s，1H)，5.24-5.18(m，1H)，4.73-4.63(m，1H)，4.57-4.53(m，1H)，4.42(s，1H)，4.33(s，2H)，4.21(dd，J＝24.5，9.8Hz，1H)，4.08-3.95(m，4H)，3.59-3.49(m，2H)，2.99(dt，J＝13.8，6.9Hz，1H)，2.21-2.05(m，3H)，2.03(d，J＝2.2Hz，2H)，2.02(s，3H)，2.01-1.98(m，1H)，1.91-1.90(m，2H)，1.80(t，J＝12.1Hz，2H)，1.66-1.56(m，2H)，1.26(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.64 (s, 1H), 5.24-5.18 (m, 1H), 4.73-4.63 (m, 1H), 4.57-4.53 (m, 1H), 4.42 (s, 1H), 4.33 (s, 2H), 4.21 (dd, J=24.5, 9.8Hz, 1H), 4.08-3.95 (m, 4H), 3.59-3.49 (m, 2H), 2.99 (dt, J=13.8, 6.9Hz, 1H), 2.21-2.05 (m, 3H), 2.03 (d, J=2.2Hz, 2H), 2.02 (s, 3H), 2.01-1.98 (m, 1H) , 1.91-1.90 (m, 2H), 1.80 (t, J=12.1Hz, 2H), 1.66-1.56 (m, 2H), 1.26 (d, J=6.9Hz, 6H).
BIOT-002-90356：化合物73B(70mg，收率：68.4％)，LC-MS m/z：551[M+H]+；BIOT-002-90356: Compound 73B (70 mg, yield: 68.4%), LC-MS m/z: 551 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.68(s，1H)，5.24-5.17(m，1H)，4.53(s，1H)，4.40(s，1H)，4.36-4.26(m，3H)，4.18(t，J＝10.5Hz，1H)，4.07-4.01(m，1H)，4.00-3.92(m，3H)，3.57-3.49(m，2H)，3.00(dt，J＝13.8，6.9Hz，1H)，2.35-2.25(m，2H)，2.12(d，J＝6.0Hz，3H)，2.07(s，1H)，2.02(s，4H)，1.98(s，1H)，1.63-1.53(m，2H)，1.27(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d 4 ) δ7.68 (s, 1H), 5.24-5.17 (m, 1H), 4.53 (s, 1H), 4.40 (s, 1H), 4.36-4.26 (m, 3H) , 4.18(t, J=10.5Hz, 1H), 4.07-4.01(m, 1H), 4.00-3.92(m, 3H), 3.57-3.49(m, 2H), 3.00 (dt, J=13.8, 6.9Hz, 1H), 2.35-2.25 (m, 2H), 2.12 (d, J=6.0Hz, 3H), 2.07 (s, 1H), 2.02 (s, 4H ), 1.98 (s, 1H), 1.63-1.53 (m, 2H), 1.27 (d, J=6.9Hz, 6H).
实施例74、3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(化合物74)的合成：
Figure PCTCN2024077920-ftappb-I100354
Example 74, Synthesis of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (Compound 74):
Figure PCTCN2024077920-ftappb-I100354
将溶有3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸吡咯烷-3-基酯(100mg，0.20mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(39mg，0.30mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(115mg，0.30mmol)和N，N-二异丙基乙胺(78mg，0.60mmol)的N，N-二甲基甲酰胺(5mL)溶液室温搅拌16小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到3-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)甲基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-((E)-4-(二甲氨基)丁-2-烯酰基)吡咯烷-3-基酯(45mg，收率：37.0％)，LC-MS m/z：623[M+H]+；A solution of 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid pyrrolidin-3-yl ester (100 mg, 0.20 mmol), (E)-4-(dimethylamino)but-2-enoic acid (39 mg, 0.30 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and N,N-diisopropylethylamine (78 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl ester (45 mg, yield: 37.0%), LC-MS m/z: 623 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.61(s，1H)，6.81-6.73(m，1H)，6.69-6.60(m，1H)，5.28(d，J＝17.6Hz，1H)，4.26(s，2H)，4.08(s，1H)，3.97(d，J＝11.6Hz，2H)，3.88-3.73(m，2H)，3.69-3.62(m，3H)，3.61-3.51(m，3H)，3.19-3.11(m，2H)，3.10-3.02(m，1H)，2.73-2.61(m，6H)，2.35(s，1H)，2.26-2.10(m，2H)，2.04(d，J＝12.4Hz，2H)，2.00-1.93(m，2H)，1.81-1.71(m，4H)，1.60-1.50(m，3H)，1.49-1.40(m，1H)，1.30(s，3H)，1.28(s，3H). 1 H NMR (400MHz, MeOD) δ7.61 (s, 1H), 6.81-6.73 (m, 1H), 6.69-6.60 (m, 1H), 5.28 (d, J=17.6Hz, 1H), 4.26 (s , 2H), 4.08 (s, 1H), 3.97 (d, J=11.6Hz, 2H), 3.88-3.73 (m, 2H), 3.69-3.62 (m, 3H), 3.61-3.51 (m, 3H), 3.19- 3.11(m, 2H), 3.10-3.02(m, 1H), 2.73-2.61(m, 6H), 2.35(s, 1H), 2.26-2.10(m, 2H), 2.04(d, J=12.4Hz, 2H), 2.00-1.93(m, 2H), 1.81-1.71(m, 4H), 1.60-1.50(m, 3H), 1.49-1.40(m, 1H), 1.30(s, 3H), 1.28(s, 3H).
实施例75、5-((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸(R)-1-(2-氟丙烯酰基)吡咯烷-3-基酯(化合物75)的合成：Example 75. Synthesis of (R)-1-(2-fluoroacryloyl)pyrrolidin-3-yl 5-((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 75):
1)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100355
1) Synthesis of tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100355
在0℃条件下，向溶有(R)-3-羟基哌啶-1-羧酸苄基酯(1.09g，4.62mmol)的四氢呋喃(10mL)，分批加入氢化钠(185mg，7.71mmol)，所得混合反应液室温搅拌30分钟。然后将5-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2g，3.85mmol)的四氢呋喃(10mL)溶液，滴加到上述反应液中。所得混合反应液室温搅拌2小时。将混合反应液加水(100mL)稀释，并用乙酸乙酯(3x 200mL)萃取。合并的有机相用饱和食盐水(1x 200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯化＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2.2g，收率：79.5％)，LC-MS m/z：719[M+H]+；At 0°C, sodium hydride (185 mg, 7.71 mmol) was added in batches to tetrahydrofuran (10 mL) containing (R)-3-hydroxypiperidine-1-carboxylic acid benzyl ester (1.09 g, 4.62 mmol), and the resulting mixed reaction solution was stirred at room temperature for 30 minutes. Then, a solution of 5-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2 g, 3.85 mmol) in tetrahydrofuran (10 mL) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: purification containing 0.1% formic acid = 25%-65% elution) to give tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.2 g, yield: 79.5%), LC-MS m/z: 719 [M+H] + ;
2)、(3R)-3-((3-异丙基-7-((八氢环戊[c]吡咯-5-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯的合成
Figure PCTCN2024077920-ftappb-I100356
2) Synthesis of benzyl (3R)-3-((3-isopropyl-7-((octahydrocyclopentyl[c]pyrrol-5-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100356
向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)(叔丁氧基羰基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(2.2g，3.06mmol)的二氯甲烷(12mL)溶液中，滴加2，2，2-三氟乙酸(4mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：619[M+H]+；2,2,2-Trifluoroacetic acid (4 mL) was added dropwise to a solution of tert-butyl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.2 g, 3.06 mmol) in dichloromethane (12 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 619[M+H] + ;
3)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100357
3) Synthesis of 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100357
在0℃条件下，向溶有3-羟基吡咯烷-1-羧酸叔丁酯(736mg，3.94mmol)和三乙胺(994mg，9.85mmol)的四氢呋喃(15mL)溶液中，分批加入三光气(487mg，1.64mmol)。所得混合反应液0℃搅拌30分钟。将(3R)-3-((3-异丙基-7-((八氢环戊[c]吡咯-5-基)氨基)吡唑并[1，5-a]嘧啶-5-基)氧基)哌啶-1-羧酸苄基酯(2.0g，3.28mmol)加入到上述混合反应液中。所得混合反应液室温搅拌过夜。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(1300mg，收率：55.0％)，LC-MS m/z：732[M+H]+；Triphosgene (487 mg, 1.64 mmol) was added in batches to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (736 mg, 3.94 mmol) and triethylamine (994 mg, 9.85 mmol) in tetrahydrofuran (15 mL) at 0°C. The resulting mixed reaction solution was stirred at 0°C for 30 minutes. (3R)-3-((3-isopropyl-7-((octahydrocyclopentyl[c]pyrrol-5-yl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid benzyl ester (2.0 g, 3.28 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(tert-butoxycarbonyl)pyrrolidin-3-yl ester (1300 mg, yield: 55.0%), LC-MS m/z: 732 [M+H] + ;
4)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100358
4) Synthesis of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100358
室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(叔丁氧羰基)吡咯烷-3-基酯(1.3g，1.78mmol)的二氯甲烷(10mL)溶液中，滴加2，2，2-三氟乙酸(2mL)。所得混和反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步，LC-MS m/z：632[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (2 mL) was added dropwise to a solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(tert-butyloxycarbonyl)pyrrolidin-3-yl ester (1.3 g, 1.78 mmol) in dichloromethane (10 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification, LC-MS m/z: 632[M+H] + ;
5)、5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100359
5) Synthesis of 1-(2-fluoroacryloyl)pyrrolidin-3-yl 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
Figure PCTCN2024077920-ftappb-I100359
室温条件下，向溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸吡咯烷-3-基酯(230mg，0.365mmol)和2-氟丙烯酸(39mg，0.437mmol)的二氯甲烷(2mL)溶液中，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(166mg，0.437mmol)和N，N-二异丙基乙胺(141mg，1.09mmol)。所得混合反应液室温搅拌2小时。将混合反应液加水(80mL)稀释，并用乙酸乙酯(3×80mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯化＝25％-65％洗脱)纯化得到5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(150mg，收率：58.5％)，LC-MS m/z：704[M+H]+；At room temperature, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.437 mmol) and N,N-diisopropylethylamine (141 mg, 1.09 mmol) were added to a solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid pyrrolidin-3-yl ester (230 mg, 0.365 mmol) and 2-fluoroacrylic acid (39 mg, 0.437 mmol) in dichloromethane (2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: purification containing 0.1% formic acid = 25%-65% elution) to give 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (150 mg, yield: 58.5%), LC-MS m/z: 704 [M+H] + ;
6)、5-((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸(R)-1-(2-氟丙烯酰基)吡咯烷-3-基酯的合成
Figure PCTCN2024077920-ftappb-I100360
6) Synthesis of 5-((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid (R)-1-(2-fluoroacryloyl)pyrrolidin-3-yl ester
Figure PCTCN2024077920-ftappb-I100360
将溶有5-((5-(((R)-1-((苄氧基)羰基)哌啶-3-基)氧基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸1-(2-氟丙烯酰基)吡咯烷-3-基酯(150mg，0.213mmol)的2，2，2-三氟乙酸(2mL)溶液加热50℃搅拌2小时。所得混合物加水(50mL)稀释，并用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(1×10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过C18柱色谱法(含有0.1％甲酸的乙腈∶含有0.1％甲酸的纯水＝25％-65％洗脱)纯化得到5-((3-异丙基-5-((((R)-哌啶-3-基)氧基)吡唑并[1，5-a]嘧啶-7-基)氨基)六氢环戊[c]吡咯-2(1H)-羧酸(R)-1-(2-氟丙烯酰基)吡咯烷-3-基酯(7mg，收率：5.7％)，LC-MS m/z：570[M+H]+；A solution of 5-((5-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (150 mg, 0.213 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was heated at 50°C and stirred for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give 5-((3-isopropyl-5-((((R)-piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (R)-1-(2-fluoroacryloyl)pyrrolidin-3-yl ester (7 mg, yield: 5.7%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，5.54-5.24(m，2H)，5.29-5.24(m，2H)，4.12-4.05(m，1H)，3.95-3.91(m，1H)，3.85-3.74(m，3H)，3.62-3.56(m，4H)，3.47-3.41(m，3H)，3.45-3.41(m，1H)，3.37-3.32(m，1H)，3.19-3.08(m，2H)，2.82(s，3H)，2.51(s，2H)，2.24-2.14(m，4H)，2.05-1.98(m，1H)，1.89-1.85(m，1H)，1.66-1.60(m，2H)，1.34(d，J＝6.8Hz，6H)， 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 5.54-5.24 (m, 2H), 5.29-5.24 (m, 2H), 4.12-4.05 (m, 1H), 3.95-3.91 (m, 1H), 3.85-3.74 (m, 3H), 3.62-3.56 (m, 4H), 3.47-3.41 (m, 3H), 3.45 -3.41 (m, 1H), 3.37-3.32 (m, 1H), 3.19-3.08 (m, 2H), 2.82 (s, 3H), 2.51 (s, 2H), 2.24-2.14 (m, 4H), 2.05 -1.98(m, 1H), 1.89-1.85(m, 1H), 1.66-1.60(m, 2H), 1.34(d, J=6.8Hz, 6H),
实施例76、3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸1-(2-氟丙烯酰基)氮杂环丁烷-3-基酯及异构体(化合物76A和76B)的合成：
Figure PCTCN2024077920-ftappb-I100361
Example 76, Synthesis of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid 1-(2-fluoroacryloyl)azetidin-3-yl ester and isomers (Compounds 76A and 76B):
Figure PCTCN2024077920-ftappb-I100361
将溶有3-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸氮杂环丁烷-3-基酯(90mg，0.18mmol)，2-氟丙烯酸(25mg，0.28mmol)，1-甲基-1H-咪唑(61.0mg，0.74mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(105mg，0.37mmol)的N，N-二甲基甲酰胺(2.5mL)溶液加热60℃搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯化＝5-95％洗脱)纯化得到两个异构体.A solution of 3-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate azetidin-3-yl ester (90 mg, 0.18 mmol), 2-fluoroacrylic acid (25 mg, 0.28 mmol), 1-methyl-1H-imidazole (61.0 mg, 0.74 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (105 mg, 0.37 mmol) in N,N-dimethylformamide (2.5 mL) was heated at 60°C and stirred for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: purification containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain two isomers.
BIOT-002-9071(化合物76A)(8mg，收率：7.7％)，LC-MS m/z：557[M+H]+；BIOT-002-9071 (Compound 76A) (8 mg, yield: 7.7%), LC-MS m/z: 557 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.64(s，1H)，5.55(dd，J＝46.9，3.4Hz，1H)，5.28-5.15(m，2H)，4.76(s，1H)，4.72-4.62(m，1H)，4.43(s，3H)，4.35(s，1H)，4.07-4.03(m，2H)，3.99(d，J＝11.4Hz，2H)，3.54(td，J＝11.6，2.0Hz，2H)，3.03-2.96(m，1H)，2.07-2.01(m，6H)，1.93-1.91(m，2H)，1.81(t，J＝11.9Hz，2H)，1.67-1.55(m，2H)，1.26(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.64 (s, 1H), 5.55 (dd, J=46.9, 3.4Hz, 1H), 5.28-5.15 (m, 2H), 4.76 (s, 1H), 4.72-4.62(m, 1H), 4.43(s, 3H), 4.35(s, 1H), 4.07-4.03(m, 2H), 3.99( d, J=11.4Hz, 2H), 3.54 (td, J=11.6, 2.0Hz, 2H), 3.03-2.96 (m, 1H), 2.07-2.01 (m, 6H), 1.93-1.91 (m, 2H) , 1.81 (t, J=11.9Hz, 2H), 1.67-1.55 (m, 2H), 1.26 (d, J=6.9Hz, 6H).
BIOT-002-90207(化合物76B)(64mg，收率：61.9％)，LC-MS m/z：557[M+H]+；BIOT-002-90207 (Compound 76B) (64 mg, yield: 61.9%), LC-MS m/z: 557 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.68(s，1H)，5.56(dd，J＝46.9，3.4Hz，1H)，5.24-5.19(m，2H)，4.59(s，1H)，4.41(s，3H)，4.35-4.29(m，2H)，4.09-4.01(m，2H)，3.97(d，J＝11.6Hz，2H)，3.53(t，J＝11.5Hz，2H)，3.04-2.97(m，，1H)，2.30(d，J＝14.7Hz，2H)，2.14-2.00(m，6H)，1.96(d，J＝17.2Hz，2H)，1.62-1.54(m，2H)，1.27(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.68 (s, 1H), 5.56 (dd, J=46.9, 3.4Hz, 1H), 5.24-5.19 (m, 2H), 4.59 (s, 1H), 4.41 (s, 3H), 4.35-4.29 (m, 2H), 4.09-4.01 (m, 2H), 3.97 (d, J=11 .6Hz, 2H), 3.53 (t, J=11.5Hz, 2H), 3.04-2.97 (m,, 1H), 2.30 (d, J=14.7Hz, 2H), 2.14-2.00 (m, 6H), 1.96 (d, J=17.2Hz, 2H), 1.62-1.54 (m, 2H), 1.27 (d, J=6.9Hz, 6H).
实施例77、4-(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C2-80)的合成：Example 77, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C2-80):
4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100362
Synthesis of 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100362
将4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(380mg，0.61mmol)和环丙基三氟硼酸钾(135mg，0.91mmol)加入到溶有Pd(dppf)Cl2(45mg，0.06mmol)和碳酸铯(596mg，1.83mmol)的1，4-二氧六环(4mL)和水(1mL)溶液中。将反应容器密封并在微波加热110℃搅拌2小时。将混合反应液加水稀释，并用乙酸乙酯(3x 20mL)萃取。合并的有机相用饱和食盐水(1x 30mL)洗涤，无水干燥。过滤后，将滤液在真空下浓缩。残留物通过C18反相柱色谱法(MeCN(0.1％FA)∶水(0.1％FA)＝25％-65％洗脱)纯化得到(4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，收率：52.6％)，LC-MS m/z：631[M+H]+；1-(tert-Butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((tert-Butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (380 mg, 0.61 mmol) and potassium cyclopropyltrifluoroborate (135 mg, 0.91 mmol) were added to a solution of Pd(dppf)Cl 2 (45 mg, 0.06 mmol) and cesium carbonate (596 mg, 1.83 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The reaction vessel was sealed and stirred at 110° C. in a microwave for 2 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3× 20 mL). The combined organic phase was washed with saturated brine (1× 30 mL) and dried over anhydrous water. After filtration, the filtrate was concentrated under vacuum. The residue was purified by C18 reverse phase column chromatography (MeCN (0.1% FA): water (0.1% FA) = 25%-65% elution) to give 1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl (4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (200 mg, yield: 52.6%), LC-MS m/z: 631 [M+H] + ;
4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100363
Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100363
将溶有4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，0.32mmol)的二氯甲烷(2mL)和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌2小时。将混合反应液加水稀释，并用乙酸乙酯(3x 20mL)萃取。合并的有机相用饱和食盐水(1x 30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱法(MeCN(0.1％FA)∶水(0.1％FA)＝25％-65％洗脱)纯化得到4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(123mg，收率：90％)，LC-MS m/z：431[M+H]+；A solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (200 mg, 0.32 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN (0.1% FA): water (0.1% FA) = 25%-65% elution) to give 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (123 mg, yield: 90%), LC-MS m/z: 431 [M+H] + ;
4-(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100364
Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100364
在室温条件下，向溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.09mmol)和(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(23mg，0.14mmol)的乙腈(2mL)溶液中，加入1-甲基-1H-咪唑(30mg，0.37mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(52mg，0.19mmol)。所得混合反应液室温搅拌2小时。冷却后，将混合反应液加水稀释，并用乙酸乙酯(3x 20mL)萃取。合并的有机相用饱和食盐水(1x 30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱法(MeCN(0.1％FA)∶水(0.1％FA)＝25％-65％洗脱)纯化得到4-(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收率：39.7％)，LC-MS m/z：542[M+H]+；To a solution of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (40 mg, 0.09 mmol) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (23 mg, 0.14 mmol) in acetonitrile (2 mL) at room temperature, 1-methyl-1H-imidazole (30 mg, 0.37 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (52 mg, 0.19 mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN (0.1% FA): water (0.1% FA) = 25%-65% elution) to give (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (20 mg, yield: 39.7%), LC-MS m/z: 542 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.83(s，1H)，6.79(s，1H)，6.36(d，J＝1.6Hz，1H)，5.99(s，1H)，4.52-4.48(m，4H)，4.29-4.14(m，4H)，3.91(s，1H)，3.54-3.50(m，2H)，3.26-3.15(m，3H)，2.57(s，6H)，2.14-2.05(m，3H)，1.65-1.62(m，2H)，1.62-1.35(m，6H)，1.33-1.02(m，4H). 1 H NMR (400MHz, MeOD) δ7.83 (s, 1H), 6.79 (s, 1H), 6.36 (d, J=1.6Hz, 1H), 5.99 (s, 1H), 4.52-4.48 (m, 4H ), 4.29-4.14(m, 4H), 3.91(s, 1H), 3.54-3.50(m, 2H), 3.26-3.15(m, 3H), 2.57(s, 6H), 2.14-2.05(m, 3H ), 1.65-1.62(m, 2H), 1.62-1.35(m, 6H), 1.33-1.02(m, 4H).
实施例78、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物78)的合成：Example 78, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 78):
1)、4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100365
1) Synthesis of 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100365
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(387.88mg，1.89mmol)，三乙胺(382.50mg，3.78mmol)，1，1′-羰基二(1，2，4-三唑)(310.19mg，1.89mmol)N，N-二甲基甲酰胺(1.5mL)氮气保护下，室温搅拌1小时。将5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(370mg，1.26mmol)加入到上述混合反应液中。所得混合反应液氮气保护，室温搅拌16小时。将混合反应液通过C18反相柱色谱(乙腈/纯水＝50-70％洗脱)纯化得到4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(530mg，收率：80.16％)，LC-MS m/z：525[M+H]+；Dissolve tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (387.88 mg, 1.89 mmol), triethylamine (382.50 mg, 3.78 mmol), 1,1′-carbonylbis(1,2,4-triazole) (310.19 mg, 1.89 mmol) in N,N-dimethylformamide (1.5 mL) and stir at room temperature for 1 hour under nitrogen protection. Add 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (370 mg, 1.26 mmol) to the above mixed reaction liquid. The obtained mixed reaction liquid is protected by nitrogen and stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 reverse phase column chromatography (acetonitrile/pure water = 50-70% elution) to obtain 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (530 mg, yield: 80.16%), LC-MS m/z: 525 [M+H] + ;
2)、4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100366
2) Synthesis of 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100366
在室温条件下，，向溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(530mg，1.01mmol)的四氢呋喃(10mL)溶液中，加入的二碳酸二叔丁酯(330.65mg，1.52mmol)，4-二甲氨基吡啶(148.07mg，1.21mmol)和N，N-二异丙基乙胺(391.60mg，3.03mmol)中。所得混合反应液加热50℃搅拌3小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝50-70％洗脱)纯化得到4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(385mg，收率：61.01％)，LC-MS m/z：625[M+H]+；At room temperature, di-tert-butyl dicarbonate (330.65 mg, 1.52 mmol), 4-dimethylaminopyridine (148.07 mg, 1.21 mmol) and N, N-diisopropylethylamine (391.60 mg, 3.03 mmol) were added to a solution of 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (530 mg, 1.01 mmol) in tetrahydrofuran (10 mL). The obtained mixed reaction solution was heated at 50°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50-70% elution) to give 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (385 mg, yield: 61.01%), LC-MS m/z: 625 [M+H] + ;
3)、4-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100367
3) Synthesis of 4-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100367
将溶有4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(385mg，0.62mmol)的1，4-二氧六环(5mL)溶液中，加入四氢-2H- 吡喃-4-胺(94.07mg，0.93mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(52.09mg，0.062mmol)和碳酸铯(606.03mg，1.86mmol)。所得混合反应液氮气保护下，加热90℃搅拌16小时。将混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝60-80％洗脱)纯化得到4-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(145mg，收率：34.13％)，LC-MS m/z：690[M+H]+；Tetrahydro-2H-pyrimidine was added to a solution of 1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (385 mg, 0.62 mmol) in 1,4-dioxane (5 mL). Pyran-4-amine (94.07 mg, 0.93 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (52.09 mg, 0.062 mmol) and cesium carbonate (606.03 mg, 1.86 mmol). The obtained mixed reaction liquid was heated at 90°C and stirred for 16 hours under nitrogen protection. The mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 60-80% elution) to give 4-((tert-butoxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (145 mg, yield: 34.13%), LC-MS m/z: 690 [M+H] + ;
4)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100368
4) Synthesis of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100368
将溶有4-((叔丁氧羰基)(3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(140mg，0.20mmol)的2，2，2-三氟乙酸(1mL)和二氯甲烷(3mL)溶液中。所得混合反应液室温搅拌1小时。将混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝30-50％洗脱)纯化得到4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(90mg，收率：90.58％)，LC-MS m/z：490[M+H]+；The mixture was added to a solution of 4-((tert-butyloxycarbonyl)(3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (140 mg, 0.20 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 30-50% elution) to give 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (90 mg, yield: 90.58%), LC-MS m/z: 490 [M+H] + ;
5)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100369
5) Synthesis of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100369
将溶有4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(45mg，0.092mmol)加入(E)-4-(二甲氨基)丁-2-烯酸(17.82mg，0.14mmol)，N，N，N’，N’-四甲基氯甲脒六氟磷酸盐(51.63mg，0.18mmol)和1-甲基-1H-咪唑(30.21mg，0.37mmol)。所得混合反应液25℃搅拌16小时。将混合反应液通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝30-50％洗脱)纯化得到4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(10mg，收率：18.11％)，LC-MS m/z：601[M+H]+；(E)-4-(dimethylamino)but-2-enoic acid (17.82 mg, 0.14 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (51.63 mg, 0.18 mmol) and 1-methyl-1H-imidazole (30.21 mg, 0.37 mmol) were added to 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (45 mg, 0.092 mmol). The resulting mixed reaction solution was stirred at 25° C. for 16 hours. The mixed reaction liquid was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 30-50% elution) to obtain 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (10 mg, yield: 18.11%), LC-MS m/z: 601 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.61(s，1H)，6.82-6.76(m，1H)，6.29-6.26(m，1H)，5.34(s，1H)，4.57-4.34(m，4H)，4.26-4.22(m，2H)，4.17-4.02(m，4H)，4.02-3.89(m，2H)，3.69-3.67(m，1H)，3.59-3.54(m，2H)，3.35-3.33(m，2H)，3.23-3.19(m，1H)，3.15-3.09(m，1H)，2.41(s，6H)，2.11-2.02(m，4H)，1.59-1.50(m，4H)，1.29(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.61 (s, 1H), 6.82-6.76 (m, 1H), 6.29-6.26 (m, 1H), 5.34 (s, 1H), 4.57-4.34 ( m, 4H), 4.26-4.22 (m, 2H), 4.17-4.02 (m, 4H), 4.02-3.89 (m, 2H), 3.69-3.67 ( m, 1H), 3.59-3.54 (m, 2H), 3.35-3.33 (m, 2H), 3.23-3.19 (m, 1H), 3.15-3.09 (m, 1H), 2.41 (s, 6H), 2.11- 2.02 (m, 4H), 1.59-1.50 (m, 4H), 1.29 (d, J=8.0Hz, 6H).
实施例79、4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物79)的合成：Example 79, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 79):
1)、4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3- 基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100370
1), 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3- Synthesis of methyl ester
Figure PCTCN2024077920-ftappb-I100370
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(1271mg，6.20mmol)，三乙胺(2.6mL，18.60mmol)和1，1′-羰基二(1，2，4-三唑)(1.02g，6.2mmol)的N，N-二甲基甲酰胺(5mL)溶液25℃搅拌1小时，然后将5-氯-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(2g，6.82mmol)加入到上述混合反应液中。所得混合反应液加热40℃搅拌16小时。将混合反应液过滤，减压浓缩滤。残余物经硅胶柱色谱(甲醇∶二氯甲烷＝0～5％洗脱)纯化得到4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(1635mg，收率：50％)，LC-MS m/z：525[M+H]+；A solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (1271 mg, 6.20 mmol), triethylamine (2.6 mL, 18.60 mmol) and 1,1′-carbonylbis(1,2,4-triazole) (1.02 g, 6.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25°C for 1 hour, and then 5-chloro-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (2 g, 6.82 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was heated at 40°C and stirred for 16 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (1635 mg, yield: 50%), LC-MS m/z: 525 [M+H] + ;
2)、4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100371
2) Synthesis of 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100371
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(1.6g，3.05mmol)，4-二甲氨基吡啶(37mg，0.305mmol)，三乙胺(930mg，9.15mmol)和二碳酸二叔丁酯(1.33g，6.1mmol)的四氢呋喃(5mL)溶液加热50℃搅拌2小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(甲醇∶二氯甲烷＝0-5％洗脱)纯化得到4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(1.9g，收率：99.73％)，LC-MS m/z：625[M+H]+；A solution of 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (1.6 g, 3.05 mmol), 4-dimethylaminopyridine (37 mg, 0.305 mmol), triethylamine (930 mg, 9.15 mmol) and di-tert-butyl dicarbonate (1.33 g, 6.1 mmol) in tetrahydrofuran (5 mL) was heated at 50° C. and stirred for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (1.9 g, yield: 99.73%), LC-MS m/z: 625 [M+H] + ;
3)、4-((叔丁氧羰基)(5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100372
3) Synthesis of 4-((tert-butyloxycarbonyl)(5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100372
将溶有4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(500mg，0.80mmol)，1，1′-二(二苯膦基)二茂铁二氯化钯(0.12g，0.16mmol)，碳酸钾(0.33g，2.40mmol)和(3，6-二氢-2H-吡喃-4-基)硼酸(0.15g，1.20mmol)的1，4-二氧六环(2mL) 和水(0.5mL)溶液氩气保护下，加热90℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(甲醇∶二氯甲烷＝0-5％洗脱)纯化得到4-((叔丁氧羰基)(5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(535mg，收率：99％)，LC-MS m/z：673[M+H]+；4-((tert-Butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-Butyloxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (500 mg, 0.80 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (0.12 g, 0.16 mmol), potassium carbonate (0.33 g, 2.40 mmol) and (3,6-dihydro-2H-pyran-4-yl)boronic acid (0.15 g, 1.20 mmol) were dissolved in 1,4-dioxane (2 mL). and water (0.5 mL) solution under argon protection, heated at 90°C with stirring for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give 4-((tert-butoxycarbonyl)(5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (535 mg, yield: 99%), LC-MS m/z: 673[M+H] + ;
4)、4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100373
4) Synthesis of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100373
将溶有4-((叔丁氧羰基)(5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(248.93mg，0.374mmol)和2，2，2-三氟乙酸(1mL，0.37mmol)的二氯甲烷(3mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：473[M+H]+；A solution of 4-((tert-butyloxycarbonyl)(5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (248.93 mg, 0.374 mmol) and 2,2,2-trifluoroacetic acid (1 mL, 0.37 mmol) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 473 [M+H] + ;
5)、4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100374
5) Synthesis of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100374
将溶有4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.11mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(62mg，0.22mmol)，1-甲基-1H-咪唑(36mg，0.44mmol)和(2E)-4-(二甲基氨基)丁-2-烯酸(0.021g，0.17mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过制备级高效液相色谱(色谱条件：Waters 3767，柱：Persuit XRS C18，21.2*250mm，10um；流动相A：含有0.1％2，2，2-三氟乙酸的纯水，B：乙腈；流速：20mL/min；梯度：27-37％；保留时间：7.3-11.7min of17min)纯化得到4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(24.23mg，收率：39.23％)，LC-MS m/z：584[M+H]+；A solution of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (50 mg, 0.11 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol), 1-methyl-1H-imidazole (36 mg, 0.44 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (0.021 g, 0.17 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic conditions: Waters 3767, column: Persuit XRS C18, 21.2*250 mm, 10 um; mobile phase A: pure water containing 0.1% 2,2,2-trifluoroacetic acid, B: acetonitrile; flow rate: 20 mL/min; gradient: 27-37%; retention time: 7.3-11.7 min of 17 min) to give (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (24.23 mg, yield: 39.23%), LC-MS m/z: 584 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ：8.07(s，1H)，6.74(s，1H)，6.72(d，J＝7.6Hz，1H)，6.52(d，J＝15.3Hz，1H)，6.48(s，1H)，4.52(dd，J＝24.7，18.4Hz，4H)，4.39(d，J＝2.7Hz，2H)，4.32-4.13(m，4H)，3.95(t，J＝5.7Hz，4H)，3.27(d，J＝6.9Hz，1H)，3.10(d，J＝23.8Hz，2H)，2.89(s，6H)，2.67(s，2H)，2.08(d，J＝11.5Hz，2H)，1.73(d，J＝10.1Hz，2H)，1.35(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ) δ: 8.07 (s, 1H), 6.74 (s, 1H), 6.72 (d, J = 7.6Hz, 1H), 6.52 (d, J = 15.3Hz, 1H) , 6.48 (s, 1H), 4.52 (dd, J=24.7, 18.4Hz, 4H), 4.39 (d, J=2.7Hz, 2H), 4.32-4.13 (m, 4H), 3 .95 (t, J=5.7Hz, 4H), 3.27 (d, J=6.9Hz, 1H), 3.10 (d, J=23.8Hz, 2H), 2.89 (s, 6H), 2.67 (s, 2H) , 2.08 (d, J=11.5Hz, 2H), 1.73 (d, J=10.1Hz, 2H), 1.35 (d, J=6.9Hz, 6H).
实施例80、(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物80)的合成：
Figure PCTCN2024077920-ftappb-I100375
Example 80, Synthesis of (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 80):
Figure PCTCN2024077920-ftappb-I100375
将溶有4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.11mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(62mg，0.22mmol)，1-甲基-1H-咪唑(36mg，0.44mmol)和丁-2-炔酸(0.014g，0.17mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(11.55mg，收率：20％)，LC-MS m/z：539[M+H]+；A solution of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (50 mg, 0.11 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol), 1-methyl-1H-imidazole (36 mg, 0.44 mmol) and but-2-ynoic acid (0.014 g, 0.17 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl ester (11.55 mg, yield: 20%), LC-MS m/z: 539 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.85(s，1H)，6.72(s，1H)，6.32(s，1H)，4.50-4.46(m，1H)，4.45-4.41(m，1H)，4.40-4.30(m，4H)，4.25-4.21(m，1H)，4.17-4.05(m，3H)，3.99-3.89(m，3H)，3.27-3.21(m，1H)，3.16-3.11(m，2H)，2.70(s，2H)，2.15-2.10(m，2H)，2.01(s，3H)，1.67-1.62(m，2H)，1.35(d，J＝8.0Hz，6H). 1 H NMR (400 MHz, MeOD-d 4 ): δ7.85 (s, 1H), 6.72 (s, 1H), 6.32 (s, 1H), 4.50-4.46 (m, 1H), 4.45-4.41 (m, 1H), 4.40-4.30 (m, 4H), 4.25-4.21 (m, 1H), 4.17-4.05 (m, 3H), 3.99-3 .89 (m, 3H), 3.27-3.21 (m, 1H), 3.16-3.11 (m, 2H), 2.70 (s, 2H), 2.15-2.10 (m, 2H), 2.01 (s, 3H), 1.67-1.62 (m, 2H), 1.35 (d, J=8.0Hz, 6H).
实施例81、4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(化合物81)的合成：
Figure PCTCN2024077920-ftappb-I100376
Example 81, Synthesis of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl)methyl ester (Compound 81):
Figure PCTCN2024077920-ftappb-I100376
将溶有4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.11mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(62mg，0.22mmol)，1-甲基-1H-咪唑(36mg，0.44mmol)和2-氟-丙-2-烯酸(15mg，0.17mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。所得混合物真减压浓缩。残余物通过制备级高效液相色谱纯化得到4-((5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(18.58mg，收率：32.25％)，LC-MS m/z：545[M+H]+；A solution of 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (50 mg, 0.11 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol), 1-methyl-1H-imidazole (36 mg, 0.44 mmol) and 2-fluoro-prop-2-enoic acid (15 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (18.58 mg, yield: 32.25%), LC-MS m/z: 545 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ8.06(s，1H)，6.74(s，1H)，6.48(s，1H)，5.58(dd，J＝46.9，3.5Hz，1H)，5.23(dd，J＝16.1，3.5Hz，1H)，4.62-4.53(m，2H)，4.48(d，J＝20.0Hz，2H)，4.41-4.37(m，2H)，4.35-4.09(m，5H)，3.95(t，J＝5.4Hz，2H)，3.27(s，1H)，3.13(s，2H)，2.67(s，2H)，2.10-2.05(m，2H)，1.75-1.70(m，2H)，1.35(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ 8.06 (s, 1H), 6.74 (s, 1H), 6.48 (s, 1H), 5.58 (dd, J=46.9, 3.5Hz, 1H), 5.23 (dd, J=16.1, 3.5Hz, 1H), 4.62-4.53 (m, 2H), 4.48 (d, J=20.0Hz, 2H), 4.41-4 .37(m, 2H), 4.35-4.09(m, 5H), 3.95(t, J=5.4Hz, 2H), 3.27(s, 1H), 3.13(s, 2H), 2.67(s, 2H), 2.10-2.05(m, 2H), 1.75-1.70(m, 2H), 1.35(d, J=8.0Hz, 6H).
实施例82、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-180)的合成：Example 82, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-180):
1)、4-((叔丁氧羰基)(3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100377
1) Synthesis of 4-((tert-butyloxycarbonyl)(3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100377
将溶有4-((叔丁氧羰基)(5-(3，6-二氢-2H-吡喃-4-基)-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(250mg，0.37mmol)和钯碳(含量10％，55％含水量，200mg)的甲醇(5mL)溶液氢气保护下，室温搅拌4小时。将混合反应液过滤，滤饼用甲醇(3×10mL)洗涤。收集滤液减压浓缩得到4-((叔丁氧羰基)(3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(230mg，收率：91.60％)，LC-MS m/z：675[M+H]+；A methanol (5 mL) solution of 4-((tert-butoxycarbonyl)(5-(3,6-dihydro-2H-pyran-4-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (250 mg, 0.37 mmol) and palladium carbon (10% content, 55% water content, 200 mg) was stirred at room temperature for 4 hours under hydrogen protection. The mixed reaction liquid was filtered and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to give 4-((tert-butoxycarbonyl)(3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (230 mg, yield: 91.60%), LC-MS m/z: 675 [M+H] + ;
2)、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100378
2) Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100378
向溶有4-((叔丁氧羰基)(3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(230mg，0.34mmol)的二氯甲烷(2.1mL)溶液中，加入2，2，2-三氟乙酸(0.7mL)，室温搅拌1小时。所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(120mg，74.2％)，LC-MS m/z：475[M+H]+；2,2,2-trifluoroacetic acid (0.7 mL) was added to a solution of 4-((tert-butoxycarbonyl)(3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (230 mg, 0.34 mmol) in dichloromethane (2.1 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (120 mg, 74.2%), LC-MS m/z: 475 [M+H] + ;
3)、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100379
3) Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100379
将溶有4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(60mg，0.13mmol)，(E)-4-(二甲氨基)丁-2-烯酸(32mg，0.19mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(72mg，0.19mmol)和N，N-二异丙基乙胺(49mg，0.38mmol)的二氯甲烷(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收 率：27.0％)，LC-MS m/z：586[M+H]+；A solution of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (60 mg, 0.13 mmol), (E)-4-(dimethylamino)but-2-enoic acid (32 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) in dichloromethane (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (20 mg, yield Rate: 27.0%), LC-MS m/z: 586[M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.86(s，1H)，6.86-6.77(m，1H)，6.23-6.10(m，2H)，4.54-4.40(m，4H)，4.24-4.04(m，6H)，3.96-3.87(m，1H)，3.62-3.54(m，2H)，3.27-3.22(m，1H)，3.18-3.11(m，4H)，2.98-2.90(m，1H)，2.26(s，6H)，2.14-2.05(m，2H)，2.04-1.92(m，2H)，1.88-1.82(m，2H)，1.69-1.56(m，2H)，1.35(s，3H)，1.33(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.86 (s, 1H), 6.86-6.77 (m, 1H), 6.23-6.10 (m, 2H), 4.54-4.40 (m, 4H), 4.24-4.04 (m, 6H), 3.96-3.87 (m, 1H), 3.62-3.54 (m, 2H), 3.27-3.2 2(m, 1H), 3.18-3.11(m, 4H), 2.98-2.90(m, 1H), 2.26(s, 6H), 2.14-2.05(m, 2H), 2.04-1.92(m, 2H), 1.88-1.82(m, 2H), 1.69-1.56(m, 2H), 1.35(s, 3H), 1.33(s, 3H).
实施例83、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物83)的合成：
Figure PCTCN2024077920-ftappb-I100380
Example 83, Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 83):
Figure PCTCN2024077920-ftappb-I100380
将溶有4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(60mg，0.13mmol)，丁-2-炔酸(16mg，0.19mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(72mg，0.19mmol)和N，N-二异丙基乙胺(49mg，0.38mmol)的二氯甲烷(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收率：29.26％)，LC-MS m/z：541[M+H]+；A solution of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (60 mg, 0.13 mmol), but-2-ynoic acid (16 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) in dichloromethane (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl ester (20 mg, yield: 29.26%), LC-MS m/z: 541 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.86(s，1H)，6.11(s，1H)，4.60-4.30(m，5H)，4.24-4.04(m，6H)，3.96-3.88(m，1H)，3.62-3.54(m，2H)，3.27-3.24(m，1H)，3.22-3.16(m，1H)，2.14-2.06(m，2H)，2.04-1.99(m，4H)，1.98-1.92(m，2H)，1.88-1.82(m，2H)，1.69-1.58(m，2H)，1.34(s，3H)，1.33(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.86 (s, 1H), 6.11 (s, 1H), 4.60-4.30 (m, 5H), 4.24-4.04 (m, 6H), 3.96-3.88 (m , 1H), 3.62-3.54(m, 2H), 3.27-3.24(m, 1H), 3.22-3.16(m, 1H), 2.14-2.06(m, 2H), 2.04-1.99(m, 4H), 1.98 -1.92(m, 2H), 1.88-1.82(m, 2H), 1.69-1.58(m, 2H), 1.34(s, 3H), 1.33(s, 3H).
实施例84、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(化合物84)的合成：
Figure PCTCN2024077920-ftappb-I100381
Example 84, Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl)methyl ester (Compound 84):
Figure PCTCN2024077920-ftappb-I100381
将溶有4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(60mg，0.13mmol)，2-氟丙烯酸(17mg，0.19mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(72mg，0.19mmol)和N，N-二异丙基乙胺(49mg，0.38mmol)的二氯加完(1mL溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(20mg，收率：28.90％)，LC-MS m/z：547[M+H]+；4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (60 mg, 0.13 mmol), 2-fluoroacrylic acid (17 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) were dissolved in 4% paraffin. mol) of dichloromethane was added (1 mL) and the solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to give 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (20 mg, yield: 28.90%), LC-MS m/z: 547 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.86(s，1H)，6.11(s，1H)，5.65-5.51(m，1H)，5.27-5.20(m，1H)，4.68-4.54(m，2H)，4.51-4.43(m，2H)，4.35-4.22(m，2H)，4.21-4.03(m，5H)，3.96-3.87(m，1H)，3.62-3.54(m，2H)，3.27-3.22(m，1H)，3.21-3.08(m，1H)，2.98-2.90(m，1H)，2.15-2.06(m，2H)，2.04-1.92(m，2H)，1.88-1.81(m，2H)，1.69-1.57(m，2H)，1.34(s，3H)，1.33(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.86 (s, 1H), 6.11 (s, 1H), 5.65-5.51 (m, 1H), 5.27-5.20 (m, 1H), 4.68-4.54 (m , 2H), 4.51-4.43(m, 2H), 4.35-4.22(m, 2H), 4.21-4.03(m, 5H), 3.96-3.87(m, 1 H), 3.62-3.54(m, 2H), 3.27-3.22(m, 1H), 3.21-3.08(m, 1H), 2.98-2.90(m, 1H), 2.15-2.06(m, 2H), 2.04- 1.92(m, 2H), 1.88-1.81(m, 2H), 1.69-1.57(m, 2H), 1.34(s, 3H), 1.33(s, 3H).
实施例85、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯(化合物C1-116)的合成：Example 85, Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl) ester (Compound C1-116):
1)、4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100382
1) Synthesis of tert-butyl 4-((tert-butyloxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100382
将溶有4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.5g，3.04mmol，三甲基-1，3，5，2，4，6-三噁三硼己环(579mg，4.56mmol)，四(三苯基膦)钯(0.35g，0.30mmol)的1.4-二氧六环(15mL)溶液，氮气保护下，加热100℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.2g，收率：83％)，LC-MS m/z：474[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.5 g, 3.04 mmol), trimethyl-1,3,5,2,4,6-trioxatriborin (579 mg, 4.56 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol) in 1.4-dioxane (15 mL) was heated at 100°C with stirring for 2 hours under nitrogen protection. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3 ·H 2 O pure water = 5-95% elution) to obtain tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.2 g, yield: 83%), LC-MS m/z: 474 [M+H] + ;
3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100383
Synthesis of 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100383
向溶有4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(1.2g，2.54mmol)的二氯甲烷(9mL)溶液中，加入2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(500mg，收率：72％)，LC-MS m/z：274[M+H]+；2,2,2-Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1.2 g, 2.54 mmol) in dichloromethane (9 mL). The resulting mixed reaction liquid was stirred at room temperature for 1 hour. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (500 mg, yield: 72%), LC-MS m/z: 274 [M+H] + ;
2)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲酯的合成
Figure PCTCN2024077920-ftappb-I100384
2) Synthesis of methyl 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)
Figure PCTCN2024077920-ftappb-I100384
在0℃条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(450mg，2.19mmol)和T三乙胺(74mg，0.73mmol)的二氯甲烷(4mL)溶液中，加入双(三氯甲基)碳酸酯(867mg，2.92mmol)。所得混合反应液0℃搅拌1小时。然后，在0℃条件下，3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(400mg，1.46mmol)加入上述的混合反应液中。加完后，所得混合反应液0℃搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲酯(250mg，收率：34％)，LC-MS m/z：505[M+H]+；At 0°C, bis(trichloromethyl)carbonate (867mg, 2.92mmol) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (450mg, 2.19mmol) and triethylamine (74mg, 0.73mmol) in dichloromethane (4mL). The resulting mixed reaction solution was stirred at 0°C for 1 hour. Then, 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (400mg, 1.46mmol) was added to the above mixed reaction solution at 0°C. After the addition, the resulting mixed reaction solution was stirred at 0°C for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (250 mg, yield: 34%), LC-MS m/z: 505 [M+H] + ;
3)、(3-氟氮杂环丁烷-3-基)4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲酯的合成
Figure PCTCN2024077920-ftappb-I100385
3) Synthesis of methyl (3-fluoroazetidine-3-yl)-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100385
向溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环 丁烷-3-基)甲酯(200mg，0.40mmol)的二氯甲烷(3mL)溶液中，加入2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：405[M+H]+；4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoronitrogen heterocyclic 2,2,2-trifluoroacetic acid (1 mL) was added to a solution of methyl 2-butane-3-yl) ester (200 mg, 0.40 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was reduced in pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 405 [M+H] + ;
4)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯的合成
Figure PCTCN2024077920-ftappb-I100386
4) Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl) ester
Figure PCTCN2024077920-ftappb-I100386
将溶有(3-氟氮杂环丁烷-3-基)4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲酯(50mg，0.12mmol)，2-氟丙-2-烯酸(16mg，0.18mmol)，1-甲基-1H-咪唑(39mg，0.48mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(67mg，0.24mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌1小时。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸甲(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)酯(2mg，收率：3.40％)，LC-MS m/z：477[M+H]+；A solution of (3-fluoroazetidine-3-yl)-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester (50 mg, 0.12 mmol), 2-fluoroprop-2-enoic acid (16 mg, 0.18 mmol), 1-methyl-1H-imidazole (39 mg, 0.48 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (67 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give methyl (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl) 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (2 mg, yield: 3.40%), LC-MS m/z: 477 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.11(s，1H)，5.58(dd，J＝48.0，3.5Hz，1H)，5.23(dd，J＝16.0，3.5Hz，1H)，4.70-4.53(m，2H)，4.47(d，J＝20.0Hz，2H)，4.34-4.21(m，1H)，4.20-4.07(m，3H)，3m，2H)，3.91-3.83(m，1H)，3.30-3.23(m，1H)，3.13-3.04(m，1H)，2.99-2.96(m，1H)，2.49(s，3H)，2.14-2.06(m，2H)，1.69-1.58(m，2H)，1.31(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.87 (s, 1H), 6.11 (s, 1H), 5.58 (dd, J=48.0, 3.5Hz, 1H), 5.23 (dd, J=16.0, 3.5Hz, 1H), 4.70-4.53(m, 2H), 4.47(d, J=20.0Hz, 2H), 4.34-4.21(m, 1H), 4.20-4.07(m , 3H), 3m, 2H), 3.91-3.83(m, 1H), 3.30-3.23(m, 1H), 3.13-3.04(m, 1H), 2.99-2.96(m, 1H), 2.49(s, 3H ), 2.14-2.06 (m, 2H), 1.69-1.58 (m, 2H), 1.31 (d, J=8.0Hz, 6H).
实施例86、(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基-4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸甲酯(化合物C1-194)的合成：
Figure PCTCN2024077920-ftappb-I100387
Example 86, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl-4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester (Compound C1-194):
Figure PCTCN2024077920-ftappb-I100387
将溶有(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸甲酯(60mg，0.15mmol)，(2E)-4-(二甲基氨基)丁-2-烯酸(29mg，0.22mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(86mg，0.22mmol)和N，N-二异丙级乙胺(58mg，0.45mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌1小时。将混合反应液通过C18反相柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基-4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸甲酯(5mg，收率：6.54％)，LC-MS m/z：516[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester (60 mg, 0.15 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (29 mg, 0.22 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (86 mg, 0.22 mmol) and N,N-diisopropylethylamine (58 mg, 0.45 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The mixed reaction liquid was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl-4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid methyl ester (5 mg, yield: 6.54%), LC-MS m/z: 516 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.89-6.77(m，1H)，6.24-6.09(m，2H)，4.56-4.38(m，5H)，4.30-4.08(m，5H)，3.87(s，1H)，3.27-3.23(m，1H)，3.17-3.11(m，2H)，2.49(s，3H)，2.15-2.05(m，6H)，2.11(s，2H)，1.64(s，2H)，1.31(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.87 (s, 1H), 6.89-6.77 (m, 1H), 6.24-6.09 (m, 2H), 4.56-4.38 (m, 5H), 4.30- 4.08(m, 5H), 3.87(s, 1H), 3.27-3.23(m, 1H), 3.17-3.11(m, 2H), 2.49(s, 3H), 2.15-2.05(m, 6H), 2.11( s, 2H), 1.64 (s, 2H), 1.31 (d, J=8.0Hz, 6H).
实施例87、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(化合物C1-190)的合成：Example 87, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C1-190):
1)、3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100388
1) Synthesis of 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100388
将溶有4-((叔丁氧羰基)(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸叔丁酯(800mg，1.69mmol)的2，2，2-三氟乙酸(1mL)和二氯甲烷(3mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(312mg，收率：67.5％)，LC-MS m/z：274[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (800 mg, 1.69 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (312 mg, yield: 67.5%), LC-MS m/z: 274[M+H] + ;
2)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100389
2) Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100389
将溶有2-(羟甲基)吡咯烷-1-羧酸叔丁酯(280mg，1.39mmol)，二(1H-1，2，4-三唑-1-基)甲酮(343mg，2.09mmol)，三乙胺(424mg，4.198mmol)和3-异丙基-5-甲基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(400mg，1.465mmol)的N，N-二甲基甲酰胺(5mL)溶液室温搅拌16小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲基酯(380mg，粗品)，LC-MS m/z：501[M+H]+；A solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (280 mg, 1.39 mmol), di(1H-1,2,4-triazol-1-yl)methanone (343 mg, 2.09 mmol), triethylamine (424 mg, 4.198 mmol) and 3-isopropyl-5-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (400 mg, 1.465 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl ester (380 mg, crude product), LC-MS m/z: 501 [M+H] + ;
3)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯的合成
Figure PCTCN2024077920-ftappb-I100390
3) Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester
Figure PCTCN2024077920-ftappb-I100390
将溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲基酯(500mg，0.998mmol)的2，2，2-三氟乙酸(1mL)和二氯甲烷(3mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(385mg，收率：96％)，LC-MS m/z：401[M+H]+；A solution of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl ester (500 mg, 0.998 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (385 mg, yield: 96%), LC-MS m/z: 401[M+H] + ;
4)、4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100391
4) Synthesis of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100391
将溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(100mg，0.25mmol)和(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(49mg，0.30mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(140mg，0.5mmol)和1-甲基-1H-咪唑(82mg，1.0mmol)的N，N-二甲基甲酰胺(2.0mL)溶液室温搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-60％洗脱)纯化得到4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(24mg，收率：19％)，LC-MS：m/z：512[M+H]+；A solution of 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (100 mg, 0.25 mmol) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (49 mg, 0.30 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (140 mg, 0.5 mmol) and 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-60% elution) to give 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl ester (24 mg, yield: 19%), LC-MS: m/z: 512 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：7.88(s，1H)，6.92-6.66(m，2H)，6.13(s，1H)，4.42-4.36(m，1H)，4.22-3.91(m，4H)，3.90-3.87(m，1H)，3.80-3.72(m，2H)，3.67(d，J＝6.4Hz，1H)，3.58-3.54(m，1H)，3.29-3.23(m，1H)，3.21-3.09(m，2H)，2.74(d，J＝8.0Hz，6H)，2.49(s，3H)，2.13-1.93(m，6H)，1.64-1.58(m，2H)，1.31(d，J＝8.0Hz，6H).1H NMR (400MHz, MeOD-d 4 ): 7.88 (s, 1H), 6.92-6.66 (m, 2H), 6.13 (s, 1H), 4.42-4.36 (m, 1H), 4.22-3.91 (m, 4H ), 3.90-3.87(m, 1H), 3.80-3.72(m, 2H), 3.67(d, J=6.4Hz, 1H), 3.5 8-3.54(m, 1H), 3.29-3.23(m, 1H), 3.21-3.09(m, 2H), 2.74(d, J=8.0Hz, 6H), 2.49(s, 3H), 2.13-1.93( m, 6H), 1.64-1.58 (m, 2H), 1.31 (d, J=8.0Hz, 6H).
实施例88、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(化合物C1-121)的合成：Example 88, Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl)methyl ester (Compound C1-121):
1)、4-((叔丁氧羰基)(8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100392
1) Synthesis of tert-butyl 4-((tert-butyloxycarbonyl)(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100392
将溶有4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1g，2.47mmol)，二碳酸二叔丁酯(1.62g，7.41mmol)，N，N-二异丙基乙胺(0.96g，7.41mmol)和4-二甲氨基吡啶(0.03g，0.25mmol)的二氯甲烷(10mL)溶液，加热60℃搅拌2小时。冷却后，将混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH4HCO3＝10-95％洗脱)纯化得到4-((叔丁氧羰基)(8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(800mg，收率：64％)，LC-MS m/z：507[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (1 g, 2.47 mmol), di-tert-butyl dicarbonate (1.62 g, 7.41 mmol), N,N-diisopropylethylamine (0.96 g, 7.41 mmol) and 4-dimethylaminopyridine (0.03 g, 0.25 mmol) in dichloromethane (10 mL) was heated at 60° C. and stirred for 2 hours. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 4 HCO 3 = 10-95% elution) to give tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (800 mg, yield: 64%), LC-MS m/z: 507 [M+H] + ;
2)、4-((叔丁氧基羰基)(8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100393
2) Synthesis of tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100393
将溶有4-((叔丁氧羰基)(8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(800mg，1.58mmol)和3-过氧苯甲酸(1.09g，6.32mmol)的二氯甲烷(10mL)溶液室温搅拌16小时。将所得混合反应液加水(100mL)稀释并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤后、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到4-((叔丁氧基羰基)(8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(650mg，收率：76.5％)，LC-MS m/z：539[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (800 mg, 1.58 mmol) and 3-peroxybenzoic acid (1.09 g, 6.32 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-40% elution) to give tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (650 mg, yield: 76.5%), LC-MS m/z: 539 [M+H] + ;
3)、4-((叔丁氧基羰基)(8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合 成
Figure PCTCN2024077920-ftappb-I100394
3) tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate become
Figure PCTCN2024077920-ftappb-I100394
在0℃条件下，向溶有4-((叔丁氧基羰基)(8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(650mg，1.21mmol)的四氢呋喃(5mL)溶液中，滴加甲基溴化镁(1.2mL，3M的四氢呋喃溶液)。将所得混合物室温搅拌16小时。将混合反应用饱和碳酸氢铵水溶液(10mL)，0℃淬灭，并用乙酸乙酯(3×10mL)萃取。合并的有机层用盐水(1×10mL)洗涤，用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-35％洗脱)纯化得到4-((叔丁氧基羰基)(8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(350mg，收率：61.2％)，LC-MS m/z：475[M+H]+；Methylmagnesium bromide (1.2 mL, 3M solution in tetrahydrofuran) was added dropwise to a solution of tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (650 mg, 1.21 mmol) in tetrahydrofuran (5 mL) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The mixed reaction was quenched with saturated aqueous ammonium bicarbonate solution (10 mL) at 0°C and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-35% elution) to give tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (350 mg, yield: 61.2%), LC-MS m/z: 475 [M+H] + ;
4)、8-异丙基-2-甲基-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺的合成
Figure PCTCN2024077920-ftappb-I100395
4) Synthesis of 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine
Figure PCTCN2024077920-ftappb-I100395
在室温条件下，向溶有4-((叔丁氧基羰基)(8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(380mg，0.80mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到8-异丙基-2-甲基-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺(138mg，收率：63％)，LC-MS m/z：275[M+H]+；To a solution of tert-butyl 4-((tert-butoxycarbonyl)(8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (380 mg, 0.80 mmol) in dichloromethane (3 mL) was added dropwise 2,2,2-trifluoroacetic acid (1 mL) at room temperature. The resulting mixed reaction liquid was stirred at room temperature for 16 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (138 mg, yield: 63%), LC-MS m/z: 275[M+H] + ;
5)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100396
5) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100396
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(135.45mg，0.66mmol)，三乙胺(134mg，1.32mmol)和二(1H-1，2，4-三唑-1-基)甲酮(108mg，0.66mmol)的N，N-二甲基甲酰胺(2mL)溶液，氩气保护下，室温搅拌1小时。然后将8-异丙基-2-甲基-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺(120mg，0.44mmol)加入到上述混合反应液中，加热40℃搅拌16小时。将所得混合反应液减压浓缩。残余物用C18柱色谱(乙腈：含有0.1％甲酸的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，收率：90.5％)，LC-MS m/z：506[M+H]+；A solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (135.45 mg, 0.66 mmol), triethylamine (134 mg, 1.32 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (108 mg, 0.66 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour under argon protection. Then 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (120 mg, 0.44 mmol) was added to the mixed reaction solution, heated at 40°C and stirred for 16 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% formic acid = 5-95% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (200 mg, yield: 90.5%), LC-MS m/z: 506 [M+H] + ;
6)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100397
6) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100397
在室温条件下，向溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，0.40mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈：含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，收率：50％)，LC-MS m/z：406[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise to a solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (200 mg, 0.40 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (80 mg, yield: 50%), LC-MS m/z: 406 [M+H] + ;
7)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100398
7) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100398
将溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.099mmol)，2-氟丙-2-烯酸(13.37mg，0.15mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(56.5mg，0.15mmol)和N，N-二异丙基乙胺(52mg 0.4mmol)的N，N-二甲基甲酰胺(0.5mL)溶液室温搅拌16小时。残余物通过C18柱纯色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(10mg，收率：21％)，LC-MS m/z：478[M+H]+；A solution of (3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (40 mg, 0.099 mmol), 2-fluoroprop-2-enoic acid (13.37 mg, 0.15 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (56.5 mg, 0.15 mmol) and N,N-diisopropylethylamine (52 mg 0.4 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (10 mg, yield: 21%), LC-MS m/z: 478 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.93(s，1H)，5.58(dd，J＝46.9，3.5Hz，1H)，5.23(dd，J＝16.0，3.5Hz，1H)，4.62(d，J＝13.8Hz，2H)，4.47(d，J＝20.0Hz，3H)，4.40(s，1H)，4.34-4.21(m，2H)，4.18(s，2H)，3.19(dt，J＝13.8，6.9Hz，1H)，3.07(s，1H)，2.49(s，3H)，2.05(d，J＝12.2Hz，2H)，1.67(d，J＝8.8Hz，2H)，1.30(d，J＝6.9Hz，6H).1H NMR (400MHz, MeOD-d4) δ7.93 (s, 1H), 5.58 (dd, J=46.9, 3.5Hz, 1H), 5.23 (dd, J=16.0, 3.5Hz, 1H), 4.62 (d, J＝13.8Hz, 2H), 4.47(d, J＝20.0Hz, 3H), 4.40(s, 1H ), 4.34-4.21(m, 2H), 4.18(s, 2H), 3.19(dt, J=13.8, 6.9Hz, 1H), 3.07(s, 1H), 2.49(s, 3H), 2.05(d, J=12.2Hz, 2H), 1.67 (d, J=8.8Hz, 2H), 1.30 (d, J=6.9Hz, 6H).
实施例89、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯(化合物C1-100)的合成：Example 89, Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester (Compound C1-100):
1)、4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100399
1) Synthesis of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100399
将溶有4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(500.0mg，1.23mmol)和2-氯过氧苯甲酸(1065mg，6.16mmol)的二氯甲烷(10mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：439[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (500.0 mg, 1.23 mmol) and 2-chloroperoxybenzoic acid (1065 mg, 6.16 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 439 [M+H] + ;
2)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100400
2) Synthesis of tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100400
在室温条件下，向溶有4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(500mg，1.14mmol)的四氢呋喃(5mL)溶液中，逐滴加入甲基溴化镁(2.3mL，3M的四氢呋喃溶液)。所得混合反应液室温搅拌过夜。在0℃条件下，加水(20mL)淬灭反应，并用二氯甲烷(3×50mL)萃取。合并的有机相用饱和食盐水(1×20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(400mg，收率：93.6％)，LC-MS m/z：375[M+H]+；At room temperature, methylmagnesium bromide (2.3 mL, 3M solution in tetrahydrofuran) was added dropwise to a solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (500 mg, 1.14 mmol) in tetrahydrofuran (5 mL). The resulting mixed reaction solution was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction at 0°C, and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (400 mg, yield: 93.6%), LC-MS m/z: 375 [M+H] + ;
3)、8-异丙基-2-甲基-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺的合成
Figure PCTCN2024077920-ftappb-I100401
3) Synthesis of 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine
Figure PCTCN2024077920-ftappb-I100401
向溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(400mg，1.07mmol)的二氯甲烷(9mL)溶液中，滴加2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物无需进一步纯化，可直接用于下一步。LC-MS m/z：275[M+H]+；2,2,2-Trifluoroacetic acid (3 mL) was added dropwise to a solution of tert-butyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (400 mg, 1.07 mmol) in dichloromethane (9 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m/z: 275 [M+H] + ;
4)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯的合成
Figure PCTCN2024077920-ftappb-I100402
4) Synthesis of methyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (1-(tert-butyloxycarbonyl)pyrrolidin-2-yl)
Figure PCTCN2024077920-ftappb-I100402
在室温条件下，向溶有的2-(羟甲基)吡咯烷-1-甲酸叔丁酯(250mg，1.24mmol)和三乙胺(250mg，2.48mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入三光气(245mg，0.83mmol)。所得混合物反应液室温搅拌1小时。在室温条件下，将8-异丙基-2-甲基-N-(哌啶-4-基)吡唑[1，5-a][1，3，5]三嗪-4-胺(227mg，0.83mmol)加入到上述混合反应液中。所得混合反应液室温搅拌过夜。将混合反应液减压浓缩并通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯(330mg，收率：79.6％)，LC-MS m/z：502[M+H]+；Triphosgene (245 mg, 0.83 mmol) was added to a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.24 mmol) and triethylamine (250 mg, 2.48 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. 8-isopropyl-2-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (227 mg, 0.83 mmol) was added to the above mixed reaction solution at room temperature. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1carboxylic acid (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl ester (330 mg, yield: 79.6%), LC-MS m/z: 502 [M+H] + ;
5)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯的合成
Figure PCTCN2024077920-ftappb-I100403
5) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester
Figure PCTCN2024077920-ftappb-I100403
室温条件下，向溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(叔丁氧羰基)吡咯烷-2-基)甲酯(330mg，0.66mmol)的二氯甲烷(9mL)溶液滴加2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，无需进一步纯化，可直接用于下一步。LC-MS m/z：402[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (3 mL) was added dropwise to a solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)pyrrolidin-2-yl)methyl ester (330 mg, 0.66 mmol) in dichloromethane (9 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 402 [M+H] + ;
6)、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100404
6) Synthesis of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100404
将溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(200mg，0.50mmol)，2-氟丙烯酸(135mg，1.50mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(569mg，1.50mmol)和N，N-二异丙基乙胺(322mg，2.50mmol)的N，N-二甲基甲酰胺(2mL)溶液，室温搅拌2小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-46％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1羧酸(1-(2-氟丙烯酰基)吡咯烷-2-基)甲基酯(65mg，收率：27.5％)，LC-MS m/z：474[M+H]+；A solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (200 mg, 0.50 mmol), 2-fluoroacrylic acid (135 mg, 1.50 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (569 mg, 1.50 mmol) and N,N-diisopropylethylamine (322 mg, 2.50 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-46% elution) to obtain 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1carboxylic acid (1-(2-fluoroacryloyl)pyrrolidin-2-yl)methyl ester (65 mg, yield: 27.5%), LC-MS m/z: 474 [M+H] + ;
1H NMR(400MHz，MeOD)δ7.90(s，1H)，5.39(d，J＝47.2Hz，1H)，5.23(dd，J＝16.7，3.4Hz，1H)，4.41-4.29(m，2H)，4.17(s，4H)，3.70(d，J＝20.0Hz，2H)，3.19(dt，J＝14.0，6.8Hz，1H)，3.03(s，1H)，2.47(s，3H)，2.04(d，J＝12.4Hz，4H)，1.95-1.87(m，2H)，1.73-1.58(m，3H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD) δ7.90 (s, 1H), 5.39 (d, J=47.2Hz, 1H), 5.23 (dd, J=16.7, 3.4Hz, 1H), 4.41-4.29 (m, 2H ), 4.17 (s, 4H), 3.70 (d, J = 20.0Hz, 2H), 3.19 (dt, J = 14.0, 6.8Hz, 1H), 3.03 (s, 1H), 2.47 (s, 3H), 2.04 (d, J=12.4Hz, 4H), 1.95-1.87 (m, 2H), 1.73-1.58 (m, 3H), 1.31 (s, 3H), 1.29 (s, 3H).
实施例90、4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(化合物C1-192)的合成：
Figure PCTCN2024077920-ftappb-I100405
Example 90, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (Compound C1-192):
Figure PCTCN2024077920-ftappb-I100405
将溶有4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸吡咯烷-2-基甲基酯(200mg，0.50mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(195mg，1.50mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(569mg，1.50mmol)和N，N-二异丙基乙胺(322mg，2.50mmol)的N，N-二甲甲基甲酰胺(2mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％甲酸的纯水＝5-20％洗脱)纯化得到4-((8-异丙基-2-甲基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)吡咯烷-2-基)甲基酯(51mg，收率：20％)，LC-MS m/z：513[M+H]+； A solution of 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (200 mg, 0.50 mmol), (E)-4-(dimethylamino)but-2-enoic acid (195 mg, 1.50 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (569 mg, 1.50 mmol) and N,N-diisopropylethylamine (322 mg, 2.50 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-20% elution) to give 4-((8-isopropyl-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methyl ester (51 mg, yield: 20%), LC-MS m/z: 513 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.90(s，1H)，6.85-6.79(m，1H)，6.78-6.58(m，1H)，4.44-4.32(m，2H)，4.21-4.12(m，2H)，3.79-3.72(m，1H)，3.70-3.64(m，1H)，3.61-3.50(m，3H)，3.41(s，1H)，3.40(s，1H)，3.22-3.15(m，1H)，3.04(s，1H)，2.60(s，3H)，2.56(s，3H)，2.47(s，3H)，2.13-1.96(m，6H)，1.71-1.60(m，2H)，1.31(s，3H)，1.29(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.90 (s, 1H), 6.85-6.79 (m, 1H), 6.78-6.58 (m, 1H), 4.44-4.32 (m, 2H), 4.21-4.12 (m, 2H), 3.79-3.72 (m, 1H), 3.70-3.64 (m, 1H), 3.61-3.50 (m, 3H), 3.41(s, 1H), 3.40(s, 1H), 3.22-3.15(m, 1H), 3.04(s, 1H), 2.60(s, 3H), 2.56(s, 3H), 2.47(s , 3H), 2.13-1.96 (m, 6H), 1.71-1.60 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H).
实施例91、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(丁-2-炔基)-3-氟氮杂环丁烷-3-基)甲酯(化合物C1-89)的合成：
Figure PCTCN2024077920-ftappb-I100406
Example 91, Synthesis of (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C1-89):
Figure PCTCN2024077920-ftappb-I100406
将溶有4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.12mmol)，丁-2-炔酸(15mg，0.18mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(35mg，0.18mmol)和4-二甲基氨基吡啶(1.5mg，0.012mmol)的二氯甲烷(1mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到甲基4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(丁-2-炔基)-3-氟氮杂环丁烷-3-基)酯(1.19mg，收率：2.05％)，LC-MS m/z：471[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.12 mmol), but-2-ynoic acid (15 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and 4-dimethylaminopyridine (1.5 mg, 0.012 mmol) in dichloromethane (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1-(but-2-ynyl)-3-fluoroazetidin-3-yl) (1.19 mg, yield: 2.05%), LC-MS m/z: 471 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.89(s，1H)，6.14(s，1H)，4.53-4.30(m，5H)，4.28-4.08(m，4H)，3.94-3.86(m，1H)，3.21-3.10(m，2H)，2.51(s，3H)，2.18-2.08(m，2H)，2.04(s，3H)，1.72-1.60(m，2H)，1.40-1.30(m，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.89 (s, 1H), 6.14 (s, 1H), 4.53-4.30 (m, 5H), 4.28-4.08 (m, 4H), 3.94-3.86 ( m, 1H), 3.21-3.10 (m, 2H), 2.51 (s, 3H), 2.18-2.08 (m, 2H), 2.04 (s, 3H), 1.72-1.60 (m, 2H), 1.40-1.30 ( m, 6H).
实施例92、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(化合物92)的合成：Example 92, Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidine-3-yl)methyl ester (Compound 92):
1)、4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100407
1) Synthesis of tert-butyl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100407
将溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(760mg，1.93mmol)，二碳酸二叔丁酯(631.83mg，2.90mmol)，4-二甲氨基吡啶(23.58mg，0.19mmol)和N，N-二异丙基乙胺(748.30mg，5.79mmol)的四氢呋喃(8mL)溶液加热50℃搅拌16小时。冷却后，将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(520mg，收率：54.55％)，LC-MS m/z：494[M+H]+；A solution of tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (760 mg, 1.93 mmol), di-tert-butyl dicarbonate (631.83 mg, 2.90 mmol), 4-dimethylaminopyridine (23.58 mg, 0.19 mmol) and N,N-diisopropylethylamine (748.30 mg, 5.79 mmol) in tetrahydrofuran (8 mL) was heated at 50° C. and stirred for 16 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 .H 2 O=5-95% elution) to give tert-butyl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (520 mg, yield: 54.55%), LC-MS m/z: 494 [M+H] + ;
2)、4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100408
2) Synthesis of tert-butyl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100408
向溶有4-((叔丁氧基羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(520mg，1.05mmol)和环丙基三氟硼烷钾(230mg，1.58mmol)的1，4-二氧六环(4mL)和水(1mL)溶液中，加入1，1′-二(二苯膦基)二茂铁二氯化钯(76.83mg，0.11mmol)和碳酸铯(1026.33mg，3.15mmol)。将微波反应容器密封并在微波加热110℃搅拌2小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯/石油醚＝-0-100％)洗脱)纯化得到4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(470mg，收率：89.4％)，LC-MS m/z：500[M+H]+； To a solution of tert-butyl 4-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (520 mg, 1.05 mmol) and potassium cyclopropyltrifluoroborane (230 mg, 1.58 mmol) in 1,4-dioxane (4 mL) and water (1 mL), 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (76.83 mg, 0.11 mmol) and cesium carbonate (1026.33 mg, 3.15 mmol) were added. The microwave reaction vessel was sealed and stirred at 110° C. for 2 hours in a microwave. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/petroleum ether = -0-100%) to give tert-butyl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (470 mg, yield: 89.4%), LC-MS m/z: 500 [M+H] + ;
3)、5-环丙基-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺的合成
Figure PCTCN2024077920-ftappb-I100409
3) Synthesis of 5-cyclopropyl-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine
Figure PCTCN2024077920-ftappb-I100409
在室温条件下，向溶有4-((叔丁氧基羰基)(5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(470mg，0.94mmol)的二氯甲烷(4.5mL)溶液中，滴加2，2，2-三氟乙酸(1.5mL)。所得混合反应液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：300[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1.5 mL) was added dropwise to a solution of tert-butyl 4-((tert-butoxycarbonyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (470 mg, 0.94 mmol) in dichloromethane (4.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 300 [M+H] + ;
4)、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100410
4) Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100410
在0℃条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(412.51mg，2.01mmol)和三乙胺(406.78mg，4.02mmol)的N，N-二甲基甲酰胺(3mL)溶液中，在分批加入二(1H-1，2，4-三唑-1-基)甲酮(329.88mg，2.01mmol)。所得混合物反应液氮气保护下，0℃搅拌30分钟。然后在0℃条件下，将5-环丙基-3-异丙基-N-(哌啶-4-基)吡唑并[1，5-a]嘧啶-7-胺(400mg，1.34mmol)分批加入到上述混合反应液中。所得混合反应液加热40℃搅拌过夜。冷却后，所将所得混合反应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(320mg，收率：45.14％)，LC-MS m/z：531[M+H]+；At 0°C, di(1H-1,2,4-triazol-1-yl)methanone (329.88 mg, 2.01 mmol) was added in batches to a solution of N,N-dimethylformamide (3 mL) containing tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (412.51 mg, 2.01 mmol) and triethylamine (406.78 mg, 4.02 mmol). The resulting mixture reaction liquid was stirred at 0°C for 30 minutes under nitrogen protection. Then, 5-cyclopropyl-3-isopropyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-7-amine (400 mg, 1.34 mmol) was added in batches to the above mixed reaction liquid at 0°C. The resulting mixed reaction liquid was heated at 40°C and stirred overnight. After cooling, the resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (320 mg, yield: 45.14%), LC-MS m/z: 531 [M+H] + ;
5)、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100411
5) Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100411
在0℃条件下，，向溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(320mg，0.60mmol)的甲醇(3mL)溶液中，滴加草酰氯(228.47mg，1.80mmol)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：431[M+H]+；At 0°C, oxalyl chloride (228.47 mg, 1.80 mmol) was added dropwise to a solution of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (320 mg, 0.60 mmol) in methanol (3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 431[M+H] + ;
6)、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲酯的合成
Figure PCTCN2024077920-ftappb-I100412
6) Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100412
将溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.12mmol)，2-氟丙-2-烯酸(16.21mg，0.18mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(67.34mg，0.24mmol)和1-甲基-1H-咪唑(39.41mg，0.48mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌1小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(3mg，收率：5.14％)，LC-MS m/z：503[M+H]+；A solution of (3-fluoroazetidin-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.12 mmol), 2-fluoroprop-2-enoic acid (16.21 mg, 0.18 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (67.34 mg, 0.24 mmol) and 1-methyl-1H-imidazole (39.41 mg, 0.48 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (3 mg, yield: 5.14%), LC-MS m/z: 503 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.71(s，1H)，5.87(s，1H)，5.48(dd，J＝4.0，3.2Hz，1H)，5.18-5.10(m，1H)，4.73-4.31(m，4H)，4.28-3.97(m，3H)，3.90-3.70(m，1H)，3.54(s，1H)，3.49-3.25(m，1H)，3.18-2.97(m，2H)，2.21-2.07(m，1H)，2.05-1.90(m，2H)，1.58-1.45(m，2H)，1.20(d，J＝7.6Hz，6H)，1.00-0.95(m，1H)，0.94-0.88(m，1H)，0.87-0.71(m，2H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.71 (s, 1H), 5.87 (s, 1H), 5.48 (dd, J=4.0, 3.2Hz, 1H), 5.18-5.10 (m, 1H) , 4.73-4.31(m, 4H), 4.28-3.97(m, 3H), 3.90-3.70(m, 1H), 3.54(s, 1H), 3.49-3.25(m , 1H), 3.18-2.97(m, 2H), 2.21-2.07(m, 1H), 2.05-1.90(m, 2H), 1.58-1.45(m, 2H), 1.20(d, J=7.6Hz, 6H ), 1.00-0.95(m, 1H), 0.94-0.88(m, 1H), 0.87-0.71(m, 2H).
实施例93、(4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲酯(化合物C2-80)的合成：
Figure PCTCN2024077920-ftappb-I100413
Example 93, Synthesis of (4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester (Compound C2-80):
Figure PCTCN2024077920-ftappb-I100413
将溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.093mmol)，(2E)-4-(二甲氨基)丁-2-烯酸(18.02mg，0.14mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(53.04mg，0.14mmol)和N，N-二异丙基乙胺(36.06mg，0.28mmol)的二氯甲烷(1mL)溶液室温搅拌1小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(3mg，收率：5.96％)，LC-MS m/z：542[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (40 mg, 0.093 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (18.02 mg, 0.14 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53.04 mg, 0.14 mmol) and N,N-diisopropylethylamine (36.06 mg, 0.28 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to obtain (4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (3 mg, yield: 5.96%), LC-MS m/z: 542 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.81(s，1H)，6.85-6.72(m，1H)，6.43(d，J＝16.0Hz，1H)，5.97(s，1H)，4.58-4.48(m，3H)，4.46(s，1H)，4.27(s，2H)，4.30-4.20(m，3H)，3.89(s，1H)，3.76-3.69(m，2H)，3.23-3.15(s，2H)，2.71(s，6H)，2.16-2.02(m，3H)，1.63(s，2H)，1.31(d，J＝8.0Hz，6H)，1.14-0.97(m，4H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.81 (s, 1H), 6.85-6.72 (m, 1H), 6.43 (d, J=16.0Hz, 1H), 5.97 (s, 1H), 4.58 -4.48(m, 3H), 4.46(s, 1H), 4.27(s, 2H), 4.30-4.20(m, 3H), 3.89(s, 1H), 3.76-3.69(m, 2H), 3.23-3.15 (s, 2H), 2.71 (s, 6H), 2.16-2.02 (m, 3H), 1.63 (s, 2H), 1.31 (d, J=8.0Hz, 6H), 1.14-0.97 (m, 4H).
实施例94、(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸酯(化合物C2-112)的合成：
Figure PCTCN2024077920-ftappb-I100414
Example 94, Synthesis of (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C2-112):
Figure PCTCN2024077920-ftappb-I100414
将溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.093mmol)，丁-2-炔酸(11.73mg，0.14mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(52.19mg，0.19mmol)和1-甲基-1H-咪唑(30.54mg，0.37mmol)的N，N-二甲基甲酰胺(1mL)溶液，室温搅拌1小 时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸酯(3mg，收率：6.50％)，LC-MS m/z：497[M+H]+；A solution of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (40 mg, 0.093 mmol), but-2-ynoic acid (11.73 mg, 0.14 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (52.19 mg, 0.19 mmol) and 1-methyl-1H-imidazole (30.54 mg, 0.37 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (3 mg, yield: 6.50%), LC-MS m/z: 497 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.80(s，1H)，5.96(s，1H)，4.50-4.40(m，3H)，4.340-4.28(m，2H)，4.26-4.19(m，1H)，4.18-4.06(m，3H)，3.92-3.83(m，1H)，3.24-3.19(m，1H)，3.17(d，J＝8.0Hz，1H)，2.14-2.08(m，2H)，2.07-2.03(m，1H)，2.01(s，3H)，1.68-1.56(m，2H)，1.31(d，J＝8.0Hz，6H)，1.09-1.04(m，2H)，1.03-0.97(m，2H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.80 (s, 1H), 5.96 (s, 1H), 4.50-4.40 (m, 3H), 4.340-4.28 (m, 2H), 4.26-4.19 ( m, 1H), 4.18-4.06 (m, 3H), 3.92-3.83 (m, 1H), 3.24-3.19 (m, 1H), 3.1 7(d, J=8.0Hz, 1H), 2.14-2.08(m, 2H), 2.07-2.03(m, 1H), 2.01(s, 3H), 1.68-1.56(m, 2H), 1.31(d, J＝8.0Hz, 6H), 1.09-1.04(m, 2H), 1.03-0.97(m, 2H).
实施例95、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-吗啉丁基-2-烯酰基)氮杂环丁烷-3-基)甲基酯(化合物95)的合成：Example 95, Synthesis of (E)-(3-fluoro-1-(4-morpholinobutyl-2-enoyl)azetidin-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 95):
1)、(E)-4-吗啉代丁酸-2-烯酸的合成
Figure PCTCN2024077920-ftappb-I100415
1) Synthesis of (E)-4-morpholinobutyric acid-2-enoic acid
Figure PCTCN2024077920-ftappb-I100415
将溶有(2E)-4-溴-2-烯酸(200mg，1.21mmol)，吗啉(316mg，3.63mmol)和三乙胺(368mg，3.63mmol)的四氢呋喃(1mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(E)-4-吗啉代丁酸-2-烯酸(150mg，收率：72％)，LC-MS m/z：172[M+H]+；A solution of (2E)-4-bromo-2-enoic acid (200 mg, 1.21 mmol), morpholine (316 mg, 3.63 mmol) and triethylamine (368 mg, 3.63 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give (E)-4-morpholinobutyric acid-2-enoic acid (150 mg, yield: 72%), LC-MS m/z: 172 [M+H] + ;
2)、4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-吗啉丁基-2-烯酰基)氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100416
2) Synthesis of 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(3-fluoro-1-(4-morpholinobutyl-2-enoyl)azetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100416
将溶有4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.19mmol)，(2E)-4-(吗啉-4-基)丁-2-烯酸(49mg，0.29mmol)和2-乙氧基-1-乙氧碳酰基-1，2-二氢喹啉(47mg，0.19mmol)的二氯甲烷(1mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到4-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-吗啉丁基-2-烯酰基)氮杂环丁烷-3-基)甲基酯(5mg，收率：4.6％)，LC-MS m/z：584[M+H]+；A solution of (3-fluoroazetidin-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (80 mg, 0.19 mmol), (2E)-4-(morpholin-4-yl)but-2-enoic acid (49 mg, 0.29 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (47 mg, 0.19 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 ·H 2 O = 5-95% elution) to give (E)-(3-fluoro-1-(4-morpholinobutyl-2-enoyl)azetidin-3-yl)methyl 4-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (5 mg, yield: 4.6%), LC-MS m/z: 584 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.80(s，1H)，6.89-6.75(m，1H)，6.29-6.16(m，1H)，5.96(s，1H)，4.58-4.35(m，4H)，4.30-4.03(m，4H)，3.92-3.82(m，1H)，3.72-3.60(m，4H)，3.24-3.06(m，5H)，2.57-2.35(m，4H)，2.19-1.99(m，3H)，1.70-1.52(m，2H)，1.31(d，J＝8.0Hz，6H)，1.12-0.95(m，4H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.80 (s, 1H), 6.89-6.75 (m, 1H), 6.29-6.16 (m, 1H), 5.96 (s, 1H), 4.58-4.35 ( m, 4H), 4.30-4.03 (m, 4H), 3.92-3.82 (m, 1H), 3.72-3.60 (m, 4H), 3.24-3.06 (m, 5H), 2.57-2.35 (m, 4H), 2.19-1.99 (m, 3H), 1.70-1.52 (m, 2H), 1.31 (d, J=8.0Hz, 6H), 1.12-0.95 (m, 4H).
实施例96、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-((E)-4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物96)的合成：Example 96, Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-((E)-4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 96):
1)、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100417
1) Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100417
室温条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(474mg，2.31mmol)和三乙胺(467mg，4.62mmol)的N，N-二甲基甲酰胺(1mL)溶液中，加入二(1H-1，2，4-三唑-1-基)甲酮(379mg，2.31mmol)。 所得混合反应液氩气保护下，室温搅拌1小时。然后在室温下，将N-((1R，3s，5S)-8-氮杂双环[3.2.1]辛烷-3-基)-5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-胺(500mg，1.54mmol)分批加入到上述混合反应液中。所得混合反应液室温搅拌1小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-39％洗脱)纯化得到(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(300mg，收率：35.1％)，LC-MS m/z：557[M+H]+；To a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (474 mg, 2.31 mmol) and triethylamine (467 mg, 4.62 mmol) in N,N-dimethylformamide (1 mL) was added di(1H-1,2,4-triazol-1-yl)methanone (379 mg, 2.31 mmol) at room temperature. The obtained mixed reaction liquid was stirred at room temperature for 1 hour under argon protection. Then, N-((1R, 3s, 5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (500 mg, 1.54 mmol) was added to the mixed reaction liquid in batches at room temperature. The obtained mixed reaction liquid was stirred at room temperature for 1 hour. The mixed reaction liquid was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 .H 2 O = 5-39% elution) to obtain (1R,3s,5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (300 mg, yield: 35.1%), LC-MS m/z: 557 [M+H] + ;
2)、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100418
2) Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100418
在室温条件下，向溶有(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(300.0mg，0.54mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：457[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise to a solution of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (300.0 mg, 0.54 mmol) in dichloromethane (3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 457 [M+H] + ;
3)、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-((E)-4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100419
3) Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-((E)-4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100419
将溶有(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(100mg，0.22mmol)，(E)-4-(二甲氨基)丁-2-烯酸(42.6mg，0.33mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(97.0mg，0.26mmol)和N，N-二异丙基乙胺(85.2mg，0.66mmol)的N，N-二甲基甲酰胺(1.5mL)溶液，室温搅拌1小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-((E)-4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收率：16.1％)，LC-MS m/z：568[M+H]+；A solution of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (100 mg, 0.22 mmol), (E)-4-(dimethylamino)but-2-enoic acid (42.6 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (97.0 mg, 0.26 mmol) and N,N-diisopropylethylamine (85.2 mg, 0.66 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-((E)-4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (20 mg, yield: 16.1%), LC-MS m/z: 568 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.79(s，1H)，6.86-6.74(m，1H)，6.23(d，J＝14.8Hz，1H)，5.99(s，1H)，4.62-4.50(m，2H)，4.50-4.43(m，2H)，4.43-4.40(m，1H)，4.36(s，2H)，4.30-4.11(m，3H)，3.22-3.16(m，2H)，2.30(d，J＝14.8Hz，6H)，2.10(s，5H)，2.00(s，2H)，1.88-1.65(m，2H)，1.31(s，3H)，1.30(s，3H)，1.10-1.05(m，2H)，1.01-0.99(m，2H). 1 H NMR (400MHz, MeOD-d4): δ7.79 (s, 1H), 6.86-6.74 (m, 1H), 6.23 (d, J=14.8Hz, 1H), 5.99 (s, 1H), 4.62- 4.50(m, 2H), 4.50-4.43(m, 2H), 4.43-4.40(m, 1H), 4.36(s, 2H), 4.3 0-4.11(m, 3H), 3.22-3.16(m, 2H), 2.30(d, J=14.8Hz, 6H), 2.10(s, 5H), 2.00(s, 2H), 1.88-1.65(m, 2H), 1.31(s, 3H), 1.30(s, 3H), 1.10-1.05(m, 2H), 1.01-0.99(m, 2H).
实施例97、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物97)的合成：
Figure PCTCN2024077920-ftappb-I100420
Example 97, Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 97):
Figure PCTCN2024077920-ftappb-I100420
将溶有(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(100mg，0.22mmol)，丁-2-炔酸(27.7mg，0.33mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(125.4mg，0.33mmol)和N，N-二异丙基乙胺(142mg 1.1mmol)的N，N-二甲基甲酰胺(2mL)溶液室温搅拌1小时。将混合反应液通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(23mg，收率：20.2％)，LC-MS m/z：523[M+H]+；A solution of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (100 mg, 0.22 mmol), but-2-ynoic acid (27.7 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125.4 mg, 0.33 mmol) and N,N-diisopropylethylamine (142 mg 1.1 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl ester (23 mg, yield: 20.2%), LC-MS m/z: 523 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.78(s，1H)，6.00(s，1H)，4.50-4.44(m，3H)，4.41-4.32(m，3H)，4.27-4.18(m，2H)，4.15-4.07(m，1H)，3.60(q，J＝7.2Hz，1H)，3.22-3.13(m，1H)，2.18-2.04(m，6H)，2.00(s，3H)，1.86-1.70(m，2H)，1.31(s，3H)，1.29(s，3H)，1.10-1.04(m，2H)，1.01-0.97(m，2H). 1 H NMR (400MHz, MeOD-d4): δ7.78 (s, 1H), 6.00 (s, 1H), 4.50-4.44 (m, 3H), 4.41-4.32 (m, 3H), 4.27-4.18 (m , 2H), 4.15-4.07 (m, 1H), 3.60 (q, J=7.2Hz, 1H), 3.22-3.13 (m, 1H), 2.18-2.04 (m, 6H), 2.00 (s, 3H), 1.86-1.70(m, 2H), 1.31(s, 3H), 1.29(s, 3H), 1.10-1.04(m, 2H), 1.01-0.97(m, 2H).
实施例98、(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(化合物98)的合成：
Figure PCTCN2024077920-ftappb-I100421
Example 98, Synthesis of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (Compound 98):
Figure PCTCN2024077920-ftappb-I100421
将溶有(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(100.0mg，0.22mmol)，2-氟丙烯酸(29.6mg，0.33mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(123.6mg，0.44mmol)和1-甲基-1H-咪唑(90.2mg，1.1mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌1小时。将所得混合反8应液减压浓缩。残余物通过C18柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-39％洗脱)纯化得到(1R，3s，5S)-3-((5-环丙基-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸(3-氟-1-(2-氟丙烯酰基)氮杂环丁烷-3-基)甲基酯(16mg，收率：13.8％)。LC-MS m/z；529[M+H]+；A solution of (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (100.0 mg, 0.22 mmol), 2-fluoroacrylic acid (29.6 mg, 0.33 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (123.6 mg, 0.44 mmol) and 1-methyl-1H-imidazole (90.2 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-39% elution) to give (1R, 3s, 5S)-3-((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid (3-fluoro-1-(2-fluoroacryloyl)azetidin-3-yl)methyl ester (16 mg, yield: 13.8%). LC-MS m/z; 529 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.78(s，1H)，5.99(s，1H)，5.56(dd，J＝48.0，3.2Hz，1H)，5.19(s，1H)，4.70-4.60(m，2H)，4.49(dd，J＝19.2，7.2Hz，2H)，4.37(s，2H)，4.33-4.15(m，3H)，3.19(dt，J＝13.6，6.8Hz，1H)，2.19-1.92(m，7H)，1.84-1.69(m，2H)，1.31(s，3H)，1.30(s，3H)，1.10-1.03(m，2H)，1.01-0.97(m，2H). 1 H NMR (400MHz, MeOD-d4): δ7.78 (s, 1H), 5.99 (s, 1H), 5.56 (dd, J=48.0, 3.2Hz, 1H), 5.19 (s, 1H), 4.70- 4.60(m, 2H), 4.49(dd, J=19.2, 7.2Hz, 2H), 4.37(s, 2H ), 4.33-4.15 (m, 3H), 3.19 (dt, J=13.6, 6.8Hz, 1H), 2.19-1.92 (m, 7H), 1.84-1.69 (m, 2H), 1.31 (s, 3H), 1.30 (s, 3H), 1.10-1.03 (m, 2H), 1.01-0.97 (m, 2H).
实施例99、4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C2-293)的合成：Example 99, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (Compound C2-293):
1)、4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100422
1) Synthesis of tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100422
将溶有4-氯-8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪(2g，8.26mmol)，4-氨基哌啶-1-羧酸叔丁酯(1.98g，9.92mmol)和N，N-二异丙基乙胺(3.20g，24.8mmol)的异丙醇(20mL)溶液加热70℃搅拌过 夜。冷却后，将混合反应液液加水(100mL)稀释，并用EtOAc(3x 200mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯：石油醚＝0～30％)纯化得到4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(2.7g，收率：80.5％)，LC-MS m/z：407[M+H]+；A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (2 g, 8.26 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.98 g, 9.92 mmol) and N,N-diisopropylethylamine (3.20 g, 24.8 mmol) in isopropanol (20 mL) was heated to 70°C and stirred for 2 hours. Overnight. After cooling, the mixed reaction liquid was diluted with water (100 mL) and extracted with EtOAc (3x 200 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to give tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (2.7 g, yield: 80.5%), LC-MS m/z: 407[M+H] + ;
2)、4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100423
2) Synthesis of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100423
将溶有4-((8-异丙基-2-(甲硫基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(2.70g，6.64mmol)和3-氯过氧苯甲酸(3.44g，19.9mmol)的二氯甲烷(20mL)溶液，室温搅拌12小时。将所得混合反应液用水(100mL)稀释并用乙酸乙酯(3x 100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝20-40％洗脱)纯化得到4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.76g，收率：60.4％)，LC-MS m/z：439[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (2.70 g, 6.64 mmol) and 3-chloroperoxybenzoic acid (3.44 g, 19.9 mmol) in dichloromethane (20 mL) was stirred at room temperature for 12 hours. The resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-40% elution) to give tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (1.76 g, yield: 60.4%), LC-MS m/z: 439 [M+H] + ;
3)、4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100424
3) Synthesis of tert-butyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100424
将溶有4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.76g，4.01mmol)，四氢-2H-吡喃-4-胺(810mg，8.02mmol)和N，N-二异丙基乙胺(1.55g，12.03mmol)的异丙醇(15mL)溶液加热90℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释，并用乙酸乙酯(3x 100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(乙酸乙酸∶石油醚＝10-50％洗脱)纯化得到4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.55g，收率：84.0％)，LC-MS m/z：460[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (1.76 g, 4.01 mmol), tetrahydro-2H-pyran-4-amine (810 mg, 8.02 mmol) and N,N-diisopropylethylamine (1.55 g, 12.03 mmol) in isopropanol (15 mL) was heated at 90°C and stirred overnight. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give tert-butyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (1.55 g, yield: 84.0%), LC-MS m/z: 460 [M+H] + ;
4)、8-异丙基-N4-(哌啶-4-基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
Figure PCTCN2024077920-ftappb-I100425
4) Synthesis of 8-isopropyl-N 4 -(piperidin-4-yl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
Figure PCTCN2024077920-ftappb-I100425
在室温下，向溶有4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(1.55g，3.37mmol)的二氯甲烷(15mL)溶液中，滴加2，2，2-三氟乙酸(5mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到8-异丙基-N4-(哌啶-4-基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(1.10g，收率：90.7％)，LC-MS m/z：360[M+H]+；To a solution of tert-butyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (1.55 g, 3.37 mmol) in dichloromethane (15 mL) was added dropwise 2,2,2-trifluoroacetic acid (5 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 .H 2 O = 5-95% elution) to give 8-isopropyl-N 4 -(piperidin-4-yl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (1.10 g, yield: 90.7%), LC-MS m/z: 360 [M+H] + ;
5)、(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100426
5) Synthesis of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100426
在0℃条件下，向搅拌的3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(795mg，3.88mmol)和三乙胺(925mg，9.15mmol)的N，N-二甲基甲酰胺(12mL)溶液中，滴加三光气(363mg，1.22mmol)，0℃搅拌1小时。在0℃下，将8-异丙基-N4-(哌啶-4-基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(1.10g，3.06mmol)加入到上述混合反应液中，0℃搅拌12小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3·H2O的纯水＝5-95％洗脱)纯化得到(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(1.12g，收率：62％)，LC-MS m/z：591[M+H]+；Triphosgene (363 mg, 1.22 mmol) was added dropwise to a stirred solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (795 mg, 3.88 mmol) and triethylamine (925 mg, 9.15 mmol) in N,N-dimethylformamide (12 mL) at 0°C, and stirred at 0°C for 1 hour. 8-isopropyl-N 4 -(piperidin-4-yl)-N 2 -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (1.10 g, 3.06 mmol) was added to the mixed reaction solution at 0°C, and stirred at 0°C for 12 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 ·H 2 O=5-95% elution) to give (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (1.12 g, yield: 62%), LC-MS m/z: 591 [M+H] + ;
6)、4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100427
6) Synthesis of 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100427
在室温条件下，(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，0.339mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(140mg，收率：84.5％)，LC-MS m/z：491[M+H]+；2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (200 mg, 0.339 mmol) in dichloromethane (1.2 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 .H 2 O = 5-95% elution) to give 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (140 mg, yield: 84.5%), LC-MS m/z: 491 [M+H] + ;
7)、4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100428
7) Synthesis of 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100428
将溶有4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.16mmol)，(E)-4-(二甲氨基)丁-2-烯酸(40.6mg，0.24mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(92.9mg，0.24mmol)和N，N-二异丙基乙胺(63.1mg，0.49mmol)的N，N-二甲基甲酰胺(1.2mL)室温搅拌2小时。将混合反应液通过C18反相柱色谱(乙腈∶含 有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(41mg，收率：41.1％)，LC-MS m/z：602[M+H]+；4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (80 mg, 0.16 mmol), (E)-4-(dimethylamino)but-2-enoic acid (40.6 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92.9 mg, 0.24 mmol) and N,N-diisopropylethylamine (63.1 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (1.2 mL) and stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 reverse phase column chromatography (acetonitrile: The product was purified by eluting with pure water containing 0.1% NH 3 .H 2 O = 5-95% (eluted with 5% NH 3 .H 2 O) to give (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (41 mg, yield: 41.1%), LC-MS m/z: 602 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.65(s，1H)，6.81(dt，J＝15.4，6.5Hz，1H)，6.24-6.15(m，1H)，4.53-4.37(m，4H)，4.25-4.01(m，6H)，3.98-3.95(m，2H)，3.57-3.50(m，2H)，3.13(d，J＝6.3Hz，2H)，3.03-2.96(m，3H)，2.26(d，J＝7.7Hz，6H)，2.08-1.96(m，4H)，1.67-1.52(m，4H)，1.26(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.65 (s, 1H), 6.81 (dt, J=15.4, 6.5Hz, 1H), 6.24-6.15 (m, 1H), 4.53-4.37 (m, 4H) , 4.25-4.01 (m, 6H), 3.98-3.95 (m, 2H), 3.57-3.50 (m, 2H), 3.13 (d, J=6.3Hz, 2H), 3.03-2.96 (m, 3H), 2.26 (d, J=7.7Hz, 6H), 2.08-1.96 (m, 4H), 1.67-1.52 (m, 4H), 1.26 (d, J=6.9Hz, 6H).
实施例100、4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C2-234)的合成：
Figure PCTCN2024077920-ftappb-I100429
Example 100, Synthesis of 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidine-3-yl)methyl ester (Compound C2-234):
Figure PCTCN2024077920-ftappb-I100429
将溶有4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.16mmol)，丁-2-炔酸(20.5mg，0.24mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(92.9mg，0.24mmol)和N，N-二异丙基乙胺(63.1mg，0.49mmol)的N，N-二甲基甲酰胺(1.2mL)室温搅拌2小时。将混合反应液通过C18反相柱色谱(乙腈∶含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到4-((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(丁-2-炔酰基)-3-氟氮杂环丁烷-3-基)甲基酯(31mg，收率：34.3％)，LC-MS m/z：557[M+H]+；A solution of (3-fluoroazetidyl)methyl 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (80 mg, 0.16 mmol), but-2-ynoic acid (20.5 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92.9 mg, 0.24 mmol) and N,N-diisopropylethylamine (63.1 mg, 0.49 mmol) in N,N-dimethylformamide (1.2 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 .H 2 O = 5-95% elution) to give 4-((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(but-2-ynyl)-3-fluoroazetidin-3-yl)methyl ester (31 mg, yield: 34.3%), LC-MS m/z: 557 [M+H] + ;
1H NMR：(400MHz，MeOD-d4)δ7.65(s，1H)，4.48-4.30(m，4H)，4.26-4.01(m，6H)，3.97(dt，J＝11.5，3.4Hz，2H)，3.54(td，J＝11.5，1.9Hz，2H)，3.14-2.96(m，3H)，2.07(d，J＝11.3Hz，2H)，2.02(s，4H)，1.99(s，1H)，1.691.53(m，4H)，1.27(d，J＝6.9Hz，6H).1H NMR: (400MHz, MeOD-d4) δ7.65 (s, 1H), 4.48-4.30 (m, 4H), 4.26-4.01 (m, 6H), 3.97 (dt, J=11.5, 3.4Hz, 2H) , 3.54 (td, J=11.5, 1.9Hz, 2H), 3.14-2.96 (m, 3H), 2.07 (d, J=11.3Hz, 2H), 2.02 (s, 4H), 1.99 (s, 1H), 1.691.53 (m, 4H), 1.27 (d, J=6.9Hz, 6H).
实施例101、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物101)的合成：Example 101, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate (Compound 101):
1)、5，7-二氯-3-异丙基-3H-咪唑并[4，5-b]吡啶的合成
Figure PCTCN2024077920-ftappb-I100430
1) Synthesis of 5,7-dichloro-3-isopropyl-3H-imidazo[4,5-b]pyridine
Figure PCTCN2024077920-ftappb-I100430
将溶有5，7-二氯-3H-咪唑并[4，5-b]吡啶(1g，5.32mmol)，2-溴丙烷(1.50g，12.24mmol)和碳酸二钾(2.21g，15.96mmol)的N，N-二甲基甲酰胺(10mL)溶液加热60℃搅拌12小时。将混合反应液过滤，二氯甲烷洗涤滤饼，收集滤液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-15％洗脱)纯化得到5，7-二氯-3-异丙基-3H-咪唑并[4，5-b]吡啶(910mg，收率：74.4％)，LC-MS m/z：230[M+H]+；A solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (1 g, 5.32 mmol), 2-bromopropane (1.50 g, 12.24 mmol) and dipotassium carbonate (2.21 g, 15.96 mmol) in N,N-dimethylformamide (10 mL) was heated at 60°C and stirred for 12 hours. The mixed reaction liquid was filtered, the filter cake was washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-15% elution) to give 5,7-dichloro-3-isopropyl-3H-imidazo[4,5-b]pyridine (910 mg, yield: 74.4%), LC-MS m/z: 230 [M+H] + ;
2)、4-((5-氯-3-异丙基-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100431
2) Synthesis of tert-butyl 4-((5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100431
将溶有5，7-二氯-3-(丙-2-基)-3H-咪唑并[4，5-b]吡啶(900mg，3.91mmol)和4-氨基哌啶-1-羧酸叔丁酯(2350mg，11.73mmol)反应液加热180℃搅拌4小时。混合反应液通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-60％洗脱)纯化得到4-((5-氯-3-异丙基-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯(500mg，收率：32.5％)，LC-MS m/z：394[M+H]+；The reaction solution containing 5,7-dichloro-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridine (900 mg, 3.91 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2350 mg, 11.73 mmol) was heated at 180°C and stirred for 4 hours. The mixed reaction solution was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-60% elution) to obtain tert-butyl 4-((5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate (500 mg, yield: 32.5%), LC-MS m/z: 394[M+H] + ;
3)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2024077920-ftappb-I100432
3) Synthesis of tert-butyl 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate
Figure PCTCN2024077920-ftappb-I100432
将溶有4-((5-氯-3-异丙基-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯(500mg，1.27mmol)，四氢-2H-吡喃-4-胺(190mg，1.91mmol)，(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(110mg，0.13mmol)和碳酸铯(1240mg，3.81mmol)的1，4-二氧六环(6mL)溶液加热100℃搅拌2小时。将混合反应液通过C18柱色谱(乙腈纯水＝0-80％洗脱)纯化得到4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯(360mg，收率：61.8％)。LC-MS m/z：459[M+H]+；A solution of tert-butyl 4-((5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate (500 mg, 1.27 mmol), tetrahydro-2H-pyran-4-amine (190 mg, 1.91 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (110 mg, 0.13 mmol) and cesium carbonate (1240 mg, 3.81 mmol) in 1,4-dioxane (6 mL) was heated at 100°C and stirred for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile pure water = 0-80% elution) to obtain tert-butyl 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate (360 mg, yield: 61.8%). LC-MS m/z: 459 [M+H] + ;
4)、3-异丙基-N7-(哌啶-4-基)-N5-(四氢-2H-吡喃-4-基)-3H-咪唑并[4，5-b]吡啶-5，7-二胺的合成
Figure PCTCN2024077920-ftappb-I100433
4) Synthesis of 3-isopropyl-N 7 -(piperidin-4-yl)-N 5 -(tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridine-5,7-diamine
Figure PCTCN2024077920-ftappb-I100433
将溶有4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸叔丁酯(355mg，0.77mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化，LC-MS m/z：359[M+H]+；A solution of tert-butyl 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylate (355 mg, 0.77 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification, LC-MS m/z: 359 [M+H] + ;
5)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
Figure PCTCN2024077920-ftappb-I100434
5) Synthesis of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
Figure PCTCN2024077920-ftappb-I100434
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(260mg，1.26mmol)，三乙胺(250mg，2.52mmol)和二(1H-1，2，4-三唑-1-基)甲酮(280mg，1.68mmol)的N，N-二甲基甲酰胺(2mL)溶液氮气保护下，室温搅拌0.5小时。然后将3-异丙基-N7-(哌啶-4-基)-N5-(四氢-2H-吡喃-4-基)-3H-咪唑并[4，5-b]吡啶-5，7-二胺(300mg，0.84mmol)加入到上述混合反应液中。所得混合反应液加热80℃搅拌16小时。将混合反应液过滤减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-95％洗脱)纯化得到4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，收率：40.5％)，LC-MS m/z：590[M+H]+；A solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (260 mg, 1.26 mmol), triethylamine (250 mg, 2.52 mmol) and di(1H-1,2,4-triazol-1-yl)methanone (280 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 hours under nitrogen protection. Then 3-isopropyl-N 7 -(piperidin-4-yl)-N 5 -(tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridine-5,7-diamine (300 mg, 0.84 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was heated at 80° C. and stirred for 16 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-95% elution) to give 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (200 mg, yield: 40.5%), LC-MS m/z: 590 [M+H] + ;
6)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
6) Synthesis of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(290mg，0.49mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅拌1小时。所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：490[M+H]+；A solution of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (290 mg, 0.49 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 490 [M+H] + ;
7)、4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
7) Synthesis of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(200mg，0.41mmol)，(E)-4-(二甲氨基)丁-2-烯酸(79mg，0.61mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(230mg，0.61mmol)和N，N-二异丙基乙胺(160mg，1.23mmol)的N，N-二甲基甲酰胺(1mL)溶液的室温25℃搅拌1小时。将混合反应液加水淬灭，并用乙酸乙酯(3×200mL)萃取。合并的有机相用饱和食盐水(1×100ml)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱(乙腈∶水＝0-95％)洗脱)纯化得到4-((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)-3H-咪唑并[4，5-b]吡啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(60mg，收率：24.5％)，LC-MS m/z：601[M+H]+；A solution of 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (200 mg, 0.41 mmol), (E)-4-(dimethylamino)but-2-enoic acid (79 mg, 0.61 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.61 mmol) and N,N-diisopropylethylamine (160 mg, 1.23 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature at 25° C. for 1 hour. The mixed reaction solution was quenched by adding water and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with saturated brine (1×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: water = 0-95%) to give 4-((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (60 mg, yield: 24.5%), LC-MS m/z: 601 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.77(s，1H)，6.85-6.78(m，1H)，6.20(d，J＝15.6Hz，1H)，5.64(s，1H)，4.73-4.69(m，1H)，4.53-4.37(m，4H)，4.21-4.16(m，2H)，4.06-3.97(m，4H)，3.97-3.94(m，1H)，3.73-3.68(m，1H)，3.58-3.53(m，2H)，3.18-3.12(m，4H)，2.25(s，6H)，2.05(t，J＝10.8Hz，4H)，1.55(d，J＝8.0Hz，6H)，1.54-1.42(m，4H). 1 H NMR (400MHz, MeOD-d4): δ7.77 (s, 1H), 6.85-6.78 (m, 1H), 6.20 (d, J=15.6Hz, 1H), 5.64 (s, 1H), 4.73- 4.69(m, 1H), 4.53-4.37(m, 4H), 4.21-4.16(m, 2H), 4.06-3.97 (m, 4H), 3.97-3.94 (m, 1H), 3.73-3.68 (m, 1H), 3.58-3.53 (m, 2H), 3.18-3.12 (m, 4H), 2.25 (s, 6H), 2.05 (t, J=10.8Hz, 4H), 1.55 (d, J=8.0Hz, 6H), 1.54-1.42 (m, 4H).
实施例102、4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物102)的合成：Example 102, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound 102):
1)、4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
1) Synthesis of tert-butyl 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有7-氯-3-(丙-2-基)-5-(三氟甲基)吡唑并[1，5-a]嘧啶(500mg，1.90mmol)，N，N-二异丙乙胺(740mg，5.7mmol)和4-氨基哌啶-1-羧酸叔丁酯(0.76g，3.8mmol)的异丙醇(10mL)溶液，加热90℃搅拌16小时。将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-25％洗脱)纯化得到4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(680mg，收率：83.88％)，LC-MS m/z：428[M+H]+；A solution of 7-chloro-3-(propan-2-yl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (500 mg, 1.90 mmol), N,N-diisopropylethylamine (740 mg, 5.7 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.76 g, 3.8 mmol) in isopropanol (10 mL) was heated at 90° C. and stirred for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give tert-butyl 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (680 mg, yield: 83.88%), LC-MS m/z: 428[M+H] + ;
2)、3-异丙基-N-(哌啶-4-基)-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-胺的合成
2) Synthesis of 3-isopropyl-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-amine
将溶有4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(400mg，0.94mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液中，室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：328[M+H]+；A solution of tert-butyl 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (400 mg, 0.94 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 328 [M+H] + ;
3)、4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(0.19g，0.92mmol)，1，1′-羰基二(1，2，4-三唑)(300mg，1.84mmol)和三乙胺(280mg，2.76mmol)的N，N-二甲基甲酰胺(5mL)溶液，室温搅拌1小时，然后将3-异丙基-N-(哌啶-4-基)-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-胺(300mg，0.92mmol)加入到上述混合反应液中，氩气保护下，加热80℃搅拌16小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱(甲醇∶二氯甲烷＝0-5％洗脱)纯化得到4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(458mg，收率：89.5％)，LC-MS m/z：559[M+H]+；A solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (0.19 g, 0.92 mmol), 1,1′-carbonylbis(1,2,4-triazole) (300 mg, 1.84 mmol) and triethylamine (280 mg, 2.76 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour, and then 3-isopropyl-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.92 mmol) was added to the mixed reaction solution, and heated at 80° C. under argon protection and stirred for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-5% elution) to give 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (458 mg, yield: 89.5%), LC-MS m/z: 559 [M+H] + ;
4)、4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3- 氟氮杂环丁烷-3-基)甲基酯(110mg，0.20mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化.LC-MS m/z：459[M+H]+；4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3- A solution of 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 459 [M+H] + ;
5)、4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.17mmol)，N，N，N’，N’-四甲基氯甲脒六氟磷酸盐(95mg，0.34mmol)1-甲基-1H-咪唑(56mg，0.68mmol)和(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(0.042g，0.26mmol)的N，N-二甲基甲酰胺(1mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶水＝5-95％洗脱)纯化得到4-((3-异丙基-5-(三氟甲基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(2.82mg，收率：2.84％)，LC-MS m/z：570[M+H]+；A solution of 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (80 mg, 0.17 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (95 mg, 0.34 mmol), 1-methyl-1H-imidazole (56 mg, 0.68 mmol) and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.042 g, 0.26 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: water = 5-95% elution) to give (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (2.82 mg, yield: 2.84%), LC-MS m/z: 570 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.76(s，1H)，6.79-6.72(m，1H)，6.61(s，1H)，6.44-4.40(m，1H)，4.58-4.48(m，2H)，4.47-4.42(m，2H)，4.31-4.11(m，3H)，4.07-4.02(m，2H)，3.71(d，J＝8.0Hz，2H)，3.14-3.07(m，3H)，2.71(s，6H)，2.13-2.09(m，2H)，1.53-1.49(m，2H)，1.32(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.76 (s, 1H), 6.79-6.72 (m, 1H), 6.61 (s, 1H), 6.44-4.40 (m, 1H), 4.58-4.48 ( m, 2H), 4.47-4.42 (m, 2H), 4.31-4.11 (m, 3H), 4.07-4.02 (m, 2H), 3.71 (d, J=8.0Hz, 2H), 3.14-3.07 (m, 3H), 2.71 (s, 6H), 2.13-2.09 (m, 2H), 1.53-1.49 (m, 2H), 1.32 (d, J=8.0Hz, 6H).
实施例103、4-((2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-((E)-4-((二甲胺基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-214)的合成：Example 103, Synthesis of 4-((2-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-((E)-4-((dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester (Compound C4-214):
1)、4-((2-(((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基基)哌啶-1-甲酸叔丁酯的合成
1) Synthesis of tert-butyl 4-((2-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
将溶有4-((8-异丙基-2-(甲基磺酰基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯(200mg，0.456mol)，(1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-胺(186mg，1.88mol)，N，N-二异丙基乙胺(180mg，1.39mol)的异丙醇(4mL)溶液加热70℃搅拌12小时，冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到4-((2-(((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基基)哌啶-1-甲酸叔丁酯(180mg，收率：86％)，LC-MS m/z：458[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazol[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (200 mg, 0.456 mol), (1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-amine (186 mg, 1.88 mol), and N,N-diisopropylethylamine (180 mg, 1.39 mol) in isopropanol (4 mL) was heated at 70° C. and stirred for 12 hours. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give tert-butyl 4-((2-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (180 mg, yield: 86%), LC-MS m/z: 458 [M+H] + ;
2)、N2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)-8-异丙基-N4-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
2) Synthesis of N 2 -((1R, 5S, 6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-8-isopropyl-N 4 -(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
将溶有4-((2-(((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基基)哌啶-1-甲酸叔丁酯(150mg，0.33mmol)的二氯甲烷(2mL)和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-35％洗脱)纯化得到N2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)-8-异丙基-N4-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(94mg，收率：80％)，LC-MS m/z：358[M+H]+；A solution of tert-butyl 4-((2-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (150 mg, 0.33 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35% elution) to give N 2 -((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-8-isopropyl-N 4 -(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (94 mg, yield: 80%), LC-MS m/z: 358 [M+H] + ;
3)、4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of 4-((2-((((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有N2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)-8-异丙基-N4-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(180mg，0.50mmol)，3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(207mg，1.01mmol)，N，N′-羰基二(1，2，4-三氮唑)(166mg，1.01mmol)和三乙胺(204mg，2.02mmol)的N，N-二甲基甲酰胺(3mL)溶液加热80℃搅拌16小时。冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(150mg，收率：50.7％)，LC-MS m/z：589[M+H]+；A solution of N 2 -((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-8-isopropyl-N 4 -(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (180 mg, 0.50 mmol), tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (207 mg, 1.01 mmol), N,N′-carbonylbis(1,2,4-triazole) (166 mg, 1.01 mmol) and triethylamine (204 mg, 2.02 mmol) in N,N-dimethylformamide (3 mL) was heated at 80° C. and stirred for 16 hours. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give 4-((2-((((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (150 mg, yield: 50.7%), LC-MS m/z: 589 [M+H] + ;
4)、4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of 4-((2-((((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(100mg，0.17mmol)的二氯甲烷(2mL)和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-35％洗脱)纯化得到4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(70mg，收率：84％)。LC-MS m/z：489[M+H]+；A solution of 4-((2-((((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (100 mg, 0.17 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35% elution) to give 4-((2-((((1R, 5S, 6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (70 mg, yield: 84%). LC-MS m/z: 489[M+H] + ;
5)、4-((2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-((E)-4-((二甲胺基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of 4-((2-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-((E)-4-((dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有4-((2-((((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.08mmol)，(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(26mg，0.16mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(59mg，0.16mmol)和N，N-二异丙基乙胺(66mg，0.51mmol)的N，N-二甲基甲酰胺(3ml)，室温搅拌16小时。将所得混合反应液在减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-35％洗脱)纯化得到4-((2-((1R，5S，6r)-3-氧杂双环[3.1.0]己烷-6-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-((E)-4-((二甲胺基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(34mg，收率：70％)，LC-MS m/z：600[M+H]+；4-((2-((((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (40 mg, 0.08 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (26 mg, 0.16 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.16 mmol) and N,N-diisopropylethylamine (66 mg, 0.08 mmol) were dissolved in a flask. .51mmol) of N,N-dimethylformamide (3ml), stirred at room temperature for 16 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35% elution) to give 4-((2-((1R, 5S, 6r)-3-oxabicyclo[3.1.0]hexane-6-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-((E)-4-((dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (34mg, yield: 70%), LC-MS m/z: 600[M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.91(s，1H)，6.79-6.68(m，1H)，6.52-6.48(m，1H)，4.58-4.40(m，4H)，4.31(s，1H)，4.29-4.12(m，4H)，4.02(s，2H)，3.94(d，J＝7.3Hz，2H)，3.78(d，J＝8.0Hz，2H)，2.99(s，3H)，2.90(s，6H)，2.70(s，1H)，2.05(s，4H)，1.74(s，2H)，1.29(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.91 (s, 1H), 6.79-6.68 (m, 1H), 6.52-6.48 (m, 1H), 4.58-4.40 (m, 4H), 4.31 ( s, 1H), 4.29-4.12 (m, 4H), 4.02 (s, 2H), 3.94 (d, J=7.3Hz, 2H), 3.78 (d, J=8.0Hz, 2H), 2.99 (s, 3H ), 2.90 (s, 6H), 2.70 (s, 1H), 2.05 (s, 4H), 1.74 (s, 2H), 1.29 (d, J = 8.0Hz, 6H).
实施例104、(S)-4-((8-异丙基-2-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-213)的合成：Example 104, Synthesis of (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester (Compound C4-213):
1)、(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
1) Synthesis of tert-butyl (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
将溶有4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(200mg，0.46mmol)，(S)-4-氨基吡咯烷-2-酮(186mg，1.86mmol)，N，N-二异丙基乙胺(180mg，1.37mmol)的异丙醇(4mL)溶液，加热70℃搅拌12小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(180mg，收率：86％)，LC-MS m/z：459[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (200 mg, 0.46 mmol), (S)-4-aminopyrrolidin-2-one (186 mg, 1.86 mmol), and N,N-diisopropylethylamine (180 mg, 1.37 mmol) in isopropanol (4 mL) was heated at 70° C. and stirred for 12 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give (S)-tert-butyl 4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (180 mg, yield: 86%), LC-MS m/z: 459 [M+H] + ;
2)、(R)-4-((8-异丙基-4-(哌啶-4-基氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氨基)吡咯烷-2-酮的合成
2) Synthesis of (R)-4-((8-isopropyl-4-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazine-2-yl)amino)pyrrolidin-2-one
将溶有(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(150mg，0.33mmol)的二氯甲烷(2mL)和2，2，2-三氟乙酸(0.5mL)溶液，室温搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱法(乙腈∶纯水＝0-35％)洗脱)纯化得到(S)-4-((8-异丙基-4-(哌啶-4-基氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氨基)吡咯烷-2-酮(94mg，收率：80％)，LC-MS m/z：359[M+H]+；A solution of (S)-tert-butyl 4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (150 mg, 0.33 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35%) to give (S)-4-((8-isopropyl-4-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)pyrrolidin-2-one (94 mg, yield: 80%), LC-MS m/z: 359 [M+H] + ;
3)、(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有(S)-4-((8-异丙基-4-(哌啶-4-基氨基)吡唑并[1，5-a][1，3，5]三嗪-2-基)氨基)吡咯烷-2-酮(180mg，0.50mmol)，3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(207mg，1.01mmol)，N，N′-羰基二(1，2，4-三氮唑)(166mg，1.01mmol)和三乙胺(204mg，2.02mmol)的N，N-二甲基甲酰胺(3mL)溶液，加热80℃搅拌16小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝20-65％洗脱)纯化得到(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(150mg，收率：51％)，LC-MS m/z：590[M+H]+；A solution of (S)-4-((8-isopropyl-4-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)pyrrolidin-2-one (180 mg, 0.50 mmol), tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (207 mg, 1.01 mmol), N,N′-carbonylbis(1,2,4-triazole) (166 mg, 1.01 mmol) and triethylamine (204 mg, 2.02 mmol) in N,N-dimethylformamide (3 mL) was heated at 80° C. and stirred for 16 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to give (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (150 mg, yield: 51%), LC-MS m/z: 590 [M+H] + ;
4)、(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(100mg，0.17mmol)的二氯甲烷(2mL)和2，2，2-三氟乙酸(0.5mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-35％洗脱)纯化得到(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(70mg，收率：84％)，LC-MS m/z：490[M+H]+；A solution of (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (100 mg, 0.17 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35% elution) to give (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (70 mg, yield: 84%), LC-MS m/z: 490 [M+H] + ;
5)、(S)-4-((8-异丙基-2-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有(S)-4-((8-异丙基-2-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(40mg，0.08mmol)，(E)-4-(二甲氨基)丁-2-烯酸盐酸盐(26mg，0.15mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(59mg，0.15mmol)和N，N-二异丙乙胺(66mg，0.51mmol)的N，N-二甲基甲酰胺(3mL)，室温搅拌16小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈∶纯水＝0-35％洗脱)纯化得到(S)-4-((8-异丙基-2-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(34mg，收率：70％)，LC-MS m/z：601[M+H]+；(S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester (40 mg, 0.08 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (26 mg, 0.15 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile: pure water = 0-35% elution) to give (S)-4-((8-isopropyl-2-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (34 mg, yield: 70%), LC-MS m/z: 601 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.79-6.69(m，1H)，6.52-6.48(m，1H)，4.59-4.40(m，4H)，4.31(s，1H)，4.28-4.08(m，4H)，3.94(d，J＝8.0Hz，2H)，3.84(t，J＝8.0Hz，1H)，3.51-3.43(m，1H)，3.32(s，1H)，3.14-2.97(m，3H)，2.90(s 6，H)，2.85-2.80(m，1H)，2.55(s，1H)，2.03(s，2H)，1.71(s，2H)，1.29(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d 4 ): δ7.87 (s, 1H), 6.79-6.69 (m, 1H), 6.52-6.48 (m, 1H), 4.59-4.40 (m, 4H), 4.31 ( s, 1H), 4.28-4.08 (m, 4H), 3.94 (d, J=8.0Hz, 2H), 3.84 (t, J=8.0Hz, 1H), 3.51-3.43 (m, 1H), 3.32 (s ,1H),3.14-2.97(m,3H),2.90(s 6, H), 2.85-2.80 (m, 1H), 2.55 (s, 1H), 2.03 (s, 2H), 1.71 (s, 2H), 1.29 (d, J=8.0Hz, 6H).
实施例105、(R)-4-((3-异丙基-5-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶 -1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物105)的合成：Example 105, (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine Synthesis of (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl-1-carboxylate (Compound 105):
1)、(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯的合成
1) Synthesis of tert-butyl (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
在室温条件下，向溶有4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(150mg，0.38mmol)的1，4-二氧六环(2ml)溶液中，加入(SP-4-1)-[1，3-双[2，6-双(1-乙基丙基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-亚基]二氯(2-甲基吡啶)钯(33.6mg，0.04mmol)，叔丁醇钾(0.5mL，1M的四氢呋喃溶液)和(R)-4-氨基吡咯烷-2-酮(72mg，0.72mmol)。所得混合反应液加热100℃搅拌5小时。将混合反应液用MeOH稀释，并通过通过反相C18柱色谱(乙腈：含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(S)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(120mg，收率：69％)，LC-MS m/z：458[M+H]+；To a solution of tert-butyl 4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (150 mg, 0.38 mmol) in 1,4-dioxane (2 ml) at room temperature, (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (33.6 mg, 0.04 mmol), potassium tert-butoxide (0.5 mL, 1 M tetrahydrofuran solution) and (R)-4-aminopyrrolidin-2-one (72 mg, 0.72 mmol) were added. The resulting mixed reaction solution was heated at 100° C. and stirred for 5 hours. The mixed reaction liquid was diluted with MeOH and purified by reverse phase C18 column chromatography (acetonitrile:pure water containing 0.1% NH 3 .H 2 O=5-95% elution) to obtain (S)-tert-butyl 4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (120 mg, yield: 69%), LC-MS m/z: 458 [M+H] + ;
2)、(R)-4-((3-异丙基-7-(哌啶-4-基氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)吡咯烷-2-酮的合成
2) Synthesis of (R)-4-((3-isopropyl-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidin-2-one
将溶有(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸叔丁酯(120mg，0.262mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液，室温搅拌5小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化。LC-MS m/z：358[M+H]+；A solution of (R)-tert-butyl 4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (120 mg, 0.262 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 5 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 358 [M+H] + ;
3)、(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(61.5mg，0.3mmol)的N，N-二甲基甲酰胺(1mL)溶液中，加入三乙胺(82mg，0.75mmol)，在10分钟后再加入二(1H-1，2，4-三唑-1-基)甲酮(41mg，0.25mmol)，室温搅拌0.5小时。然后将(R)-4-((3-异丙基-7-(哌啶-4-基氨基)吡唑并[1，5-a]嘧啶-5-基)氨基)吡咯烷-2-酮(90mg，0.25mmol)加入上述混合反应液中。所得混合反应液加热40℃搅拌8小时。将混合反应液加甲醇淬灭，并通过C18反相柱色谱(乙腈：含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(80mg，收率：54.4％)，LC-MS m/z：589[M+H]+； Triethylamine (82 mg, 0.75 mmol) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (61.5 mg, 0.3 mmol) in N,N-dimethylformamide (1 mL). After 10 minutes, di(1H-1,2,4-triazol-1-yl)methanone (41 mg, 0.25 mmol) was added and stirred at room temperature for 0.5 hours. Then (R)-4-((3-isopropyl-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidin-2-one (90 mg, 0.25 mmol) was added to the above mixed reaction solution. The obtained mixed reaction solution was heated at 40°C and stirred for 8 hours. The mixed reaction solution was quenched with methanol, and purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3 .H 2 O = 5-95% elution) to obtain (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (80 mg, yield: 54.4%), LC-MS m/z: 589 [M+H] + ;
4)、(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.136mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌5小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步，无需进一步纯化，LC-MS m/z：489[M+H]+；A solution of (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (80 mg, 0.136 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 5 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 489 [M+H] + ;
5)、(R)-4-((3-异丙基-5-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
向溶有(R)-4-((3-异丙基-5-((5-氧吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(60mg，0.12mmol)和(E)-4-(二甲氨基)丁-2-烯酸(31mg，0.24mmol)的N，N-二甲基甲酰胺(1.0mL)溶液中，加入N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(67.2mg，0.24mmol)和1-甲基-1H-咪唑(39.4mg，0.48mmol)，室温搅拌3小时。将混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈：含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(R)-4-((3-异丙基-5-((5-氧代吡咯烷-3-基)氨基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(5mg，收率：7.0％)，LC-MS：m/z：600[M+H]+；N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (67.2 mg, 0.24 mmol) and 1-methyl-1H-imidazole (39.4 mg, 0.48 mmol) were added to a solution of (R)-4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (60 mg, 0.12 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (31 mg, 0.24 mmol) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 .H 2 O=5-95% elution) to give (R)-(E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (5 mg, yield: 7.0%), LC-MS: m/z: 600 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.89(s，1H)，6.72(dt，J＝14.8，7.2Hz，1H)，6.53(d，J＝15.2Hz，1H)，5.55(s，1H)，4.76(dd，J＝7.2，4.0Hz，1H)，4.63-4.55(m，1H)，4.54-4.40(m，3H)，4.33-4.11(m，4H)，4.06-3.88(m，4H)，3.40(dd，J＝10.8，3.2Hz，1H)，3.22-2.86(m，10H)，2.38(dd，J＝17.2，4.0Hz，1H)，2.06(d，J＝11.6Hz，2H)，1.70(d，J＝9.2Hz，2H)，1.44-1.24(m，6H). 1 H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 6.72 (dt, J=14.8, 7.2Hz, 1H), 6.53 (d, J=15.2Hz, 1H), 5.55 (s, 1H), 4.76 (dd, J=7.2, 4.0Hz, 1H), 4.63-4.55 (m, 1H), 4.54-4.40 (m, 3H), 4.33- 4.11(m, 4H), 4.06-3.88(m, 4H), 3.40(dd, J＝10.8, 3.2Hz, 1H), 3.22-2.86(m, 10H), 2.38(dd, J＝17.2, 4.0Hz, 1H), 2.06 (d, J=11.6Hz, 2H), 1.70 (d, J=9.2Hz, 2H), 1.44-1.24 (m, 6H).
实施例106、4-(3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-258)的合成：Example 106, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-258):
1)、(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯的合成
1) Synthesis of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(100mg，0.19mmol)和4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶(116.88mg，0.57mmol)和碳酸钾(78.78mg，0.57mol)和1，1′-二(二苯膦基)二茂铁二氯化钯(II)(12.38mg，0.019mmol)的水(0.2mL)和1，4-二氧六环(0.8mL)溶液氮气保护下，加热90℃搅拌16小时。冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱(乙酸乙酯∶石油醚＝0～25％洗脱)纯化得到(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(78mg，收率：72.14％)，LC-MS m/z：568[M+H]+；A solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (100 mg, 0.19 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (116.88 mg, 0.57 mmol), potassium carbonate (78.78 mg, 0.57 mol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (12.38 mg, 0.019 mmol) in water (0.2 mL) and 1,4-dioxane (0.8 mL) was heated at 90° C. and stirred for 16 hours under nitrogen protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (78 mg, yield: 72.14%), LC-MS m/z: 568 [M+H] + ;
2)、(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯的合成
2) Synthesis of (3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(78mg，0.14mmol)和2，2，2-三氟乙酸(0.3mL)的二氯甲烷(0.9mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：468[M+H]+；A solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (78 mg, 0.14 mmol) and 2,2,2-trifluoroacetic acid (0.3 mL) in dichloromethane (0.9 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 468 [M+H] + ;
3)、4-(3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(40mg，0.086mmol)和(2E)-4-(二甲基氨基)丁-2-烯酸(13.33mg，0.10mmol)的HATU(49mg，0.13mmol)和DIEA(33.34mg，0.26mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN∶H2O(0.1％FA)＝60-95％洗脱)纯化得到(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(吡啶-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(8mg，收率：16.16％)，LC-MS m/z：579[M+H]+；A solution of (3-fluoroazetidin-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (40 mg, 0.086 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid (13.33 mg, 0.10 mmol) in HATU (49 mg, 0.13 mmol) and DIEA (33.34 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% FA) = 60-95% elution) to give (3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (8 mg, yield: 16.16%), LC-MS m/z: 579 [M+H]+;
1H NMR(400MHz，MeOD)δ8.67(d，J＝5.7Hz，2H)，8.18(d，J＝6.2Hz，2H)，7.96(s，1H)，6.81-6.73(m，2H)，6.38(d，J＝15.3Hz，1H)，4.58-4.40(m，4H)，4.31-4.04(m，5H)，3.62(d，J＝6.8Hz，2H)，3.35(dd，J＝13.0，6.0Hz，1H)，3.15(d，J＝17.7Hz，2H)，2.63(s，6H)，2.15(d，J＝12.1Hz，2H)，1.68(d，J＝10.1Hz，2H)，1.42(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ8.67 (d, J=5.7Hz, 2H), 8.18 (d, J=6.2Hz, 2H), 7.96 (s, 1H), 6.81-6.73 (m, 2H), 6.38(d, J=15.3Hz, 1H), 4.58-4.40(m, 4H), 4.31-4.04(m, 5H), 3.62 (d, J=6.8Hz, 2H), 3.35 (dd, J=13.0, 6.0Hz, 1H), 3.15 (d, J=17.7Hz, 2H), 2.63 (s, 6H), 2.15 (d, J =12.1Hz, 2H), 1.68 (d, J = 10.1Hz, 2H), 1.42 (d, J = 6.9Hz, 6H).
实施例107、4-(3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-234)的合成： Example 107, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-234):
1)、4-((3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
1) Synthesis of 4-((3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(100mg，0.19mmol)和2-甲氧基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)嘧啶(134.57mg，0.57mmol)和碳酸钾(78.78mg，0.57mol)和二氯(1，1-双(二叔丁基膦)二茂铁)钯(II)(13.87mg，0.019mmol)的水(0.2mL)和1，4-二氧六环(0.8mL)溶液氮气保护下，加热90℃搅拌16小时。冷却后，将混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0～25％洗脱)纯化得到4-((3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(110mg，收率：96.47％)，LC-MS m/z：599[M+H]+；A solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (100 mg, 0.19 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (134.57 mg, 0.57 mmol), potassium carbonate (78.78 mg, 0.57 mol), and dichloro(1,1-bis(di-tert-butylphosphino)ferrocene)palladium(II) (13.87 mg, 0.019 mmol) in water (0.2 mL) and 1,4-dioxane (0.8 mL) was heated at 90° C. and stirred for 16 hours under nitrogen protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to give 4-((3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (110 mg, yield: 96.47%), LC-MS m/z: 599 [M+H] + ;
2)、4-((3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
2) Synthesis of 4-((3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(110mg，0.18mmol)的二氯甲烷(0.9mL)和2，2，2-三氟乙酸(0.3mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：499[M+H]+；A solution of 4-((3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (110 mg, 0.18 mmol) in dichloromethane (0.9 mL) and 2,2,2-trifluoroacetic acid (0.3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 499 [M+H] + ;
3)、4-(3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有4-((3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(50mg，0.1mmol)和(2E)-4-(二甲基氨基)丁-2-烯酸(15.5mg，0.12mmol)，HATU(57.03mg，0.15mmol)和DIEA(38.77mg，0.3mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN∶H2O(0.1％FA)＝60-95％洗脱)纯化得到4-(3-异丙基-5-(2-甲氧基嘧啶-5-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收率：32.71％)，LC-MS m/z：610[M+H]+；A solution of (3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.1 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (15.5 mg, 0.12 mmol), HATU (57.03 mg, 0.15 mmol) and DIEA (38.77 mg, 0.3 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN: H 2 O (0.1% FA)=60-95% elution) to give (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-(3-isopropyl-5-(2-methoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (20 mg, yield: 32.71%), LC-MS m/z: 610 [M+H] + ;
1H NMR(400MHz，MeOD)δ9.28(s，2H)，7.93(s，1H)，6.78(dt，J＝14.0，6.8Hz，1H)，6.67(s，1H)，6.37(d，J＝15.4Hz，1H)，4.56-4.40(m，4H)，4.32-4.11(m，4H)，4.11-4.03(m，4H)，3.58(d，J＝7.5Hz，2H)，3.36-3.32(m，1H)，3.13(d，J＝1.7Hz，2H)，2.61(d，J＝6.6Hz，6H)，2.14(d，J＝11.3Hz，2H)，1.67(d，J＝11.3Hz，2H)，1.40(d，J＝6.9Hz，6H). 1 H NMR (400MHz, MeOD) δ9.28 (s, 2H), 7.93 (s, 1H), 6.78 (dt, J=14.0, 6.8Hz, 1H), 6.67 (s, 1H), 6.37 (d, J =15.4Hz, 1H), 4.56-4.40(m, 4H), 4.32-4.11(m, 4H), 4.11-4.03( m, 4H), 3.58 (d, J = 7.5Hz, 2H), 3.36-3.32 (m, 1H), 3.13 (d, J = 1.7Hz, 2H), 2.61 (d, J = 6.6Hz, 6H), 2.14 (d, J=11.3Hz, 2H), 1.67 (d, J=11.3Hz, 2H), 1.40 (d, J=6.9Hz, 6H).
实施例108、(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物108)的合成：Example 108, Synthesis of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 108):
1)、(S)-4-(8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的合成
1) Synthesis of tert-butyl (S)-4-(8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
将溶有4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(600mg，1.37mmol)，(S)-2-(甲氧基甲基)吡咯烷(236mg，2.05mmol)和N，N-二异丙基乙胺(529mg，4.10mmol)的异丙醇(8mL)溶液加热90℃搅拌过夜。冷却后，将所得混合反应液加水(100mL)稀释，并用乙酸乙酯(3 x 100mL)萃取。合并的有机相用饱和食盐水(1×100mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝10-50％洗脱)纯化得到(S)-4-(8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(579mg，收率：89.4％)，LC-MS m/z：474[M+H]+；A solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (600 mg, 1.37 mmol), (S)-2-(methoxymethyl)pyrrolidine (236 mg, 2.05 mmol) and N,N-diisopropylethylamine (529 mg, 4.10 mmol) in isopropanol (8 mL) was heated at 90°C and stirred overnight. After cooling, the resulting mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to give (S)-tert-butyl 4-(8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (579 mg, yield: 89.4%), LC-MS m/z: 474 [M+H] + ;
2)、(S)-8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺的合成
2) Synthesis of (S)-8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine
在室温条件下，溶有(S)-4-(8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯(579mg，1.22mmol)的二氯甲烷(9mL)溶液中，滴加2，2，2-三氟乙酸(3mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈：含有0.1％NH3H2O的纯水＝5-95％洗脱)纯化得到(S)-8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺(418mg，收率：91.5％)，LC-MS m/z：374[M+H]+；At room temperature, 2,2,2-trifluoroacetic acid (3 mL) was added dropwise to a solution of (S)-tert-butyl 4-(8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (579 mg, 1.22 mmol) in dichloromethane (9 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 H 2 O=5-95% elution) to give (S)-8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (418 mg, yield: 91.5%), LC-MS m/z: 374 [M+H] + ;
3)、(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
在0℃条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(291mg，1.42mmol)和三乙胺(339mg，3.35mmol)的N，N-二甲基甲酰胺(8mL)溶液中，滴加三光气(133mg，0.45mmol)，0℃搅拌1小时。在0℃下，将(S)-8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)-N-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-4-胺(418mg，1.12mmol)加入上述混合反应液中，0℃搅拌12小时。将混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈：含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(356mg，收率：52.7％)，LC-MS m/z：605[M+H]+；Triphosgene (133 mg, 0.45 mmol) was added dropwise to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (291 mg, 1.42 mmol) and triethylamine (339 mg, 3.35 mmol) in N,N-dimethylformamide (8 mL) at 0°C, and stirred at 0°C for 1 hour. (S)-8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-4-amine (418 mg, 1.12 mmol) was added to the mixed reaction solution at 0°C, and stirred at 0°C for 12 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH 3 .H 2 O=5-95% elution) to give (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (356 mg, yield: 52.7%), LC-MS m/z: 605 [M+H] + ;
4)、(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
在室温下，向溶有(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(1-(叔丁氧羰基)-3-氟氮杂环丁烷-3-基)甲基酯(200mg，0.33mmol)的二氯甲烷(1.2mL)溶液中，滴加2，2，2-三氟乙酸(0.4mL)。所得混合反应液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(乙腈：含有0.1％NH3.H2O的纯水＝5-95％洗脱)纯化得到(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(149mg，收率：89.4％)，At room temperature, 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise to a solution of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butyloxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (200 mg, 0.33 mmol) in dichloromethane (1.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (acetonitrile:pure water containing 0.1% NH3.H2O=5-95% elution) to give (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (149 mg, yield: 89.4%).
LC-MS m/z：505[M+H]+；LC-MS m/z: 505 [M+H] + ;
5)、(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidine-3-yl)methyl ester
将(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.16mmol)，(E)-4-(二甲氨基)丁-2-烯酸(30.7mg，0.24mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(90.4mg，0.24mmol)和N，N-二异丙基乙胺(61.4mg，0.48mmol)的N，N-二甲基甲酰胺(1.2mL)溶液室温搅拌2小时。将混合反应液通过C18反相柱色谱(乙腈：含有0.1％NH 3.H 2 O的纯水＝5-95％洗脱)纯化得到(S)-4-((8-异丙基-2-(2-(甲氧基甲基)吡咯烷-1-基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-羧酸(E)-(1-(4-(二甲氨基)丁-2-烯酰基)-3-氟氮杂环丁烷-3-基)甲基酯(38mg，收率：38.3％)，LC-MS m/z：616[M+H]+；A solution of (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (80 mg, 0.16 mmol), (E)-4-(dimethylamino)but-2-enoic acid (30.7 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (90.4 mg, 0.24 mmol) and N,N-diisopropylethylamine (61.4 mg, 0.48 mmol) in N,N-dimethylformamide (1.2 mL) was stirred at room temperature for 2 hours. The mixed reaction liquid was purified by C18 reverse phase column chromatography (acetonitrile: pure water containing 0.1% NH 3.H 2 O = 5-95% elution) to obtain (S)-4-((8-isopropyl-2-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enoyl)-3-fluoroazetidin-3-yl)methyl ester (38 mg, yield: 38.3%), LC-MS m/z: 616 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.65(s，1H)，6.88-6.72(m，1H)，6.46-6.43(m，1H)，4.57-4.41(m，4H)，4.34-4.08(m，6H)，3.82-3.70(m，3H)，3.64-3.52(m，2H)，3.42(s，1H)，3.38(s，3H)，3.03-2.99(m，3H)，2.77-2.70(m，6H)，2.13-1.98(m，5H)，1.96-1.88(m，1H)，1.67-1.62(m，2H)，1.28(dd，J＝8.0，4.0Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.65 (s, 1H), 6.88-6.72 (m, 1H), 6.46-6.43 (m, 1H), 4.57-4.41 (m, 4H), 4.34-4.08 (m, 6H), 3.82-3.70 (m, 3H), 3.64-3.52 (m, 2H), 3.42(s, 1H), 3.38(s, 3H), 3.03-2.99(m, 3H), 2.77-2.70(m, 6H), 2.13-1.9 8(m, 5H), 1.96-1.88(m, 1H), 1.67-1.62(m, 2H), 1.28(dd, J=8.0, 4.0Hz, 6H) .
实施例109、(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(化合物C4-180)的合成：Example 109, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-180):
1)、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
1) Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
在室温条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(250mg，1.22mmol)的N，N-二甲基甲酰胺(2mL)溶液中，加入三乙胺(165mg，1.63mmol)。然后在0℃，加入N，N′-羰基二(1，2，4-三氮唑)(200mg，1.22mmol)，并在搅拌0.5小时。然后将3-异丙基-N-(哌啶-4-基)-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-胺(140mg，0.408mmol)的N，N-二甲基甲酰胺(1mL)溶液滴加到上述混合物。所得混合反应液加热40℃搅拌16小时。LCMS监测反应完全。将所得混合反应液通过C18反相柱色谱法(MeCN∶H2O (0.1％NH3.H2O)＝5-95％洗脱)纯化得到4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，收率：94％)，LC-MS m/z：575[M+H]+；Triethylamine (165 mg, 1.63 mmol) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (250 mg, 1.22 mmol) in N,N-dimethylformamide (2 mL) at room temperature. N,N′-carbonylbis(1,2,4-triazole) (200 mg, 1.22 mmol) was then added at 0°C and stirred for 0.5 hours. A solution of 3-isopropyl-N-(piperidin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (140 mg, 0.408 mmol) in N,N-dimethylformamide (1 mL) was then added dropwise to the mixture. The resulting mixed reaction solution was heated at 40°C and stirred for 16 hours. The reaction was complete when monitored by LCMS. The resulting mixed reaction solution was purified by C18 reverse phase column chromatography (MeCN: H 2 O (0.1% NH3.H2O) = 5-95% elution) to give 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (220 mg, yield: 94%), LC-MS m/z: 575 [M+H] + ;
2)、4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
2) Synthesis of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，0.383mmol)和2，2，2-三氟乙酸(1mL)的二氯甲烷(3mL)溶液室温搅拌2小时。通过LCMS监测反应完成。将混合反应液减压浓缩得到粗产物，下一步骤中直接使用，无需进一步纯化。LC-MS m/z：475.3[M+H]+；A solution of 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (220 mg, 0.383 mmol) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The reaction was monitored to completion by LCMS. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 475.3[M+H] + ;
3)、(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯的合成
3) Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl-4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(150mg，0.316mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(79mg，0.474mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(177mg，0.632mmol)和1-甲基-1H-咪唑(104mg，1.264mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌4小时。通过LCMS监测反应完成。将混合反应液通过C18反相柱色谱法(MeCN∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-(四氢-2H-吡喃-4-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(5mg，收率：2.7％)，LC-MS m/z：586[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (150 mg, 0.316 mmol), (E)-4-(dimethylamino)but-2-enoic acid (79 mg, 0.474 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (177 mg, 0.632 mmol) and 1-methyl-1H-imidazole (104 mg, 1.264 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 4 hours. The reaction was monitored for completion by LCMS. The mixed reaction liquid was purified by C18 reverse phase column chromatography (MeCN: H2O (0.1% NH3.H2O ) = 5-95% elution) to obtain (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl-4-((3-isopropyl-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (5 mg, yield: 2.7%), LC-MS m/z: 586 [M+H] + ;
1H NMR(400MHz，MeOD-d4)δ7.95(s，1H)，6.79-6.69(m，1H)，6.50(d，J＝16.0Hz，1H)，6.23(s，1H)，4.60-4.40(m，5H)，4.32-4.13(m，4H)，4.08(dd，J＝12.0，4.0Hz，2H)，4.02(s，1H)，3.93(d，J＝8.0Hz，2H)，3.58(t，J＝12.0Hz，3H)，3.28-3.22(m，2H)，2.89(s，6H)，2.09(d，J＝12.0Hz，2H)，1.99(td，J＝12.0，4.0Hz，2H)，1.87(d，J＝12.0Hz，2H)，1.67(d，J＝12.0Hz，2H)，1.34(d，J＝8.0Hz，6H). 1 H NMR (400MHz, MeOD-d4) δ7.95 (s, 1H), 6.79-6.69 (m, 1H), 6.50 (d, J=16.0Hz, 1H), 6.23 (s, 1H), 4.60-4.40 (m, 5H), 4.32-4.13 (m, 4H), 4.08 (dd, J=12.0, 4.0Hz, 2H), 4.02 (s, 1H), 3.93 (d, J=8.0 Hz, 2H), 3.58 (t, J=12.0Hz, 3H), 3.28-3.22 (m, 2H), 2.89 (s, 6H), 2.09 (d, J=12.0Hz, 2H), 1.99 (td, J =12.0, 4.0Hz, 2H), 1.87 (d, J = 12.0Hz, 2H), 1.67 (d, J = 12.0Hz, 2H), 1.34 (d, J = 8.0Hz, 6H).
实施例110、4-(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C4-127)的合成：Example 110, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-127):
1)、4-((叔丁氧基羰基)(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸叔丁酯的合成
1) Synthesis of tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有4-((叔丁氧羰基)(5-氯-3-异丙基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸叔丁酯(300mg，0.61mmol)，吡啶-3-基硼酸(112mg，0.91mmol)和Pd(dppf)Cl2(44mg，0.06mmol)和碳酸钾(251mg，1.82mmol)的1，4-二氧六环(3.2mL)和水(0.8mL)溶液氮气保护下，加100℃搅拌4小时。将混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN：H2O(0.1％FA)＝5-95％洗脱)纯化得到4-((叔丁氧基羰基)(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸叔丁酯(260mg，收率：79.78％)，LC-MS m/z：537[M+H]+；A solution of tert-butyl 4-((tert-butyloxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (300 mg, 0.61 mmol), pyridin-3-ylboronic acid (112 mg, 0.91 mmol), Pd(dppf)Cl 2 (44 mg, 0.06 mmol), and potassium carbonate (251 mg, 1.82 mmol) in 1,4-dioxane (3.2 mL) and water (0.8 mL) was stirred at 100°C for 4 hours under nitrogen protection. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN:H 2 O (0.1% FA) = 5-95% elution) to give tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (260 mg, yield: 79.78%), LC-MS m/z: 537 [M+H] + ;
2)、3-异丙基-N-(哌啶-4-基)-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-胺的合成
2) Synthesis of 3-isopropyl-N-(piperidin-4-yl)-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine
将溶有4-((叔丁氧基羰基)(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸叔丁酯(260mg，0.48mmol)的2，2，2-三氟乙酸(1mL)和二氯甲烷(3mL)溶液中，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(MeCN∶H2O(水中0.1％FA)＝5-95％洗脱)纯化3-异丙基-N-(哌啶-4-基)-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-胺(150mg，收率：92.08％)，LC-MS m/z：337[M+H]+；A solution of tert-butyl 4-((tert-butoxycarbonyl)(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (260 mg, 0.48 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN:H 2 O (0.1% FA in water) = 5-95% elution) to give 3-isopropyl-N-(piperidin-4-yl)-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, yield: 92.08%), LC-MS m/z: 337 [M+H] + ;
3)、4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of methyl 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)
室温条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(137mg，0.67mmol)和三乙胺(135mg，1.34mmol)的N，N-二甲基甲酰胺(2mL)溶液中，加入N，N′-羰基二(1，2，4-三氮唑)(219mg，1.34mmol)的N，N-二甲基甲酰胺(1.5mL)溶液，室温搅拌0.5小时。然后将3-异丙基-N-(哌啶-4-基)-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-胺(150mg，0.45mmol)的N，N-二甲基甲酰胺(1.5mL)溶液加入的到上述混合反应液中。所得混合反应液室温搅拌4小时。所得的混合反应液减压浓缩。残余物通过C18反相柱色谱(MeCN∶H2O(水中0.1％FA)＝5-95％洗脱)纯化得到4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，收率：86.93％)，LC-MS m/z：568[M+H]+；At room temperature, N, N'-carbonylbis(1,2,4-triazole) (219 mg, 1.34 mmol) in N, N-dimethylformamide (1.5 mL) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (137 mg, 0.67 mmol) and triethylamine (135 mg, 1.34 mmol) in N, N-dimethylformamide (2 mL), and stirred at room temperature for 0.5 hours. Then, a solution of 3-isopropyl-N-(piperidin-4-yl)-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-amine (150 mg, 0.45 mmol) in N, N-dimethylformamide (1.5 mL) was added to the above mixed reaction solution. The obtained mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN: H 2 O (0.1% FA in water) = 5-95% elution) to give (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (220 mg, yield: 86.93%), LC-MS m/z: 568 [M+H] + ;
4)、4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
向溶有4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，0.39mmol)的二氯甲烷(2.4mL)溶液中，添加2，2，2-三氟乙酸(0.8mL)溶液，室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(MeCN∶H2O(水中0.1％FA)＝5-95％洗脱)纯化得到4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(150mg，收率：82.78％)，LC-MS m/z：468[M+H]+；2,2,2-trifluoroacetic acid (0.8 mL) solution was added to a solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (220 mg, 0.39 mmol) in dichloromethane (2.4 mL), and the mixture was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN: H 2 O (0.1% FA in water) = 5-95% elution) to give (3-fluoroazetidin-3-yl)methyl 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (150 mg, yield: 82.78%), LC-MS m/z: 468 [M+H] + ;
5)、4-(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有4-((3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(150mg，0.32mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(80mg，0.48mmol)，HATU(183mg，0.48mmol)和DIEA(124mg，0.96mmol)的DCM(3mL)溶液室温搅拌2小时。将所得的混合反应液减压浓缩。残余物通过C反相18柱色谱(CH3CN∶H2O(0.1％NH3·H2O)＝5-95％洗脱)纯化得到4-(3-异丙基-5-(吡啶-3-基)吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(40mg，收率：21.54％)，LC-MS m/z：579[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl 4-((3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (150 mg, 0.32 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (80 mg, 0.48 mmol), HATU (183 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) in DCM (3 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C reverse phase 18 column chromatography (CH 3 CN: H 2 O (0.1% NH 3 ·H 2 O)=5-95% elution) to give (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-(3-isopropyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (40 mg, yield: 21.54%), LC-MS m/z: 579 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ9.30-9.27(m，1H)，8.63-8.55(m，2H)，7.94(s，1H)，7.60-7.55(m，1H)，6.86-6.77(m，1H)，6.71(s，1H)，6.23-6.17(m，1H)，4.52-4.40(m，4H)，4.27-4.06(m，5H)，3.35-3.33(m，1H)，3.23-3.17(m，1H)，3.16-3.12(m，3H)，2.25(s，6H)，2.19-2.11(m，2H)，1.74-1.61(m，2H)，1.42(s，3H)，1.40(s，3H). 1 H NMR (400MHz, MeOD-d4): δ9.30-9.27 (m, 1H), 8.63-8.55 (m, 2H), 7.94 (s, 1H), 7.60-7.55 (m, 1H), 6.86-6.77 (m, 1H), 6.71 (s, 1H), 6.23-6.17 (m, 1H), 4.52-4.40 (m , 4H), 4.27-4.06(m, 5H), 3.35-3.33(m, 1H), 3.23-3.17(m, 1H), 3.16-3.12(m, 3H), 2.25(s, 6H), 2.19-2.11 (m, 2H), 1.74-1.61 (m, 2H), 1.42 (s, 3H), 1.40 (s, 3H).
实施例111、(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物111)的合成：Example 111, Synthesis of (S)-(E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-((8-isopropyl-2-((1-methoxyprop-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (Compound 111):
1)、(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)哌啶-1-甲酸叔丁酯的合成
1) Synthesis of tert-butyl (S)-4-((8-isopropyl-2-((1-methoxypropyl-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
将溶有4-((8-异丙基-2-(甲基磺酰基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯(600mg，1.37mmol)，(S)-1-甲氧基丙-2-胺(180mg，2.06mmol)和N，N-二异丙基乙胺(530mg，4.11mmol)的1，4-二氧六环(8mL)溶液加热90℃搅拌16小时。冷却后，将所得混合反应液减压浓缩。残余物通过硅胶柱色谱法(乙酸乙酯∶石油醚＝0-50％洗脱)纯化得到(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)哌啶-1-甲酸叔丁酯(200mg，收率：32.7％)，LC-MS m/z：448[M+H]+； A solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (600 mg, 1.37 mmol), (S)-1-methoxypropan-2-amine (180 mg, 2.06 mmol) and N,N-diisopropylethylamine (530 mg, 4.11 mmol) in 1,4-dioxane (8 mL) was heated at 90° C. and stirred for 16 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to give (S)-tert-butyl 4-((8-isopropyl-2-((1-methoxypropan-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (200 mg, yield: 32.7%), LC-MS m/z: 448 [M+H] + ;
2)、(S)-8-异丙基-N2-(1-甲氧基丙-2-基)-N4-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
2) Synthesis of (S)-8-isopropyl-N 2 -(1-methoxyprop-2-yl)-N 4 -(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
将溶有(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)胺基)哌啶-1-甲酸叔丁酯(190mg，0.42mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：348[M+H]+；A solution of (S)-tert-butyl 4-((8-isopropyl-2-((1-methoxypropyl-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (190 mg, 0.42 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 348 [M+H] + ;
3)、(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (S)-4-((8-isopropyl-2-((1-methoxypropyl-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
将溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(180mg，0.87mmol)，三乙胺(180mg、1.74mmol)和N，N′-羰基二(1，2，4-三氮唑)(190mg，1.16mmol)的N，N-二甲基甲酰胺(2mL)溶液氮气保护下室温搅拌0.5小时。然后将(S)-8-异丙基-N2-(1-甲氧基丙-2-基)-N4-(哌啶-4-基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(200mg，0.58mmol)加入到上述混合反应液中。所得混合反应液加热80℃搅拌16小时。将混合反应液减压浓缩。残余物通过C18柱色谱法(ACN∶H2O＝0-95％洗脱)纯化得到(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(240mg，收率：72.1％)，LC-MS m/z：579[M+H]+；A solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (180 mg, 0.87 mmol), triethylamine (180 mg, 1.74 mmol) and N,N′-carbonylbis(1,2,4-triazole) (190 mg, 1.16 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 hours under nitrogen protection. Then (S)-8-isopropyl-N 2 -(1-methoxyprop-2-yl)-N 4 -(piperidin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (200 mg, 0.58 mmol) was added to the above mixed reaction liquid. The obtained mixed reaction liquid was heated at 80° C. and stirred for 16 hours. The mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (ACN: H 2 O=0-95% elution) to give (S)-(1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((1-methoxypropan-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (240 mg, yield: 72.1%), LC-MS m/z: 579 [M+H] + ;
4)、(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of (S)-4-((8-isopropyl-2-((1-methoxypropyl-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(230mg，0.40mmol)的二氯甲烷(6mL)和2，2，2-三氟乙酸(2mL)溶液室温搅拌1小时。将所得混合反应液减压浓缩得到粗产物直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：479[M+H]+；A solution of (S)-4-((8-isopropyl-2-((1-methoxypropyl-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (230 mg, 0.40 mmol) in dichloromethane (6 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was directly used in the next step without further purification. LC-MS m/z: 479 [M+H] + ;
5)、(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of (S)-4-((8-isopropyl-2-((1-methoxypropan-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl ester
将溶有(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(150mg，0.31mmol)，(E)-4-(二甲基氨基)丁-2-烯酸(60mg，0.46mmol)，1-甲基-1H-咪唑(100mg，1.24mmol)和N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(170mg，0.62mol)的N，N-二甲基甲酰胺(3mL)溶液室温搅拌16小时。残留物通过C18柱色谱法(MeCN∶H2O(NH4HCO3)＝0-60％洗脱)纯化得到(S)-4-((8-异丙基-2-((1-甲氧基丙-2-基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(100mg，收率：54.1％)，LC-MS m/z：590[M+H]+；A solution of (S)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((1-methoxypropan-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (150 mg, 0.31 mmol), (E)-4-(dimethylamino)but-2-enoic acid (60 mg, 0.46 mmol), 1-methyl-1H-imidazole (100 mg, 1.24 mmol) and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (170 mg, 0.62 mol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (MeCN: H2O ( NH4HCO3 )=0-60% elution) to give (S)-(E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((1-methoxypropan-2-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (100 mg, yield: 54.1%), LC-MS m/z: 590 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.89(s，1H)，6.74(dt，J＝14.4，7.2Hz，1H)，6.52(d，J＝15.2Hz，1H)，4.56-4.51(m，1H)，4.50-4.32(m，4H)，4.31-4.14(m，4H)，3.94(d，J＝7.2Hz，2H)，3.52(s，2H)，3.41(s，3H)，2.99(s，3H)，2.88(d，J＝15.6Hz，7H)，2.05(d，J＝11.2Hz，2H)，1.72(d，J＝12.0Hz，2H)，1.32(d，J＝6.8Hz，3H)，1.29(dd，J＝6.8，1.4Hz，6H). 1 H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 6.74 (dt, J=14.4, 7.2Hz, 1H), 6.52 (d, J=15.2Hz, 1H), 4.56-4.51 ( m, 1H), 4.50-4.32 (m, 4H), 4.31-4.14 (m, 4H), 3.94 (d, J=7.2Hz, 2H), 3.52(s, 2H), 3.41(s, 3H), 2.99(s, 3H), 2.88(d, J＝15.6Hz, 7H), 2.05(d, J＝11.2Hz, 2H), 1.72( d, J=12.0Hz, 2H), 1.32 (d, J=6.8Hz, 3H), 1.29 (dd, J=6.8, 1.4Hz, 6H).
实施例112、((R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物112)的合成：Example 112, Synthesis of ((R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 112):
1)、(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯的合成
1) Synthesis of tert-butyl (R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate
在室温条件下，向溶有4-((8-异丙基-2-(甲基磺酰基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯(200mg，0.46mmol)的乙腈(4mL)溶液中，加入N，N-二甲丙基乙胺(177mg，1.37mmol)和(R)-1-(吡啶-4-基)乙烷-1-胺(83mg，0.68mmol)。所得混合反应液加热60℃搅拌16小时。将混合反应液通过C18反相柱色谱(CH3CN∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯(180mg，收率：82％)，LC-MS m/z：481[M+H]+；At room temperature, N,N-dimethylpropylethylamine (177 mg, 1.37 mmol) and (R)-1-(pyridin-4-yl)ethane-1-amine (83 mg, 0.68 mmol) were added to a solution of tert-butyl 4-((8-isopropyl-2-(methylsulfonyl)pyrazol[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylate (200 mg, 0.46 mmol) in acetonitrile (4 mL). The resulting mixed reaction solution was heated at 60° C. and stirred for 16 hours. The mixed reaction liquid was purified by C18 reverse phase column chromatography (CH 3 CN:H 2 O (0.1% NH 3 .H 2 O)=5-95% elution) to obtain (R)-tert-butyl 4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (180 mg, yield: 82%), LC-MS m/z: 481[M+H] + ;
2)、(R)-8-异丙基-N4-(哌啶-4-基)-N2-(1-(吡啶-4-基)乙基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺的合成
2) Synthesis of (R)-8-isopropyl-N 4 -(piperidin-4-yl)-N 2 -(1-(pyridin-4-yl)ethyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
将溶有(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸叔丁酯(180mg，0.39mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌5小时。将所得的混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：381[M+H]+； A solution of (R)-tert-butyl 4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazol[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (180 mg, 0.39 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 5 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 381 [M+H] + ;
3)、(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
在室温条件下，向溶有(R)-8-异丙基-N4-(哌啶-4-基)-N2-(1-(吡啶-4-基)乙基)吡唑并[1，5-a][1，3，5]三嗪-2，4-二胺(130mg，0.34mmol)的N，N-二甲基甲酰胺(1mL)溶液中，加入三乙胺(106mg，1.05mmol)和N，N′-羰基二(1，2，4-三氮唑)(57.4mg，0.35mol)。所得混合反应液室温搅拌0.5小时。然后将3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(72mg，0.35mmol)加入到上述混合反应中。所得混合反应液加热40℃搅拌8小时。将混合反应液用MeOH稀释，并通过C18反相柱色谱(乙腈∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(80mg，收率：38.2％)，LC-MS m/z：612[M+H]+；Triethylamine (106 mg, 1.05 mmol) and N,N′-carbonylbis(1,2,4-triazole) (57.4 mg, 0.35 mol) were added to a solution of (R)-8-isopropyl-N 4 -(piperidin-4-yl)-N 2 -(1-(pyridin-4-yl)ethyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. Then tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (72 mg, 0.35 mmol) was added to the above mixed reaction solution. The resulting mixed reaction solution was heated at 40°C and stirred for 8 hours. The mixed reaction solution was diluted with MeOH and purified by C18 reverse phase column chromatography (acetonitrile: H2O (0.1% NH3.H2O ) = 5-95% elution) to give (R)-(1-( tert -butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (80 mg, yield: 38.2%), LC-MS m/z: 612 [M+H] + ;
4)、(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
4) Synthesis of (R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(80mg，0.134mmol)的二氯甲烷(3mL)和2，2，2-三氟乙酸(1mL)溶液室温搅拌5小时。将所得混合反应液减压浓缩得到粗产物，直接用于下一步骤中，而无需进一步纯化。LC-MS m/z：512[M+H]+；A solution of (R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (80 mg, 0.134 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 5 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 512 [M+H] + ;
5)、((R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
5) Synthesis of ((R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl ester
向溶有(R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(60mg，0.12mmol)和(E)-4-(二甲氨基)丁-2-烯酸(31mg，0.24mmol)的N，N-二甲基甲酰胺(1.0mL)溶液中，加入N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(67.2mg，0.24mmol)和1-甲基-1H-咪唑(39.4mg，0.48mmol)。所得混合反应液室温搅拌3小时。残余物通过C18反相柱色谱(乙腈∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到((R)-4-((8-异丙基-2-((1-(吡啶-4-基)乙基)氨基)吡唑[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(5mg，收率：6.8％)，LC-MS m/z：623[M+H]+；N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (67.2 mg, 0.24 mmol) and 1-methyl-1H-imidazole (39.4 mg, 0.48 mmol) were added to a solution of (R)-4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (60 mg, 0.12 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (31 mg, 0.24 mmol) in N,N-dimethylformamide (1.0 mL). The resulting mixed reaction solution was stirred at room temperature for 3 hours. The residue was purified by C18 reverse phase column chromatography (acetonitrile: H2O (0.1% NH3.H2O ) = 5-95% elution) to give ((R)-(E ) -(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-((8-isopropyl-2-((1-(pyridin-4-yl)ethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (5 mg, yield: 6.8%), LC-MS m/z: 623 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ8.44(d，J＝4.8Hz，2H)，7.62(s，1H)，7.46(d，J＝6.0Hz，2H)，6.89-6.74(m，1H)，6.20(d，J＝15.2Hz，1H)，5.07(d，J＝7.2Hz，1H)，4.51-4.33(m，6H)，4.29-4.04(m，6H)，3.15(d，J＝6.8Hz，2H)，2.26(s，6H)，1.99(s，2H)，1.54(t，J＝12.0Hz，5H)，1.20(s，6H). 1 H NMR (400MHz, MeOD-d4): δ8.44 (d, J=4.8Hz, 2H), 7.62 (s, 1H), 7.46 (d, J=6.0Hz, 2H), 6.89-6.74 (m, 1H), 6.20 (d, J=15.2Hz, 1H), 5.07 (d, J=7.2Hz, 1H), 4.51-4.33 (m, 6H), 4.29-4.04 (m, 6H), 3.15 (d, J =6.8Hz, 2H), 2.26(s, 6H), 1.99(s, 2H), 1.54(t, J=12.0Hz, 5H), 1.20(s, 6H).
实施例113、(R)-4-((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物113)的合成：Example 113, Synthesis of (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl ester (Compound 113):
1)、(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
1) Synthesis of (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester
室温条件下，向溶有(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基-4-((8-异丙基-2-(甲基磺酰基)吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸酯(375mg，0.659mmol)和(R)-2-氨基丁-1-醇(70mg，0.791mmol)的异丙醇(5mL)溶液中，加入N，N-二异丙基乙胺(255mg，1.977mmol)。所得混合反应液在＝阿吉热70℃搅拌3小时。冷却后，将混合反应液加水稀释，并用乙酸乙酯(3 x 50mL)萃取。合并的有机相用饱和食盐水(3 x 30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱法(ACN(0.1％NH4HCO3)：水(0.1％NH4HCO3)＝60％-80％洗脱)纯化得到(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，收率：57.8％)，LC-MS m/z：579[M+H]+；N,N-diisopropylethylamine (255 mg, 1.977 mmol) was added to a solution of (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl-4-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (375 mg, 0.659 mmol) and (R)-2-aminobutan-1-ol (70 mg, 0.791 mmol) in isopropanol (5 mL) at room temperature. The resulting mixed reaction solution was stirred at 70°C for 3 hours. After cooling, the mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (ACN (0.1% NH 4 HCO 3 ): water (0.1% NH 4 HCO 3 ) = 60%-80% elution) to give (R)-(1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl 4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (220 mg, yield: 57.8%), LC-MS m/z: 579 [M+H] + ;
2)、(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
2) Synthesis of (R)-4-((2-((1-hydroxybutane-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
在室温条件下，向溶有(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(220mg，0.381mmol)的二氯甲烷(3mL)溶液中，滴加2，2，2-三氟乙酸(1mL)。所得混合反应液室温搅拌2小时，将混合反应液加水释，并用乙酸乙酯(3 x 60mL)萃取。合并的有机相用饱和食盐水(3 x 30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱法(ACN(0.1％FA)：水(0.1％FA)＝25％-65％洗脱)纯化得到(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(100mg，收率：55.0％)，LC-MS m/z：479[M+H]+；To a solution of (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-4-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (220 mg, 0.381 mmol) in dichloromethane (3 mL) was added dropwise 2,2,2-trifluoroacetic acid (1 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 2 hours, the mixed reaction solution was diluted with water, and extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%-65% elution) to give (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (100 mg, yield: 55.0%), LC-MS m/z: 479 [M+H] + ;
3)、(R)-4-((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl ester
室温条件下，向溶有(R)-4-((2-((1-羟基丁烷-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(100mg，0.209mmol)和(E)-4-(二甲基氨基)丁-2-烯酸(32mg，0.251mmol)的二氯甲烷(2mL)溶液，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(159mg，0.418mmol)和N，N-二异丙基乙胺(81mg，0.628mmol)。所得混合反应液室温搅拌2小时。将混合反应液液加水稀释，并用乙酸乙酯(4 x 80mL)萃取。合并的有机相用饱和食盐水(2x20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过C18反相柱色谱法(ACN(0.1％FA)：水(0.1％FA)＝25％-65％洗脱)纯化得到(R)-4-((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1，5-a][1，3，5]三嗪-4-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(20mg，收率：16.2％)，LC-MS m/z：590[M+H]+； To a solution of (R)-3-fluoroazetidin-3-yl)methyl 4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylate (100 mg, 0.209 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (32 mg, 0.251 mmol) in dichloromethane (2 mL) at room temperature was added 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (159 mg, 0.418 mmol) and N,N-diisopropylethylamine (81 mg, 0.628 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (4 x 80 mL). The combined organic phase was washed with saturated brine (2x20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%-65% elution) to give (R)-4-((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)piperidine-1-carboxylic acid (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl ester (20 mg, yield: 16.2%), LC-MS m/z: 590 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.65(s，1H)，6.84-6.77(m，1H)，6.21(d，J＝15.6Hz，1H)，4.53-4.38(m，4H)，4.27-4.10(m，5H)，3.97-3.90(m，1H)，3.67-3.60(m，2H)，3.18(d，J＝5.6Hz，2H)，3.12-2.93(m，3H)，2.29(s，6H)，2.07-2.02(m，2H)，1.78-1.69(m，1H)，1.62-1.51(m，3H)，1.26(d，J＝6.8Hz，6H)，0.99(t，J＝7.6Hz，3H). 1 H NMR (400MHz, MeOD-d4): δ7.65 (s, 1H), 6.84-6.77 (m, 1H), 6.21 (d, J=15.6Hz, 1H), 4.53-4.38 (m, 4H), 4.27-4.10(m, 5H), 3.97-3.90(m, 1H), 3.67-3.60(m, 2H), 3.18(d, J=5.6Hz, 2H), 3.12-2.93(m, 3H), 2.29(s, 6H), 2.07-2.02(m, 2H), 1.78-1.69(m, 1H), 1.62-1.51( m, 3H), 1.26 (d, J=6.8Hz, 6H), 0.99 (t, J=7.6Hz, 3H).
实施例114、4-(9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(化合物C1-195)的合成：Example 114, Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylate (Compound C1-195):
1)、4-((9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
1) Synthesis of methyl 4-((9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylate (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)
在室温条件下，向溶有3-氟-3-(羟甲基)氮杂环丁烷-1-羧酸叔丁酯(898mg，4.38mmol)的N，N-二甲基甲酰胺(2mL)溶液中，加入三乙胺(590mg，5.84mmol)。然后在0℃条件下，加入N，N′-羰基二(1，2，4-三氮唑)(718mg，4.38mmol)，在0℃搅拌0.5小时。然后将9-异丙基-2-甲基-N-(哌啶-4-基)-9H-嘌呤-6-胺(400mg，1.46mmol)的N，N-二甲基甲酰胺(1mL)加入到上述混合物，，加热80℃搅拌16小时。LCMS检测反应完成。将混合反应液通过C18反相柱色谱法(MeCN∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到4-((9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(250mg，收率：33.9％)，LC-MS m/z：506[M+H]+；At room temperature, triethylamine (590 mg, 5.84 mmol) was added to a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (898 mg, 4.38 mmol) in N, N-dimethylformamide (2 mL). Then, N, N′-carbonylbis(1,2,4-triazole) (718 mg, 4.38 mmol) was added at 0°C and stirred at 0°C for 0.5 hours. Then, 9-isopropyl-2-methyl-N-(piperidin-4-yl)-9H-purine-6-amine (400 mg, 1.46 mmol) in N, N-dimethylformamide (1 mL) was added to the above mixture and heated at 80°C and stirred for 16 hours. The reaction was completed by LCMS detection. The mixed reaction solution was purified by C18 reverse phase column chromatography (MeCN: H2O (0.1% NH3.H2O ) = 5-95% elution) to obtain 4-((9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl ester (250 mg, yield: 33.9%), LC-MS m/z: 506 [M+H] + ;
2)、4-((9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯的合成
2) Synthesis of 4-((9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidine-3-yl)methyl ester
将溶有4-((9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)甲基酯(250mg，0.495mmol)和2，2，2-三氟乙酸(0.4mL)的二氯甲烷(1.2mL)溶液室温搅拌2小时。LCMS检测反应完成。将混合反应液减压浓缩得到粗产物，直接用于下一步下一步骤中，无需进一步纯化。LC-MS m/z：406[M+H]+；A solution of 4-((9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylic acid (1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-yl)methyl ester (250 mg, 0.495 mmol) and 2,2,2-trifluoroacetic acid (0.4 mL) in dichloromethane (1.2 mL) was stirred at room temperature for 2 hours. The reaction was complete by LCMS. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 406 [M+H] + ;
3)、4-(9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidine-3-yl)methyl 4-(9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylate
将溶有4-((9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(3-氟氮杂环丁烷-3-基)甲基酯(10mg，0.0247mmol)，(E)-4-(二甲基氨基)丁-2-烯酸盐酸盐(6mg，0.037mmol)，N，N，N′，N′-四甲基氯甲脒六 氟磷酸盐(14mg，0.0494mmol)和1-甲基-1H-咪唑(8mg，0.0988mmol)的N，N-二甲基甲酰胺(1mL)加热40℃搅拌4小时。LCMS检测反应完成。将所得混合通过C18反相柱色谱法(MeCN∶H2O(0.1％NH3.H2O)＝5-95％洗脱)纯化得到4-(9-异丙基-2-甲基-9H-嘌呤-6-基)氨基)哌啶-1-甲酸(E)-(1-(4-(二甲基氨基)丁-2-烯基)-3-氟氮杂环丁烷-3-基)甲基酯(4mg，收率：3.14％)，LC-MS m/z：517[M+H]+；A mixture of 4-((9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylic acid (3-fluoroazetidin-3-yl)methyl ester (10 mg, 0.0247 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (6 mg, 0.037 mmol), N,N,N′,N′-tetramethylchloroformamidine hexachloride (10 mg, 0.0247 mmol) and 1,2-dichloro-2-nitropropanediol (10 mg, 0.0247 mmol) was added. Fluorophosphate (14 mg, 0.0494 mmol) and 1-methyl-1H-imidazole (8 mg, 0.0988 mmol) in N,N-dimethylformamide (1 mL) were heated at 40°C and stirred for 4 hours. The reaction was completed by LCMS. The resulting mixture was purified by C18 reverse phase column chromatography (MeCN: H 2 O (0.1% NH 3 .H 2 O) = 5-95% elution) to give (E)-(1-(4-(dimethylamino)but-2-enyl)-3-fluoroazetidin-3-yl)methyl 4-(9-isopropyl-2-methyl-9H-purin-6-yl)amino)piperidine-1-carboxylate (4 mg, yield: 3.14%), LC-MS m/z: 517 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ8.10(s，1H)，6.82(dt，J＝15.4，6.5Hz，1H)，6.20(d，J＝15.4Hz，1H)，4.82-4.77(m，1H)，4.58-4.35(m，6H)，4.29-4.05(m，4H)，3.14(d，J＝6.4Hz，2H)，2.53(s，3H)，2.26(s，7H)，2.07(d，J＝12.9Hz，2H)，1.58(s，3H)，1.56(s，4H)，1.53(s，2H). 1 H NMR (400MHz, MeOD-d4): δ8.10 (s, 1H), 6.82 (dt, J=15.4, 6.5Hz, 1H), 6.20 (d, J=15.4Hz, 1H), 4.82-4.77 ( m, 1H), 4.58-4.35 (m, 6H), 4.29-4.05 (m, 4H), 3.14 (d, J=6.4Hz, 2H), 2.53 (s, 3H), 2.26 (s, 7H), 2.07 (d, J=12.9Hz, 2H), 1.58(s, 3H), 1.56(s, 4H), 1.53(s, 2H).
实施例115、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(4-甲氧基哌啶-1-基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯(化合物C4-182)的合成：Example 115, Synthesis of (E)-(3-fluoro-1-(4-(4-methoxypiperidin-1-yl)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-182):
1)、(E)-4-(4-甲氧基哌啶-1-基)丁-2-烯酸的合成
1) Synthesis of (E)-4-(4-methoxypiperidin-1-yl)but-2-enoic acid
将溶有4-甲氧基哌啶(100mg，0.87mmol)，(E)-4-溴丁-2-烯酸(212mg，1.30mmol)和三乙胺(263mg，2.61mmol)的四氢呋喃(2mL)溶液室温搅拌4小时。将所得混合反应液减压浓缩。残余物通过C18反相柱纯色谱(CH3CN∶H2O(0.1％FA)＝5-95％洗脱)纯化得到(E)-4-(4-甲氧基哌啶-1-基)丁-2-烯酸(70mg，收率：40.46％)，A solution of 4-methoxypiperidine (100 mg, 0.87 mmol), (E)-4-bromobut-2-enoic acid (212 mg, 1.30 mmol) and triethylamine (263 mg, 2.61 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 4 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN: H 2 O (0.1% FA) = 5-95% elution) to give (E)-4-(4-methoxypiperidin-1-yl)but-2-enoic acid (70 mg, yield: 40.46%).
2)、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(4-甲氧基哌啶-1-基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯的合成
2) Synthesis of (E)-(3-fluoro-1-(4-(4-methoxypiperidin-1-yl)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(50mg，0.12mmol)，(E)-4-(4-甲氧基哌啶-1-基)丁-2-烯酸(30mg，0.15mmol)，N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(42mg，0.15mmol)和1-甲基-1H-咪唑(24.6mg，0.30mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN∶H2O(0.1％NH3·H2O)＝5-95％洗脱)纯化得到4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(4-甲氧基哌啶-1-基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯(5mg，收率：6.9％)，LC-MS m/z：586[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.12 mmol), (E)-4-(4-methoxypiperidin-1-yl)but-2-enoic acid (30 mg, 0.15 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (42 mg, 0.15 mmol) and 1-methyl-1H-imidazole (24.6 mg, 0.30 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN: H 2 O (0.1% NH 3 ·H 2 O)=5-95% elution) to give (E)-(3-fluoro-1-(4-(4-methoxypiperidin-1-yl)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (5 mg, yield: 6.9%), LC-MS m/z: 586 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.88-6.79(m，1H)，6.22-6.16(m，1H)，6.11(s，1H)，4.54-4.37(m，4H)，4.29-4.08(m，4H)，3.92-3.82(m，1H)，3.30-3.29(m，3H)，3.28-3.23(m，2H)，3.19-3.08(m，4H)，2.76-2.66(m，2H)，2.49(s，3H)，2.29-2.17(m，2H)，2.14-2.04(m，2H)，1.94-1.83(m，2H)，1.68-1.51(m，4H)，1.32(s，3H)，1.30(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.87 (s, 1H), 6.88-6.79 (m, 1H), 6.22-6.16 (m, 1H), 6.11 (s, 1H), 4.54-4.37 (m , 4H), 4.29-4.08 (m, 4H), 3.92-3.82 (m, 1H), 3.30-3.29 (m, 3H), 3.2 8-3.23(m, 2H), 3.19-3.08(m, 4H), 2.76-2.66(m, 2H), 2.49(s, 3H), 2.29-2.17(m, 2H), 2.14-2.04(m, 2H ), 1.94-1.83(m, 2H), 1.68-1.51(m, 4H), 1.32(s, 3H), 1.30(s, 3H).
实施例116、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(异丙基(甲基)氨基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯(化合物C4-100)的合成：Example 116, Synthesis of (E)-(3-fluoro-1-(4-(isopropyl(methyl)amino)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (Compound C4-100):
1)、(E)-4-(异丙基氨基)丁-2-烯酸的合成
1) Synthesis of (E)-4-(isopropylamino)but-2-enoic acid
将溶有(E)-4-溴丁-2-烯酸(200mg，1.21mmol)的丙-2-胺(2.0mL)溶液加热30℃搅拌3小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN∶H2O(0.1％FA)＝5-95％洗脱)纯化得到(E)-4-(异丙基氨基)丁-2-烯酸(150mg，收率：85.4％)，LC-MS m/z：144[M+H]+；A solution of (E)-4-bromobut-2-enoic acid (200 mg, 1.21 mmol) in propan-2-amine (2.0 mL) was heated at 30°C and stirred for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN:H 2 O (0.1% FA) = 5-95% elution) to give (E)-4-(isopropylamino)but-2-enoic acid (150 mg, yield: 85.4%), LC-MS m/z: 144 [M+H] + ;
2)、(E)-4-(异丙基(甲基)氨基)丁-2-烯酸的合成
2) Synthesis of (E)-4-(isopropyl(methyl)amino)but-2-enoic acid
将溶有(E)-4-(异丙基氨基)丁-2-烯酸(150mg，1.05mmol)，多聚甲醛(63mg，2.10mmol)和氰基硼氢化钠(132mg，2.10mol)的乙酸(0.2mL)和二氯甲烷(2mL)溶液室温搅拌0.5小时。将混合反应液过滤，减压浓缩。残余物通过C18反相柱色谱法(MeCN∶H2O(0.1％FA)＝5-95％洗脱)纯化得到(E)-4-(异丙基(甲基)氨基)丁-2-烯(80mg，收率：48.58％)，LC-MS m/z：158[M+H]+；A solution of (E)-4-(isopropylamino)but-2-enoic acid (150 mg, 1.05 mmol), paraformaldehyde (63 mg, 2.10 mmol) and sodium cyanoborohydride (132 mg, 2.10 mol) in acetic acid (0.2 mL) and dichloromethane (2 mL) was stirred at room temperature for 0.5 hours. The mixed reaction liquid was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN: H 2 O (0.1% FA) = 5-95% elution) to give (E)-4-(isopropyl(methyl)amino)but-2-ene (80 mg, yield: 48.58%), LC-MS m/z: 158 [M+H] + ;
3)、4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(异丙基(甲基)氨基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯的合成
3) Synthesis of (E)-(3-fluoro-1-(4-(isopropyl(methyl)amino)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate
将溶有(3-氟氮杂环丁烷-3-基)甲基-4-((3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-甲酸酯(50mg，0.12mmol)，(E)-4-(异丙基(甲基)氨基)丁-2-烯酰胺(25mg，0.15mmol)、N，N，N′，N′-四甲基氯甲脒六氟磷酸盐(42mg，0.15mmol)和1-甲基-1H-咪唑(24mg，0.30mmol)的N，N-二甲基甲酰胺(1mL)溶液室温搅拌2小时。将所得混合反应液减压浓缩。残余物通过C18反相柱色谱(CH3CN∶H2O(0.1％NH3·H2O)＝5-95％洗脱)纯化得到4-(3-异丙基-5-甲基吡唑并[1，5-a]嘧啶-7-基)氨基)哌啶-1-羧酸(E)-(3-氟-1-(4-(异丙基(甲基)氨基)丁-2-烯基)氮杂环丁烷-3-基)甲基酯的(5mg，收率：7.4％)，LC-MS m/z：544[M+H]+；A solution of (3-fluoroazetidine-3-yl)methyl-4-((3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (50 mg, 0.12 mmol), (E)-4-(isopropyl(methyl)amino)but-2-enamide (25 mg, 0.15 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (42 mg, 0.15 mmol) and 1-methyl-1H-imidazole (24 mg, 0.30 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH 3 CN:H 2 O (0.1% NH 3 ·H 2 O)=5-95% elution) to give (E)-(3-fluoro-1-(4-(isopropyl(methyl)amino)but-2-enyl)azetidin-3-yl)methyl 4-(3-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-carboxylate (5 mg, yield: 7.4%), LC-MS m/z: 544 [M+H] + ;
1H NMR(400MHz，MeOD-d4)：δ7.87(s，1H)，6.88-6.79(m，1H)，6.25-6.18(m，1H)，6.11(s，1H)，4.61-4.31(m，5H)，4.29-4.07(m，4H)，3.92-3.83(m，1H)，3.28-3.25(m，2H)，3.19-3.05(m，2H)，2.90-2.79(m，1H)，2.49(s，3H)，2.20(s，3H)，2.09(d，J＝8.0Hz，2H)，1.69-1.54(m，2H)，1.32(s，3H)，1.30(s，3H)，1.05(s，3H)，1.03(s，3H). 1 H NMR (400MHz, MeOD-d4): δ7.87 (s, 1H), 6.88-6.79 (m, 1H), 6.25-6.18 (m, 1H), 6.11 (s, 1H), 4.61-4.31 (m , 5H), 4.29-4.07(m, 4H), 3.92-3.83(m, 1H), 3.28-3.25(m, 2 H), 3.19-3.05 (m, 2H), 2.90-2.79 (m, 1H), 2.49 (s, 3H), 2.20 (s, 3H), 2.09 (d, J=8.0Hz, 2H), 1.69-1.54 (m, 2H), 1.32 (s, 3H), 1.30 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H).
实施例117、如下化合物的合成：Example 117, Synthesis of the following compound:
参考以上实施例类似的合成步骤，可以得到以下化合物：
















































































Referring to the similar synthesis steps of the above examples, the following compounds can be obtained:
















































































生物学测试、Biological tests,
测试例1、CDK7酶活抑制测试Test Example 1: CDK7 enzyme activity inhibition test
1)试剂与耗材：
1) Reagents and consumables:
2)实验前准备及储备液配制：2) Preparation before experiment and preparation of stock solution:
1倍assay buffer溶液配制：将5X Enzymatic buffer用H2O稀释5倍，DTT(1M)稀释至1mM，MgCl2(1M)稀释至50mM；Preparation of 1x assay buffer solution: dilute 5X Enzymatic buffer 5 times with H2O, dilute DTT (1M) to 1mM, and dilute MgCl2 (1M) to 50mM;
底物和ATP混合溶液：底物(1mM)和ATP(10mM)用1x assay buffer稀释分别稀释浓度至2.5μM和12.5μM；CDK7 recombinant enzyme：用1倍assay buffer溶液稀释成25ng/ul的浓度；Substrate and ATP mixed solution: substrate (1mM) and ATP (10mM) were diluted to 2.5μM and 12.5μM respectively with 1x assay buffer; CDK7 recombinant enzyme: diluted to 25ng/ul with 1x assay buffer solution;
化合物：由客户提供，用DMSO稀至10mM备用；Compound: Provided by the customer, diluted to 10 mM with DMSO for later use;
3)实验方法及过程
3) Experimental methods and process
4)数据处理与结果：4) Data processing and results:
化合物孔的Luminescence记为Lumcompound，对照孔的Luminescence记为Lumvehicle，空白对照孔的Luminescence记为Lumblank。The luminescence of the compound wells is recorded as Lum compound , the luminescence of the control wells is recorded as Lum vehicle , and the luminescence of the blank control wells is recorded as Lum blank .
抑制率用以下公式计算：The inhibition rate was calculated using the following formula:
抑制率＝(Lumvehicle-Lumcompound)/(Lumvehicle-Lumblank)×100％ Inhibition rate=(Lum vehicle -Lum compound )/(Lum vehicle -Lum blank )×100%
表1、部分代表性化合物数据分析与结果
Table 1. Data analysis and results of some representative compounds
测试例2、肿瘤细胞增殖抑制活性测试：Test Example 2: Tumor cell proliferation inhibition activity test:
应用Luminescent Cell Viability Assay(CTG)检测试剂盒检测化合物对4株细胞系的增殖抑制作用。
application The Luminescent Cell Viability Assay (CTG) kit was used to detect the inhibitory effect of the compounds on the proliferation of 4 cell lines.
试剂和耗材
Reagents and consumables
仪器设备
Instruments and Equipment
试验条件及操作
Test conditions and operation
1)配制完全培养基，充分混匀。 1) Prepare complete culture medium and mix thoroughly.
2)复苏细胞，传两代左右选择生长状态良好的细胞系。2) Resuscitate the cells, pass them for about two generations and select cell lines with good growth status.
3)收集对数生长期细胞计数并检测细胞活力。3) Collect cells in the logarithmic growth phase, count them and detect cell viability.
4)用完全培养液重悬细胞至合适密度。4) Resuspend the cells to an appropriate density in complete culture medium.
5)将细胞悬液接种于96孔板，每孔加100μL细胞悬液。标记细胞名称，种板密度，日期等详细信息，将培养板放置于高湿度，37℃，5％CO2培养箱中过夜。5) Inoculate the cell suspension in a 96-well plate, add 100 μL of cell suspension to each well. Label the cell name, plate density, date and other detailed information, and place the culture plate in a high humidity, 37°C, 5% CO2 incubator overnight.
6)用DMSO按所需稀释倍数稀释待测试剂到相应浓度(9个浓度梯度，含0浓度)。然后用培养基进一步稀释待测试剂至5x的工作液。6) Dilute the test agent with DMSO to the corresponding concentration (9 concentration gradients, including 0 concentration) according to the required dilution multiple. Then further dilute the test agent with culture medium to 5x working solution.
化合物稀释方法(以10mM起始浓度，4倍梯度稀释，9个浓度点)：Compound dilution method (starting at 10 mM, 4-fold gradient dilution, 9 concentration points):
7)依据化合物作用浓度，按25μL/孔将稀释好的化合物加入相应细胞孔中。7) According to the concentration of the compound, add the diluted compound into the corresponding cell wells at 25 μL/well.
8)细胞板放入高湿度，37℃，5％CO2培养箱中孵育72h。8) The cell plate was placed in a high humidity, 37°C, 5% CO2 incubator and incubated for 72 h.
9)加入50μL的CTG检测液，室温避光孵育15～30分钟左右。9) Add 50 μL of CTG detection solution and incubate at room temperature in the dark for about 15 to 30 minutes.
10)轻轻震荡后在Envision进行Luminescence模式测定，计算抑制率。10) After gently shaking, perform Luminescence mode measurement in Envision and calculate the inhibition rate.
11)按下式计算药物对各细胞生长的抑制率：11) Calculate the inhibition rate of the drug on the growth of each cell according to the following formula:
细胞生长抑制率％＝(1-As/Ac)×100％Cell growth inhibition rate % = (1-As/Ac) × 100%
As：样品的OA(细胞+CTG+待测化合物)As: OA of sample (cells + CTG + test compound)
Ac：正常生长细胞对照的OA(细胞+CTG+DMSO)Ac: OA of normal growth cell control (cells + CTG + DMSO)
运用软件Graphpad Prism 6并采用计算公式XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor)vs.response-Variable slope(four parameters)进行IC50曲线拟合并计算出IC50值。The IC50 curve was fitted and the IC50 value was calculated using the software Graphpad Prism 6 and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters).
表2、部分代表性化合物CDK7酶活抑制肿瘤细胞增殖抑制数据分析与结果

Table 2. Data analysis and results of CDK7 enzyme activity inhibition of tumor cell proliferation by some representative compounds

测试例3、代表性受试物的小鼠药代动力学研究：Test Example 3: Pharmacokinetic study of representative test substances in mice:
通过小鼠药代动力学实验评估部分本发明化合物的药代动力学特性：使用SPF级雄性ICR小鼠，每组6只，来源于北京维通利华实验动物技术有限公司。受试化合物溶于5％DMSO10％solutol/90％saline。单次静脉给药，剂量为2mg/kg，给药体积为5mL/kg。单次灌胃给药，剂量为10mg/kg，给药体积为10mL/kg。动物在实验前禁食过夜不禁水，给药后4小时恢复摄食。给药后0.0830(IV)，0.25、0.5、1、2、4、6、8和24小时采血。动物隐静脉采血约0.2mL全血，放于EDTA-K2抗凝管中，样品于4℃、4200rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆样品分析使用乙腈沉淀蛋白质法萃取小鼠血浆中的待测化合物和内标(Labetalol & tolbutamide & Verapamil & dexamethasone & glyburide & Celecoxib)，萃取液通过LC/MS/MS分析。测到的个体动物的血浆浓度-时间数据用Phoenix WinNonlin 7.0(Pharsight，USA)软件按非房室模型进行分析，得到小鼠药代动力学参数如下表：最大(峰值)血浆药物浓度Cmax；达峰时间Tmax；半衰期T1/2和外推到无限长时间的血药浓度-时间曲线下面积AUC0-inf。The pharmacokinetic properties of some of the compounds of the present invention were evaluated by mouse pharmacokinetic experiments: SPF-grade male ICR mice, 6 mice per group, were used, and were sourced from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The test compound was dissolved in 5% DMSO 10% solutol/90% saline. A single intravenous administration, the dose was 2 mg/kg, and the administration volume was 5 mL/kg. A single oral administration, the dose was 10 mg/kg, and the administration volume was 10 mL/kg. The animals were fasted overnight before the experiment but not water, and resumed eating 4 hours after administration. Blood was collected at 0.0830 (IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. About 0.2 mL of whole blood was collected from the animal's saphenous vein and placed in an EDTA-K2 anticoagulant tube. The sample was centrifuged at 4°C and 4200 rpm for 5 minutes, and the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma sample analysis: The test compounds and internal standards (Labetalol & tolbutamide & Verapamil & dexamethasone & glyburide & Celecoxib) in mouse plasma were extracted by acetonitrile protein precipitation method, and the extract was analyzed by LC/MS/MS. The plasma concentration-time data of individual animals were analyzed by Phoenix WinNonlin 7.0 (Pharsight, USA) software according to the non-compartmental model, and the pharmacokinetic parameters of mice were obtained as follows: maximum (peak) plasma drug concentration Cmax ; peak time Tmax ; half-life T1 /2 and area under the blood drug concentration-time curve extrapolated to infinite time AUC0 -inf .
表3、代表性化合物的小鼠药代动力学参数

Table 3. Pharmacokinetic parameters of representative compounds in mice

从上表中结果可以看出，与临床在研参照化合物CT7001比较，本发明的部分代表性化合物如化合物12、化合物27、化合物C2-78等均具有更低的清除率，更高的暴露量和口服生物利用度，因此更适合作为药物开发。It can be seen from the results in the above table that compared with the clinical reference compound CT7001, some representative compounds of the present invention such as compound 12, compound 27, compound C2-78, etc. have lower clearance rates, higher exposure amounts and oral bioavailability, and are therefore more suitable for drug development.
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims (10)

  1. 式(I)所示化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体；
    A compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof;
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环A和B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；当A环为不存在时，L1和L2可以直接相连；Rings A and B are arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R 3 can be directly connected to Y; when ring A is absent, L 1 and L 2 can be directly connected;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , or C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结 构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic ring. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  2. 根据权利要求1所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-1A)结构，
    The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof, which has the structure of formula (I-1A),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可 含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily independently selected from a monocyclic or polycyclic structure having no or 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can be Contains 0 to more unsaturated olefinic bonds; and when ring B is absent, R 3 can be directly connected to Y;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷 基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkyl and any two of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 , R d10 , R d11 , R d12 , R d13 , R d14 , R d15 , R d16 , R d17 , R d18 , R d19 , R d20 , R d21 , R d22 , R d3 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 , R d9 , R d10 d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    优选地，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1B)结构，
    Preferably, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (I-1B),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、 -C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(＝O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    优选地，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1C)结构，
    Preferably, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1C),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代； Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    优选地，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1D)结构，
    Preferably, the compound or a pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1D):
    其中，in,
    X独立地选自N、CR；X is independently selected from N, CR;
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
    L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、 -C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L1 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝ S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )( R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 together with the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代， 且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which they are attached, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 and OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1或2中的整数；t is an integer arbitrarily selected from 0, 1 or 2;
    优选地，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(I-1E)结构，
    Preferably, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (I-1E),
    其中，in,
    X独立地选自N、CR；X is independently selected from N, CR;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以和Y直接相连；Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when Ring B is absent, R 3 can be directly connected to Y;
    L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Y独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；Y is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3R01；且R0上的氢任选最佳被1至多个取代基取代，所述取代基任意独立地选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基或C3-10杂环基；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 R 01 ; and the hydrogen on R 0 is optionally substituted with 1 to more substituents, and the substituents are arbitrarily independently selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl or C 3-10 heteroalkyl or C 3-10 heterocyclic groups;
    L3独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O) C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3)-, -N(Rd3 ) -, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 ) )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O) C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R01独立地选自氢、氘、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基；更进一步地R01上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；R 01 is independently selected from hydrogen, deuterium, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; further, the hydrogen on R 01 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R3可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、炔基酰胺基、烷基磺酰基、烯基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkynylamido, alkylsulfonyl, alkenylsulfonyl, acrylamido, N,N-dimethylbutenamido, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的碳原子一起形成3-18元单环或多环结构；R2也可以与Rd3连接起来一起形成3-18元单环或多环结构；所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R R 2 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure; R 2 can also be connected with R d3 to form a 3-18 membered monocyclic or polycyclic structure; the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally substituted with one or more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2 , dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R and the carbon atoms connected to them on the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1和Rd2也可以与其附着的碳一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 and any two of R d1 and R d2 are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, and saturated or partially saturated C 3-6 cycloalkyl; and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen , deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two of R d1 and R d2 can also form a 3-18 membered monocyclic or polycyclic structure together with the carbon to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1或2中的整数。t is arbitrarily selected from an integer of 0, 1 or 2.
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，L1独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；优先选自-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-或-C(Rd1)(Rd2)N(Rd3)-； According to the compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, isotope substituted product or isomer thereof, L1 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3) - )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -C(R d1 )(R d2 )C(R d1 ) (R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 ) C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d 1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(═O) 2 -; preferably selected from -C(═O)N(R d3 )-, -N(R d3 )-, -C(═NR d3 )- or -C(R d1 )(R d2 )N(R d3 )-;
    环B任意独立地选自为不存在或3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R1可以和Y直接相连；优选为不存在或单环结构；最优选不存在、苯环、吡啶环、噻唑环、吡唑环、氮杂环丁烷、氮杂环戊烷、氮杂环己烷。Ring B is arbitrarily and independently selected from a monocyclic or polycyclic structure that is absent or has 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is absent, R1 can be directly connected to Y; preferably, it is absent or a monocyclic structure; most preferably, it is absent, a benzene ring, a pyridine ring, a thiazole ring, a pyrazole ring, an azetidine, an azocyclopentane, and an azohexane.
  4. 根据权利要求1-3任一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-2)结构，
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof, which has a structure of formula (I-2),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂 环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, The aliphatic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    优选地，所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-2C)结构，
    Preferably, the compound or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof has a structure of formula (I-2C),
    其中， in,
    X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
    环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
    L、L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L, L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、 C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy , C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl , C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more than one selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 , wherein the R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
    优选地，所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-2D)结构
    Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof has the structure of formula (I-2D):
    其中，in,
    X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
    X7任意独立地选自-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；且X7上的氢最佳任选地被1至多个R3取代； X7 is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 ) )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 ) N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C( Rd1 )( Rd2 )-, -OC( Rd1)(Rd2 ) -, -SC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )C(＝O)O-, -OC(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )C(＝O)-, -C( Rd1 )( Rd2 )C(＝S)-, -S(＝O)C( Rd1 )( Rd2 )-, or -C( Rd1 )( Rd2 )S(＝O) 2- ; and the hydrogen on X7 is optionally substituted by 1 to more R3 ;
    L、L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L, L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、 -C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
    优选地，所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-2E) 结构
    Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof has the formula (I-2E): structure
    其中，in,
    X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
    L和L1各自独立地选自为-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L and L1 are each independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、 C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl , C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R2 is optionally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH3 , carboxyl, OH, CN, C1-10 alkyl, C3-10 cycloalkyl, C C4-10 heterocyclyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    R5、R6和R7可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且R5、R6和R7上的氢最佳任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者R5、R6和R7任意两个可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; The hydrogen on R7 is most preferably optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and C1-6 alkyl and C1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH , OCH3 , OCH2CH3 , and saturated or partially saturated C3-6 cycloalkyl; or R5 , R6 and R 7 Any two of the atoms to which they are attached may form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
    优选地，所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-2F)结构
    Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof has a structure of formula (I-2F):
    其中，in,
    X任意独立地选自N、CR；X is arbitrarily and independently selected from N, CR;
    L和L1各自独立地选自为-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-；L and L1 are each independently selected from -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C(Rd2) d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基 或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 1-10 alkyl substituted with C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted with carboxyl or carboxyl substitute; or any two R 2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    R5、R6和R7可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且R5、R6和R7上的氢最佳任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者R5、R6和R7任意两个可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；R 5 , R 6 and R 7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and R 5 , R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; The hydrogen on R7 is most preferably optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and C1-6 alkyl and C1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH , OCH3 , OCH2CH3 , and saturated or partially saturated C3-6 cycloalkyl; or R5 , R6 and R 7 Any two of the atoms to which they are attached may form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自2、3和4中的整数；m is an integer arbitrarily selected from 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    t任意地选自0、1、2、3和4中的整数。t is arbitrarily selected from an integer of 0, 1, 2, 3 and 4.
  5. 根据权利要求1-4任一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-4A)结构，
    The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof, which has a structure of formula (I-4A),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR；X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、 C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamide, N,N-dimethylbutenamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C3-10 saturated or partially saturated heterocyclyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl , C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R2 together with the atoms connected to them on the ring form a 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; further, the hydrogen on R2 is optionally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH3 , carboxyl, OH, CN, C1-10 alkyl, C3-10 cycloalkyl, C C4-10 heterocyclyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 wherein the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxo, and saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally further substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 and saturated or partially saturated C3-6 cycloalkyl; or any two of Rd1 , Rd2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
    优选地，所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其具有式(I-4B)结构，
    Preferably, the compound or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof has a structure of formula (I-4B),
    其中，in,
    任意独立地选自单键或双键； Any independently selected from a single bond or a double bond;
    X、X0、X1、X2、X3、X4、X5和X6任意独立地选自N、CR； X, X 0 , X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are arbitrarily and independently selected from N, CR;
    环B任意独立地选自不存在、单键或为3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；且当环B为不存在时，R3可以为不存在或也可以直接连接在L2上；Ring B is arbitrarily and independently selected from non-existent, single bond or monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, cyclic ring, spirocyclic ring or bridged ring structure can contain 0 to more unsaturated olefinic bonds; and when ring B is non-existent, R 3 can be non-existent or can also be directly connected to L 2 ;
    L1和L2各自独立地选自为不存在、单键、-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-N(Rd3)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L1 and L2 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -N( Rd3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )(Rd2) d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-,- C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )- or -C(R d1 )(R d2 )S(=O) 2 -;
    R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基或-L3-Q；且R0上的氢任选最佳被1至多个选自H、氘、卤素、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基、C1-10烷氧基氨基、OCH3、羧基、OH、CN的取代基进一步取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy or -L 3 -Q; and the hydrogen on R 0 is optionally further substituted with 1 to more substituents selected from H, deuterium, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyamino, OCH 3 , carboxyl, OH, CN;
    L3独立地选自为不存在、单键或-C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd2)-、炔键、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-C(＝O)N(Rd3)-、-C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)-、-S(＝O)2N(Rd3)-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)O-、-C(Rd1)(Rd2)C(＝O)N(Rd3)-、-C(Rd1)(Rd2)C(Rd1)(Rd2)N(Rd3)-、-C(Rd1)(Rd2)C(＝NRd3)-、-C(Rd1)(Rd2)N(Rd3)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2N(Rd3)-、-N(Rd3)C(Rd1)(Rd2)-、-OC(Rd1)(Rd2)-、-SC(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)O-、-OC(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-S(＝O)C(Rd1)(Rd2)-或-C(Rd1)(Rd2)S(＝O)2-； L3 is independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd2 )-, an acetylenic bond, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -C(=O)N( Rd3 )-, -C(= NRd3 )-, -C( Rd1 )( Rd2 )N( Rd3 )-, -S(=O) 2N ( Rd3 )-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -OC( Rd1 )( Rd2) )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )-or-C(R d1 )(R d2 )S(=O) 2 -;
    Q任意独立地选自3至18个碳原子的单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地Q最佳被1至多个R1取代基取代；Q is arbitrarily and independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; further, Q is preferably substituted by 1 to more R 1 substituents;
    每一个R可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；且R上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy; and the hydrogen on R is optionally and optimally replaced by 1 to more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R1可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、二烷基磷氧基、烷基磺酰基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R1与其在环上相连的碳原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；更进一步地R1上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN的取代基取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphinoyl, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN;
    每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、二烷基磷氧基、烷基磺酰基、-COOH、丙烯酰胺基、N，N-二甲基丁烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R2与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；更进一步地R2上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphinoyl, alkylsulfonyl, -COOH, acrylamido, N,N-dimethylbutenamido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 2 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; further, the hydrogen on R 2 is optionally replaced by one or more selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个R3可以相同或不同，彼此独立地选自不存在、氢、氘、卤素、-CN、-OH、-SH和-NH2、CH＝O、二烷基磷氧基、烷基磺酰基、丙烯酰胺基、N，N-二甲基丁烯酰胺基、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、芳基、杂芳基、C3-10饱和或部分饱和的杂环基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；或者任意两个R3与其在环上相连的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键；更进一步地R3上的氢任选最佳被1至多个选自H、氘、卤素、氨基、OCH3、羧基、OH、CN、C1-10烷基、C3-10环烷基、C4-10杂环基、C2-10烯基、C2-10炔基或C1-10烷氧基的取代基取代；Each R 3 may be the same or different and is independently selected from absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , CH=O, dialkylphosphinoyl, alkylsulfonyl, acrylamido, N,N-dimethylbutenamido, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 3 and the atoms connected to it on the ring form a 3-18 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R 3 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, amino, OCH 3 , carboxyl, OH, CN, C 1-10 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
    每一个Rd1、Rd2和Rd3可以相同或不同，且彼此独立地选自氢、氘、卤素、氰基、氨基、羟基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10环 烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、芳基、杂芳基；且所述的烷基、烯基、炔基、芳基、饱和或部分饱和的环烷基、杂环烷基任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地进一步被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3和饱和或部分饱和的C3-6环烷基的基团取代；或者任意两个Rd1、Rd2或Rd3可以与其附着的原子一起形成3-18元单环或多环结构，所述的单环或多环结构可任意地选自芳环、杂芳环、脂肪环、杂环、并环、螺环或桥环结构；且所述的脂肪环、杂环、并环、螺环或桥环结构可含有0至多个不饱和烯键及0至多个杂原子；其中，所述环烷基、杂环烷基、芳基、杂芳基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；Each of R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cyclo Alkyl acyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , oxo, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two of R d1 , R d2 or R d3 can form a 3-18 membered monocyclic or polycyclic structure together with the atoms to which it is attached, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the alicyclic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl group is optionally substituted by 1 to multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
    所述的杂代表着任意独立地选自O、N、S、S＝O、S(＝O)2、P的原子或基团及其同位素；The hetero group represents an atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and isotopes thereof;
    所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
    m任意地选自0、1、2、3和4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;
    n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  6. 根据权利要求1-5任意一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其中：优先选自如下结构： R如权利要求1-5所述。The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, hydrate, isotope-substituted product or isomer thereof, wherein: Preferred is selected from the following structures: R is as described in claims 1-5.
  7. 根据权利要求1-6任意一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，根据本发明的实施方案，环A选自3-10元杂环基、C3-8环烷基、C6-10芳基、5-10元杂芳基；According to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, hydrate, isotope substituted product or isomer thereof, according to an embodiment of the present invention, Ring A is selected from a 3-10 membered heterocyclyl, a C 3-8 cycloalkyl, a C 6-10 aryl, a 5-10 membered heteroaryl;
    优选地，环A选自 Preferably, ring A is selected from
    优选地，环B不存在或选自4-6元杂环基、C6-10芳基；例如氮杂环丁烷基、四氢吡咯基、哌啶基、苯基；Preferably, ring B is absent or selected from 4-6 membered heterocyclyl, C 6-10 aryl; for example azetidinyl, tetrahydropyrrolyl, piperidinyl, phenyl;
    优选地，环B不存在或选自 Preferably, ring B is absent or selected from
    优选地，X、X1、X2、X3、X4、X5、X6选自N、C、CR；Preferably, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are selected from N, C, CR;
    优选地，R选自H、C1-6烷基、C3-8环烷基，例如乙基、异丙基、环丙基；Preferably, R is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, such as ethyl, isopropyl, cyclopropyl;
    优选地，Y不存在或选自O、C(O)、无取代或任选被一个或两个C1-6烷基取代的CH2-O；Preferably, Y is absent or selected from O, C(O), CH 2 —O which is unsubstituted or optionally substituted with one or two C 1-6 alkyl groups;
    优选地，L1选自NH、CH2-NH；Preferably, L 1 is selected from NH, CH 2 -NH;
    优选地，L2不存在或选自C(O)、NH、N(C1-6烷基)、N-亚C1-6烷基；Preferably, L 2 is absent or selected from C(O), NH, N(C 1-6 alkyl), N-C 1-6 alkylene;
    优选地，Y-L2选自OC(O)、无取代或任选被一个或两个C1-6烷基取代的下列基团：NH、CH2-OC(O)、C(O)NH、O-CH2-C(O)；Preferably, YL 2 is selected from the following groups: OC(O), unsubstituted or optionally substituted with one or two C 1-6 alkyl groups: NH, CH 2 -OC(O), C(O)NH, O-CH 2 -C(O);
    优选地，R0选自C1-6烷基、C3-8环烷基、卤代C1-6烷基、-L3R01；Preferably, R 0 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, -L 3 R 01 ;
    L3不存在或选自O、NH、N-亚C1-6烷基(例如NH-CH2、NH-CH(CH3))；L 3 is absent or selected from O, NH, N-C 1-6 alkylene (eg NH—CH 2 , NH—CH(CH 3 ));
    R01选自无取代或任选被一个、两个或更多个OH、氧代(＝O)、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、卤代C3-8环烷基-C1-6烷基、苄氧羰基取代的下列基团：C1-6烷基、5-6元杂环基(例如哌啶基、四氢吡咯基、四氢吡喃基、)、5-10元杂芳基(例如吡啶基、嘧啶基)；R 01 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more OH, oxo (═O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, halogenated C 3-8 cycloalkyl-C 1-6 alkyl, benzyloxycarbonyl: C 1-6 alkyl, 5-6 membered heterocyclyl (e.g., piperidinyl, tetrahydropyrrolyl, tetrahydropyranyl, ), 5-10 membered heteroaryl (e.g. pyridyl, pyrimidinyl);
    优选地，R0选自甲基、异丙基、环丙基、三氟甲基、 Preferably, R 0 is selected from methyl, isopropyl, cyclopropyl, trifluoromethyl,
    优选地，R2选自H、C1-6烷基、C1-6烷氧基；Preferably, R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy;
    优选地，R3选自H、C2-6烯基-C(O)、C2-6烯基-C(O)NH、卤代C2-6烯基-C(O)、(C1-6烷基)2N-C2-6烯基-C(O)、3-8元含氮杂环基-C2-6烯基-C(O)、C1-6烷氧基-3-8元含氮杂环基-C2-6烯基-C(O)、C2-6炔基-C(O)；Preferably, R 3 is selected from H, C 2-6 alkenyl-C(O), C 2-6 alkenyl-C(O)NH, halogenated C 2-6 alkenyl-C(O), (C 1-6 alkyl) 2 NC 2-6 alkenyl-C(O), 3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 1-6 alkoxy-3-8 membered nitrogen-containing heterocyclyl-C 2-6 alkenyl-C(O), C 2-6 alkynyl-C(O);
    优选地，R3选自H、 Preferably, R3 is selected from H,
    优选地，m选自0、1、2、3或4；Preferably, m is selected from 0, 1, 2, 3 or 4;
    优选地，n选自0、1、2、3、4或5。Preferably, n is selected from 0, 1, 2, 3, 4 or 5.
  8. 根据权利要求1-7任意一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，其为选自说明书实施例中所公开结构的化合物1至113、化合物C1-1至C1-582、化合物C2-77至C2-335、化合物C3-77至C3-362、化合物C4-77至C4-258。The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, hydrate, isotope substituted product or isomer thereof, which is selected from compounds 1 to 113, compounds C1-1 to C1-582, compounds C2-77 to C2-335, compounds C3-77 to C3-362, and compounds C4-77 to C4-258 of the structures disclosed in the examples of the specification.
  9. 权利要求1-8任意一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，用于制备预防及/或治疗本文所讨论的CDKs靶点相关疾病包括肿瘤、炎症、自免疫性疾病(如红斑狼疮、牛皮癣、银屑病)等病症的药物中的用途。The compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, for use in the preparation of a medicament for preventing and/or treating the CDKs target-related diseases discussed herein, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and the like.
  10. 一种药物组合物，其主要活性成分包括权利要求1-8任意一项所述化合物或其药学上可接受的盐、溶剂合物、水合物、同位素取代物或其异构体，以及其它的一些辅助成分，使之可以适合用于多种形式的药物剂型如液体制剂(包括口服液、注射液、滴眼液等)、固体制剂(包括片剂、胶囊、丸剂、颗粒剂等)，该药物组合物可用于制备预防及/或治疗本文所讨论的CDKs靶点相关疾病包括肿瘤、炎症、自免疫性疾病(如红斑狼疮、牛皮癣、银屑病)等病症的药物中的用途。 A pharmaceutical composition, the main active ingredients of which include the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, and some other auxiliary ingredients, so that it can be suitable for use in various forms of pharmaceutical dosage forms such as liquid preparations (including oral liquids, injections, eye drops, etc.), solid preparations (including tablets, capsules, pills, granules, etc.), and the pharmaceutical composition can be used to prepare drugs for preventing and/or treating the CDKs target-related diseases discussed herein, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis), and other diseases.
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