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WO2025201469A1 - Organic compound having mtor inhibitory activity and use thereof - Google Patents

Organic compound having mtor inhibitory activity and use thereof

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Publication number
WO2025201469A1
WO2025201469A1 PCT/CN2025/085403 CN2025085403W WO2025201469A1 WO 2025201469 A1 WO2025201469 A1 WO 2025201469A1 CN 2025085403 W CN2025085403 W CN 2025085403W WO 2025201469 A1 WO2025201469 A1 WO 2025201469A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
membered
independently selected
alkoxy
deuterated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/085403
Other languages
French (fr)
Chinese (zh)
Inventor
陈伟
王永辉
黄亚飞
程耀邦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Littdd Medicines Ltd
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Littdd Medicines Ltd
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Publication of WO2025201469A1 publication Critical patent/WO2025201469A1/en
Pending legal-status Critical Current
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present application relates to organic compounds having mTOR inhibitory activity, methods for their preparation, pharmaceutical compositions containing them, and their use for treating or preventing diseases or conditions responsive to mTOR inhibition.
  • the compounds of the present invention can be used to treat or prevent diseases responsive to mTOR inhibition or conditions requiring mTOR inhibition, such as cancer, neurological diseases, metabolic diseases, autoimmune diseases, or organ fibrosis, or can be used as immunosuppressants.
  • mTOR The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved, atypical serine-threonine protein kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family of proteins.
  • PIKK phosphatidylinositol kinase-related kinase
  • mTOR kinases can bind to different proteins to form two structurally and functionally distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
  • the mTORC1 core complex is composed of mTOR, the scaffolding protein Raptor, and mLST8/G ⁇ L.
  • mTORC1 also contains two inhibitory subunits, PRAS40 and DEPTOR, which participate in regulating mTORC1 activity.
  • mTORC1 regulates important life processes such as cell growth and development and autophagy by sensing and integrating external signals, such as growth factors, nutrients (amino acids, glucose, etc.), energy status, and oxygen levels.
  • activated mTORC1 stimulated by external signals such as nutrients or hormones, promotes various cellular anabolic pathways, including protein and ribosome biogenesis, lipogenesis, and nucleotide synthesis, by phosphorylating various substrates, such as ribosomal protein S6 kinase (S6K) ⁇ 1 (S6K1), eukaryotic translation initiation factor 4E binding protein (4E-BP), and the transcription factor TFEB.
  • S6K ribosomal protein S6 kinase
  • S6K1 eukaryotic translation initiation factor 4E binding protein
  • 4E-BP eukaryotic translation initiation factor 4E binding protein
  • TFEB transcription factor TFEB
  • mTORC2 contains two core units common to mTORC1: mTOR and mLST8, as well as core components unique to mTORC2, primarily the scaffolding proteins Rictor, mSin1, PRR5/Protor1/2, and the negative regulatory element DEPTOR. Unlike mTORC1, mTORC2 primarily functions as an effector of insulin/PI3K signaling, regulating cell proliferation, survival, and cytoskeletal organization.
  • the PI3K-AKT pathway activated by extracellular signals such as insulin, insulin-like growth factor 1 (IGF-1), and leptin, enhances the activity of AKT kinase and other downstream effectors of the insulin signaling pathway through mTORC2.
  • the primary identified phosphorylation substrates of mTORC2 are several members of the AGC (PKA/PKG/PKC) family, including the kinase AKT, serum glucocorticoid-regulated kinase (SGK), and protein kinase C ⁇ (PKC ⁇ ).
  • PKA/PKG/PKC kinase AKT
  • SGK serum glucocorticoid-regulated kinase
  • PKC ⁇ protein kinase C ⁇
  • the most important role of mTORC2 may be phosphorylation and activation of AKT.
  • AKT is a key effector of insulin/PI3K signaling.
  • AKT promotes cell survival, proliferation, and growth by phosphorylating and inhibiting several key substrates, including FoxO1/3a transcription factors, GSK3b, and TSC2.
  • SGK1 activated by mTORC2 phosphorylation, regulates ion transport and cell survival.
  • the mTOR signaling pathway is involved in many physiological activities in cells. Studies have shown that abnormalities in the mTOR signaling pathway are closely related to cancer, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. By regulating the mTOR signaling pathway, it is possible to have a positive effect on cancer, neurodegenerative diseases, metabolic diseases, and autoimmune diseases.
  • diseases that respond to mTOR inhibition can be treated or prevented, including but not limited to: cancers, such as melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, uterine cancer, cervical cancer or leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, lymphangioleiomyomas, subependymal giant cell astrocytomas, lymphomas, soft tissue sarcomas, Sarcoma, meningioma, glioblastoma, non-Hodgkin's lymphoma, refractory central nervous system lymphoma, tuberous sclerosis-associated angiofibrom
  • cancers such as melanoma, breast cancer, colorectal
  • the compounds of the present invention have satisfactory mTOR inhibitory activity, in particular good mTORC1 and/or mTORC2 inhibitory activity, and show good activity in inhibiting cancer cell proliferation. They can be used to treat diseases responsive to mTOR inhibition, such as cancer, nervous system diseases, metabolic diseases, autoimmune diseases, and organ fibrosis, as well as conditions requiring mTOR inhibition, and can be used as immunosuppressants.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg deuterated derivative) or solvate.
  • the present invention provides a method of treating or preventing a disease responsive to mTOR inhibition in an individual, the method comprising administering to the individual an effective amount of a compound of the present invention.
  • the present invention provides a method for preparing the compound of the present invention.
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;
  • R2 is H, halogen, CN, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, NRaRb , NRaRbCO-, NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl ) -CO-, ( C1-6 alkyl )-SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)-;
  • R 3 is hydrogen, deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl;
  • each R 4 is independently halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy , C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO
  • R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-;
  • RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ;
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;
  • L represents a valence bond, a C 1-6 alkylene group optionally substituted with one or more RL , -NR a -, -O-, -CO-, -SO- or -SO 2 -;
  • A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ;
  • R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy , NRaRb , NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl)-SO-, ( C1-6 alkyl ) -SO2- , ( C1-6 alkyl)-SO(NH)-, ( C1-6 alkoxy)-CO-, and C3-8 cycloalkyl; ( C1-6 alkyl)-CO-; ( C1-6 alkyl)-SO-; ( C1-6 alkyl) -SO2- ;
  • R 3 is hydrogen, deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl;
  • each R 4 is independently halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy , C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO
  • R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-;
  • RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ;
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;
  • A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ;
  • Ring B is connected to A 2 or A 3 and represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 3-10 membered heterocycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
  • R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy , NRaRb , NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl)-SO-, ( C1-6 alkyl ) -SO2- , ( C1-6 alkyl)-SO(NH)-, ( C1-6 alkoxy)-CO-, and C3-8 cycloalkyl; ( C1-6 alkyl)-CO-; ( C1-6 alkyl)-SO-; ( C1-6 alkyl) -SO2- ;
  • R4 is each independently halogen, cyano, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C3-8 cycloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkylene-, NRaRb , NRaRb - CO- , NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl )-CO-, ( C1-6 alkyl ) -SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)- , or two R4 together form a C1-3 alkylene bridge ;
  • Selected from It contains The ring is aromatic. In some embodiments, Preferably selected from More preferably selected from Still more preferably selected from The most preferred It contains The ring is aromatic.
  • the ring is aromatic, and other symbols are as defined herein.
  • the formula (I) has the structure of any one of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If), and most preferably has the structure of (Ic).
  • L represents a bond, C 1-6 alkylene, -NR a -, -O-, -CO-, or -SO 2 -. In some embodiments, L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -. In some embodiments, L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-, preferably a bond, C 1-6 alkylene, or -N(C 1-6 alkyl)-.
  • L represents a bond, -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, -SO-, or -SO 2 -.
  • L is a bond.
  • L is C 1-6 alkylene.
  • L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -.
  • L is -NH-, -N(C 1-6 alkyl)-, or -N(C 3-8 cycloalkyl-C 1-6 alkylene-)- (e.g., -N(cyclopropyl-CH 2 -)-).
  • L is -O-, -CO-, -SO-, or -SO 2 -.
  • L represents a bond, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -.
  • A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, more preferably represents C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, still more preferably represents 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more, for example, one to three independently selected R 4.
  • A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl, each optionally substituted by one or more, for example, one to three independently selected R 4 .
  • A represents C 1-6 alkyl, for example C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, each optionally substituted by one or more, for example one to three independently selected R 4 .
  • A represents C 3-8 cycloalkyl, for example C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by one or more, for example one to three independently selected R 4 .
  • A represents C 3-8 cycloalkenyl, for example C 3-6 cycloalkenyl, such as cyclopentenyl, cyclohexenyl or cyclohexadienyl, each optionally substituted by one or more, for example one to three independently selected R 4 .
  • A represents a 3-10 membered, for example, 6-10 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example, one to three independently selected R 4.
  • A represents a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3, for example, 1 or 2 heteroatoms independently selected from N, O or S.
  • A represents piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridine, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, oxazinane, morpholinyl, thiomorpholinyl, thiadiazinyl, 1,1-dioxothiomorpholine 1,1-dioxide, tetrahydro-2H(1,1-dioxo)thiopyranyl, tetrahydro-2H- ...
  • A represents C 6-10 aryl, such as phenyl or naphthyl, each optionally substituted with one or more, such as one to three, independently selected R 4 .
  • X is O, -CH 2 -, or -NH-;
  • the compound of formula (I) of the present invention has formula (Ij):
  • m is 1 and n is 1. In other embodiments, m is 1 and n is 2. In other embodiments, m is 2 and n is 1. In other embodiments, m is 2 and n is 2.
  • each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy , NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl )-CO-, and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge.
  • each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.
  • each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), and (C 1-6 alkyl)-SO 2 -.
  • each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, and (C 1-6 alkyl )-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO- and (C 1-6 alkyl)-CO-, or two R 4 are taken together to form a C 1-3 alkylene bridge.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b -CO-, or two R 4 are taken together to form a C 1-3 alkylene bridge. More preferably, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy, or two R 4 together form a C 1-3 alkylene bridge.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, or C 1-6 haloalkoxy.
  • A represents C 1-6 alkyl, such as C 1-4 alkyl, each optionally substituted by one or more, such as one to three, independently selected R 4 , wherein R 4 is as defined herein.
  • R 4 is each independently selected from cyano, NR a R b , (C 1-6 alkyl)-SO 2 - and (C 1-6 alkyl)-SO(NH)-, more preferably NR a R b , wherein R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy.
  • A represents C 1-6 alkyl, such as C 1-4 alkyl, each optionally substituted by one or more, such as one to three, independently selected R 4 , wherein R 4 is each independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, preferably selected from halogen, cyano, hydroxy, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, more preferably selected from cyano, (C 1-6 alkyl)
  • A represents a C 3-8 cycloalkyl group, for example a C 3-6 cycloalkyl group, each optionally substituted by one or more, for example one to three, independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, hydroxyl and NH 2 , more preferably cyano.
  • A represents a C 3-8 cycloalkyl group, for example a C 3-6 cycloalkyl group, each optionally substituted by one or more, for example one to three, independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, C 1-6 alkoxy, hydroxy and NH 2 , more preferably cyano and C 1-6 alkoxy.
  • A represents a C 3-8 cycloalkenyl group, such as a C 3-6 cycloalkenyl group, each optionally substituted with one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, hydroxyl, NH 2.
  • A represents a C 3-8 cycloalkenyl group, such as a C 3-6 cycloalkenyl group, optionally substituted with one or more C 1-6 alkyl groups such as methyl.
  • A represents a 3-10 membered heterocycloalkyl, for example a 3-10 membered, for example a 6-10 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example one to three independently selected R 4 , the heterocycloalkyl may be a monocyclic or bicyclic cyclic group (including spirocycles), and any N and S heteroatoms of the heterocycloalkyl are optionally oxidized, for example in the form of NO, SO, SO 2 .
  • R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl.
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy , NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl.
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl.
  • A represents a 3-10 membered, preferably a 3-8 membered, heterocycloalkyl group containing 1, 2 or 3, for example 1 or 2, heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and N R a R b , or two R 4 together form a C 1-3 alkylene bridge; preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated
  • A represents C 6-10 aryl, such as phenyl or naphthyl, each optionally substituted by one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-; preferably selected from NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-; more preferably NR a R b -CO-, such as NH 2 -CO-, NH (C 1-6 alkyl) -CO- or N (C 1-6 alkyl) (C 1-6 alkyl) -CO-.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 de
  • A represents a 5-10 membered, preferably a 5-7 membered, heteroaryl group, e.g., a 5- or 6 membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, e.g., one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl and C 1-6 haloalkyl; preferably selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl and C 1-6 haloalkyl; more preferably selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • A represents wherein R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl.
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl ) -SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl.
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl.
  • A represents wherein R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl , and NR a R b , or two R 4 together form a C 1-3 alkylene bridge; preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, and (C 1-6 alkyl)-CO-, or two R 4 together form a C 1-3 alkylene bridge; more preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuter
  • A represents wherein Y is C or N, and when there is more than one R 4 , at least one of said R 4 is located at an ortho position relative to Y. Further, said R 4 located at an ortho position relative to Y is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NH 2 , NH(C 1-6 alkyl)-CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - or (C 1-6 alkyl)-SO(NH)-, preferably selected from C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 haloalkyl, for example, methyl, deuterated methyl or trifluoromethyl
  • A is selected from:
  • A is selected from:
  • ring B represents a C 6-10 aryl group, such as phenyl or naphthyl, preferably phenyl.
  • B represents C6-10 aryl or 5-10 membered heteroaryl, preferably represents phenyl or 5-7 membered, for example 5- or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • R2 is selected from H, halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-, preferably selected from H, C1-6 alkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-, more preferably selected from H, C1-6 alkyl or NH( C1-6 alkyl)CO-.
  • B represents a C6-10 aryl group (e.g., phenyl or naphthyl), and R2 is selected from H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, preferably selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, more preferably NH( C1-6 alkyl)CO-.
  • R2 is selected from H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, preferably selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, more preferably NH( C1-6 alkyl)CO-.
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy, (C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; C 1-6 alkoxy; C 1-6 haloalkoxy; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; C 3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene, 3-10 membered heterocycloalkyl-C 1-6 alkylene, C 6-10 aryl-C 1-6 alkylene, or 5-10 membered heteroaryl-C 1-6 alkylene, wherein
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C The 6-10 membered aryl group is phenyl, or the 5-10 membere
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl.
  • R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetanyl.
  • R 1 is: cyano, C 1-6 alkyl, or C 1-6 haloalkyl, such as cyano, methyl, or CF 3 .
  • R 1 is: absent; hydrogen; halogen; cyano; hydroxy; C 1-6 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl , each independently optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NRaRb (such as NH2 ), NRaRbCO- , NRaRbSO- , NRaRbSO2- , C 1-6 alkoxy , (C 1-6 alkyl ) -CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO2-, (C 1-6 alkyl)-SO( NH )-, ( C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl )-SO-; (C 1-6 alkyl )-
  • R 1 is: absent; hydrogen; halogen; cyano; hydroxy; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, (C 1-6 alkyl)-SO(NH)-, (C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (such as phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO-; NR a R b
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.
  • substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.
  • substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8
  • R 1 is: hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more, e.g., one, two, or three, substituents independently selected from halogen, cyano, hydroxy, NR a R b (e.g., NH 2 ), C 1-6 alkoxy, and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.
  • substituents independently selected from halogen, cyano, hydroxy, NR a R b (e.g., NH 2 ), C 1-6 alkoxy, and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10
  • R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (eg, NH 2 ) and C 1-6 alkoxy; C 3-8 cycloalkyl; or 3-10 membered heterocycloalkyl.
  • R 1 is C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 haloalkyl substituted by C 1-6 alkoxy, C 1-6 haloalkyl substituted by amino, or C 1-6 haloalkyl substituted by hydroxy.
  • R is a 3-10 membered heterocycloalkyl, for example, a 3-10 membered, preferably a 3-8 membered, heterocycloalkyl containing 1, 2 or 3, for example 1 or 2 , heteroatoms independently selected from N, O or S.
  • R is azetidinyl, oxetanyl, azepanyl, oxolanyl, azepanyl, oxetanyl, azepanyl, oxepanyl.
  • R is azetidinyl, oxetanyl, more preferably R is oxetanyl.
  • R 1 is selected from the group consisting of: absent, hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, methyl, CF 2 H—, CF 3 , (CF 3 )CH 2 —, (CF 3 )(CH 3 )CH—, (CF 3 )CHF—, (CF 3 )CF 2 —, fluoropropyl; CN—CH 2 —, (CN)(CH 3 )CH—, (CN)(CH 3 O)CH—, hydroxypropyl, (CF 3 )(OH)CH—, (CF 3 )(OH) 2 C—, (CF 3 )(NH 2 )CH—, (CF 3 )(CH 3 O)CH—, CH 3 OC(O)—CH(CH 3 )—, cyclopropyl-(CH 2 )—, cyclopropyl, oxetanyl, phenyl, CH 3 CO—, Et—SO 2
  • W is N or CR 3
  • R 3 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl (such as C 1-4 alkyl), or C 1-6 haloalkyl (such as C 1-4 haloalkyl).
  • R 3 is hydrogen, deuterium, halogen, cyano, or C 1-6 alkyl (such as C 1-4 alkyl). More preferably, R 3 is hydrogen, deuterium, halogen, or C 1-6 alkyl (such as C 1-4 alkyl).
  • R 3 is hydrogen, deuterium, or halogen, for example, hydrogen or halogen.
  • R 3 is hydrogen, halogen, cyano, or C 1-3 haloalkyl. In other embodiments, R 3 is hydrogen, halogen, or cyano. In other embodiments, R 3 is hydrogen or halogen.
  • W is N or CR 3 , wherein R 3 is H or halogen. In other embodiments, W is N. In other embodiments, W is CH. In some embodiments, W is CR 3 , wherein R 3 is deuterium. In other embodiments, W is CR 3 , wherein R 3 is halogen. In some embodiments, W is CR 3 , wherein R 3 is C 1-6 alkyl (such as C 1-4 alkyl).
  • Ra and R are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy. In some embodiments, Ra and R are both hydrogen. In some embodiments, one of Ra and R is hydrogen, and the other is C 1-6 alkyl optionally substituted by C 1-6 alkoxy. In some embodiments, Ra and R are both C 1-6 alkyl optionally substituted by C 1-6 alkoxy. For example, Ra is C 1-6 alkyl and R is C 1-6 alkyl optionally substituted by C 1-6 alkoxy.
  • Ra is hydrogen
  • Rb is C3-8cycloalkyl - C1-6alkylene- .
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -;
  • A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;
  • 3-10 membered heterocycloalkyl e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • C 6-10 aryl e.g.
  • Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a pyridyl group, a pyridonyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group;
  • a C6-10 aryl group e.g., phenyl or naphthyl
  • R2 is H, halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-;
  • R 3 is hydrogen, deuterium, halogen or C 1-6 alkyl (such as C 1-4 alkyl);
  • R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-;
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-;
  • Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group or a pyridyl group;
  • a C6-10 aryl group e.g., phenyl or naphthyl
  • a 5-10 membered heteroaryl group e.g., a 5-10 membered, e.g., a 5-7 membered, e.g.,
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C 6-10- membered aryl is phenyl, or the 5-10-membered heteroaryl
  • R2 is H, C1-6 alkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-;
  • R3 is hydrogen, deuterium or halogen
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;
  • R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy;
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond, C 1-6 alkylene or -N(C 1-6 alkyl)-;
  • A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;
  • 3-10 membered heterocycloalkyl e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • C 6-10 aryl e.g. phenyl or naphthyl
  • Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group;
  • a C6-10 aryl group e.g., phenyl or naphthyl
  • a 5-10 membered heteroaryl group e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroary
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;
  • R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;
  • R3 is hydrogen, deuterium or halogen
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;
  • R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy;
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond, C 1-6 alkylene or -N(C 1-6 alkyl)-;
  • A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;
  • 3-10 membered heterocycloalkyl e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • C 6-10 aryl e.g. phenyl or naphthyl
  • Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group;
  • a C6-10 aryl group e.g., phenyl or naphthyl
  • a 5-10 membered heteroaryl group e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroary
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;
  • R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;
  • R3 is hydrogen, deuterium or halogen
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;
  • R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy;
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond
  • A represents a 3-10 membered heterocycloalkyl group (e.g. a 3-10 membered, e.g. a 6-10 membered, heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S) or a 5-10 membered heteroaryl group (e.g. a 5-10 membered, preferably a 5-7 membered, e.g. a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S), preferably a 3-10 membered heterocycloalkyl group, each optionally substituted by one or more independently selected R 4 ;
  • a 3-10 membered heterocycloalkyl group e.g. a 3-10 membered, e.g. a 6-10 membered, heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • a 5-10 membered heteroaryl group e.g.
  • Ring B is connected to A 2 or A 3 , preferably connected to A 2 , and represents a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6 membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a pyrazolyl group;
  • R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetane;
  • R2 is H or C1-6 alkyl
  • R3 is hydrogen, deuterium or halogen
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If).
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-, preferably a bond, C 1-6 alkylene, -NH-, or -N(C 1-6 alkyl)-;
  • A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;
  • Ring B is connected to A 2 or A 3 , preferably connected to A 2, and represents a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a pyrazolyl group;
  • R 1 is cyano, C 1-6 alkyl or C 1-6 haloalkyl, such as cyano, methyl or CF 3 ;
  • R 2 is H or C 1-6 alkyl; preferably, R 2 is H;
  • R 3 is hydrogen, deuterium or halogen; preferably, R 3 is hydrogen or deuterium;
  • R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- and (C 1-6 alkyl)-SO 2 -;
  • R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy;
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic).
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:
  • W is N or CR 3 ;
  • a 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;
  • L represents a valence bond
  • A represents C3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R4 ;
  • 3-10 membered heterocycloalkyl e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S
  • C6-10 aryl e.g. phenyl or naphthyl
  • R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;
  • R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;
  • R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO- and (C 1-6 alkyl)-CO-, or two R 4 together form a C 1-3 alkylene bridge;
  • the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).
  • the present invention provides the compounds of the embodiments or pharmaceutically acceptable salts, tautomers, stereoisomers, deuterated derivatives or solvates thereof.
  • the compounds of the embodiments are selected from:
  • Representative examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, etc.
  • alkylene alone or as part of another group refers to a fully saturated straight-chain or branched divalent hydrocarbon group composed of carbon and hydrogen atoms.
  • Alkylene is, for example, C 1-6 alkylene, preferably C 1-3 alkylene, and more preferably C 1-2 alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, and the like.
  • haloalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by halogen. It will be understood that when there are more than one halogen substituent, the halogen substituents may be the same or different and may be located on the same or different carbon atoms.
  • the haloalkyl group is preferably a C 1-6 haloalkyl group, more preferably a C 1-4 haloalkyl group or a C 1-3 haloalkyl group.
  • Representative examples include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl and trifluoropropyl, and the like.
  • hydroxyalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, for example, 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, for example, 1, 2, or 3 hydrogen atoms, are replaced by hydroxy groups.
  • Hydroxyalkyl is preferably a C 1-6 hydroxyalkyl, more preferably a C 1-4 hydroxyalkyl or a C 1-3 hydroxyalkyl. Representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.
  • cyanoalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, for example, 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, for example, 1, 2 or 3 hydrogen atoms, are replaced by a cyano group.
  • the cyanoalkyl group is preferably a C 1-6 cyanoalkyl group, more preferably a C 1-4 cyanoalkyl group or a C 1-3 cyanoalkyl group. Representative examples include, but are not limited to, cyanomethyl, cyanoethyl, cyanopropyl, and the like.
  • alkoxy or "alkyloxy” are used interchangeably and refer to an alkyl group as defined above attached through an oxygen bridge.
  • Alkoxy is preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group or a C 1-3 alkoxy group.
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentoxy (including n-pentoxy, isopentoxy, neopentoxy, etc.), hexyloxy, heptyloxy, octyloxy, and the like.
  • alkylthio or “alkylthio” are used interchangeably and refer to an alkyl group as defined above connected through a sulfur bridge.
  • Alkylthio is preferably a C 1-6 alkylthio, more preferably a C 1-4 alkylthio or a C 1-3 alkylthio.
  • Representative examples include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, etc.), pentylthio (including n-pentylthio, isopentylthio, neopentylthio, etc.), hexylthio, heptylthio, octylthio, etc.
  • haloalkoxy or "haloalkyloxy” is used interchangeably to refer to an alkoxy group as defined above that is substituted with one or more halogens.
  • the haloalkoxy group is preferably a C 1-6 haloalkoxy group, more preferably a C 1-4 haloalkoxy group or a C 1-3 haloalkoxy group.
  • hydroxyalkoxy refers to an alkoxy group as defined above substituted by one or more hydroxy groups.
  • the hydroxyalkoxy group is preferably a C 1-6 hydroxyalkoxy group, more preferably a C 1-4 hydroxyalkoxy group or a C 1-3 hydroxyalkoxy group.
  • cyanoalkoxy refers to an alkoxy group as defined above which is substituted by one or more cyano groups.
  • the cyanoalkoxy group is preferably a C 1-6 cyanoalkoxy group, more preferably a C 1-4 cyanoalkoxy group or a C 1-3 cyanoalkoxy group.
  • deuterated means that one or more H in a compound or group is replaced by deuterium (D). It is understood that, unless otherwise indicated, the compounds or groups described herein encompass their deuterated forms (e.g., deuterated derivatives).
  • deuterated alkoxy refers to an alkoxy group as defined above in which one or more H groups are replaced by deuterium (D).
  • Deuterated alkoxy is preferably a C 1-6 deuterated alkoxy group, more preferably a C 1-4 deuterated alkoxy group or a C 1-3 deuterated alkoxy group.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms.
  • the cycloalkyl group is preferably a C 3-8 cycloalkyl group, more preferably a C 5-8 cycloalkyl group.
  • Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group composed of carbon and hydrogen atoms and containing one or more double bonds.
  • the cycloalkenyl group is preferably a C3-8 cycloalkenyl group, and more preferably a C5-8 cycloalkenyl group.
  • Representative examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • heterocycloalkyl refers to a saturated monocyclic or bicyclic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4, for example 1, 2 or 3 heteroatoms independently selected from N, O or S and the remaining ring members being carbon, including spirocycles. It is understood that heterocycloalkyl can be substituted by completely unsaturated or partially unsaturated substituents.
  • heterocycloalkyl herein includes those in which the carbon members are optionally replaced by -CO-, those in which the arbitrary N and S heteroatom ring members are optionally oxidized, and/or those in which the arbitrary N heteroatom ring members are optionally quaternized.
  • heterocycloalkyl include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, imidazolonyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperidonyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, oxepanyl, azepanyl, oxazazepanyl, etc.
  • Heterocycloalkyl can be connected to the rest of the molecule by a carbon atom or a heteroatom, as long as it is chemically feasible.
  • a heterocycloalkyl contains only oxygen as a heteroatom, it can be referred to as an "oxepanyl".
  • aryl refers to an aromatic carbon ring having one or more rings, preferably 1 or 2 rings.
  • Aryl is preferably a C 6-10 aryl. Representative examples include, but are not limited to, phenyl (i.e., C 6 aryl), naphthyl, and the like.
  • heteroaryl refers to a cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4, heteroatoms independently selected from N, O or S, and the remaining ring members being carbon.
  • heteroaryl herein includes those in which carbon members are optionally replaced by -CO-, those in which any N and S heteroatom ring members are optionally oxidized, and/or those in which any N heteroatom ring members are optionally quaternized.
  • any N and S heteroatoms of the heteroaryl group may be optionally oxidized (e.g., in NO, SO, SO 2 ) and any N heteroatom may be optionally quaternized (e.g., in [NR] + Cl - , [NR] + OH - ).
  • the heteroaryl group is preferably a 5- to 10-membered heteroaryl group, more preferably a 5- to 7-membered heteroaryl group, and most preferably a 5- or 6-heteroaryl group.
  • Representative examples include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, oxazinyl, oxadiazinyl, indolyl, isoindolyl, azaindolyl (e.g., 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl), benzofuranyl, isobenzofuranyl, benzothiophenyl, benzothiazole aryl, benzoxazolyl, benzoimidazolyl, benzoxazolyl, quinolinyl,
  • hydroxy refers to OH.
  • NH2 represents an amino group.
  • -NH( C1-6alkyl ) represents an amino group substituted with one C1-6alkyl group.
  • -N( C1-6alkyl )( C1-6alkyl ) represents an amino group substituted with two identical or different C1-6alkyl groups, for example, dimethylamino, (methyl)(ethyl)amino-, etc.
  • -PO- represents a phosphoryl group
  • a hyphen (“-") that is not between two letters or symbols indicates the point of attachment of a substituent.
  • -NRaRb indicates that the group is attached to the rest of the molecule through the nitrogen atom
  • -C1-3alkylene - C3-8cycloalkyl indicates that the point of attachment of the group is on the C1-3alkylene group.
  • the bond passes through the ring, e.g. In the embodiment, it means that the ring is connected to other parts through any available position on the ring.
  • the ring is an aromatic ring, that is, the selection of A1 to A5 in the general formula makes the formed ring satisfy the valence bond theory of aromatic rings and is chemically feasible and stable.
  • each of the Rs may be the same or different, and the Rs may be located on the same or different atoms.
  • substituted by one or more substituents independently selected from A, B and C refers to the case of being substituted by one or more substituents each independently selected from A, B and C, for example, substituted by one or more A, substituted by one or more B, substituted by one or more C, substituted by one or more A and one or more B, substituted by one or more A and one or more C, substituted by one or more B and one or more C, substituted by one or more A, one or more B and one or more C, etc.
  • compound of the present invention refers to a compound according to formula (I) or its subformulae, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij), or a salt thereof, in particular a pharmaceutically acceptable salt, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformers (including rotamers and atropisomers), metabolites, prodrugs and isotopic derivatives (including deuterated derivatives), including polymorphs, solvates and/or hydrates, including those defined in the embodiments and examples.
  • formula (I) or its subformulae such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij), or a salt thereof, in particular a pharmaceutically acceptable salt, as
  • compound of the present invention refers specifically to the compound of the examples or a salt thereof, in particular a pharmaceutically acceptable salt, as well as tautomers, stereoisomers, geometric isomers, conformers, metabolites, prodrugs and isotopic derivatives (e.g., deuterated derivatives), including polymorphs, solvates and/or hydrates.
  • references to formula (I) also include subformulas thereof, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij).
  • phrases “pharmaceutically acceptable” refers to substances or compositions that do not produce adverse, allergic or other undesirable reactions when administered to animals, such as humans.
  • the compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” include acid addition salts and base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to those salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable.
  • Acid addition salts can be formed with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, bisulfates, nitrates, carbonates, phosphates, and the like, and organic acid salts such as formates, acetates, trifluoroacetates, propionates, glycolates, gluconates, lactates, pyruvates, oxalates, malates, malonates, glutarates, adipates, succinates, fumarates, maleates, tartrates, citrates, aspartates, xinafoates, ascorbates, glutamates, o-aminobutyrates, thiazolinone ...
  • organic acids such as hydrochlorides, hydrobromides, sulfates, bisulfates, nitrates, carbonates, phosphates, and the like
  • organic acid salts such as formates, acetates, trifluoroacetates,
  • Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like; and those derived from non-toxic organic bases: primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Salts can be synthe
  • the compounds of the present invention may contain one or more asymmetric carbon atoms.
  • the compounds may exist as diastereomers, enantiomers, or mixtures thereof.
  • the synthesis of the compounds may employ racemates, diastereomers, or isomers as starting materials or as intermediates.
  • a mixture of specific diastereomeric compounds may be separated or enriched for one or more specific diastereomers by chromatography or crystallization methods.
  • enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques or other techniques known in the art.
  • Asymmetric carbon or nitrogen atoms may each be in R or S configuration, both of which are within the scope of the present invention.
  • all stereoisomers are included as compounds of the present invention.
  • the stereochemical definitions and conventions used herein follow the common conventions in the art.
  • diastereoisomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and biological activities. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
  • isotopes that can be incorporated into the compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of hydrogen (e.g., 2H , 3H ); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ). It will be appreciated that isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures using appropriate isotopic
  • metabolite refers to a product produced by the metabolism of a particular compound or its salt in vivo. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound.
  • the structure of the metabolite is determined in a conventional manner, for example, by MS, LC/MS or NMR analysis. Generally, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites can be used in diagnostic assays for therapeutic doses of the compounds of the present invention, as long as they are not found in vivo.
  • prodrug refers to a chemically modified active or inactive compound that, after administration to a subject, undergoes physiological action in vivo (e.g., hydrolysis, necrolysis, etc.) to convert into a compound of the present invention.
  • physiological action e.g., hydrolysis, necrolysis, etc.
  • the techniques for making and using prodrugs are well known to those skilled in the art.
  • polymorph refers to crystalline forms having the same chemical structure/composition but differing in the spatial arrangement of the molecules and/or ions that form the crystals.
  • the compounds of the present invention may be provided as amorphous solids or crystalline solids. The scope of the present invention is intended to encompass all such physical forms.
  • solvate refers to an association or complex of one or more solvent molecules with a compound of the present invention.
  • solvents that form solvates include water, isopropanol, ethanol, MeOH, DMSO, EA, acetic acid, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.
  • the compounds of the present invention also encompass N-oxides that may exist, and those skilled in the art will be able to determine stable and viable N-oxides of the compounds of the present invention.
  • the compounds of the present invention also encompass metabolites of the compounds of the present invention, i.e., substances formed in vivo by oxidation, reduction, hydrolysis, amidation, esterification, etc., when the compounds of the present invention are administered, which can be identified by techniques well known in the art.
  • subject refers to an animal, preferably a mammal.
  • subjects include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), horses, cows, sheep, cats, dogs, rabbits, rabbits, and rodents (e.g., mice and rats).
  • the subject is a human, including a child, adolescent, or adult.
  • treating refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, and optionally (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.
  • “treating” refers to improving at least one physical parameter, which may not be noticeable to the patient.
  • “treating” refers to modulating a disease or condition physically (e.g., stabilizing a noticeable symptom) or physiologically (e.g., stabilizing a physical parameter), or both.
  • prevention refers to the administration of one or more pharmaceutical substances, particularly compounds of the present invention and/or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease or condition in question, in order to prevent the individual from developing the disease.
  • inhibitor and “alleviate” and the like refer to a reduction or suppression of a particular condition, symptom or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • disease responsive to mTOR inhibition refers to a disease in which abnormalities in the mTOR signaling pathway contribute to the onset and progression of the disease, or in which mTOR inhibition reduces the incidence, alleviates, or eliminates disease symptoms.
  • diseases responsive to mTOR inhibition include, but are not limited to, cancer, neurological diseases, metabolic diseases, and autoimmune diseases, which are associated with abnormalities in the mTOR signaling pathway.
  • condition requiring mTOR inhibition refers to situations in which mTOR inhibition can produce beneficial effects or can reduce or prevent adverse effects, and the situations can be disease or non-disease, such as situations requiring immunosuppression, such as transplant organ rejection, or can be used for vascular stent coatings to exert anti-rejection effects.
  • an effective amount refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the required dosage and for the required period of time. It can be determined by the attending physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Generally, a “prophylactically effective amount” will be less than a "therapeutically effective amount.”
  • preparation refers to a composition suitable for administration to an animal, preferably a mammal (including a human) comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient.
  • the preparation of the present invention can be any preparation suitable in the art, such as a tablet, capsule, liquid preparation, etc.
  • pharmaceutically acceptable carrier refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to a subject.
  • pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.
  • treating refers to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and/or desired product.
  • a "and/or" B includes A alone, B alone, and the case of A+B.
  • the term "about” when used in conjunction with a numerical value means a range of ⁇ 20%, preferably ⁇ 10%, and more preferably ⁇ 5% of that numerical value.
  • the compounds of the present invention have good mTOR inhibitory activity, particularly good mTORC1 and/or mTORC2 inhibitory activity, and exhibit good activity in inhibiting cancer cell proliferation.
  • the compounds of the present invention also exhibit good in vivo and/or in vitro pharmacokinetic properties, such as good dissolution and/or absorption, good metabolic stability, improved bioavailability, reduced side effects, etc.
  • the compounds of the present invention also have good physical and/or chemical stability. Therefore, the compounds of the present invention can be used in a variety of applications requiring mTOR inhibitory activity, particularly mTORC1 and/or mTORC2 inhibitory activity.
  • the compounds of the present invention are useful for treating or preventing diseases responsive to mTOR inhibition, particularly diseases responsive to mTORC1 and/or mTORC2 inhibition, such as cancer, neurological diseases, metabolic diseases, autoimmune diseases, or organ fibrosis.
  • diseases responsive to mTOR inhibition particularly diseases responsive to mTORC1 and/or mTORC2 inhibition, such as cancer, neurological diseases, metabolic diseases, autoimmune diseases, or organ fibrosis.
  • the compounds of the present invention can be used to treat or prevent cancer, such as melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, uterine cancer, cervical cancer or leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, lymphangioleiomyomas, subependymal giant cell astrocytomas, lymphomas, soft tissue sarcomas, sarcomas, meningiomas, glioblastomas, non-Hodgkin's lymphomas, refractory central nervous system lymphomas, tuberous sclerosis-associated angiofibromas, etc.
  • cancer such as melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer
  • the compounds of the present invention can be used to treat or prevent neurological diseases such as neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.
  • neurological diseases such as neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.
  • the compounds of the present invention can be used to treat or prevent metabolic diseases, such as diabetes, insulin resistance, obesity, aging, and the like.
  • the compounds of the present invention can be used to treat or prevent autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, and the like.
  • autoimmune diseases such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, and the like.
  • the compounds of the invention are useful in treating organ fibrosis, such as idiopathic pulmonary fibrosis.
  • the compound of the present invention and other active agents can be (i) before the combination product is sent to the physician (e.g., in the case of a kit comprising the compound of the present invention and other active agents); (ii) by the physician himself (or under the guidance of a physician) before administration; or (iii) by the patient himself, such as during the sequential administration of the compound of the present invention and other active agents, added to the combination therapy.
  • the present application provides a pharmaceutical composition comprising a compound of the present invention and one or more other active agents.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the starting materials and intermediates in the synthetic reaction schemes can be separated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc.
  • the materials can be characterized by conventional methods including physical constants and spectral data.
  • Step 1 Compound A1 reacts with an amine in the presence of a base such as DIEA and in a solvent such as NMP under heating (e.g., at 100° C.) to obtain a compound of formula A2;
  • Step 2 reacting a compound of formula A2 with an amine in the presence of a base such as DIEA in a solvent such as NMP with heating (e.g., at 130° C.) to obtain a compound of formula A3;
  • Step 3 Suzuki coupling of the compound of formula A3 with boronic acid or boronic ester in the presence of a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4 and heating in a solvent such as dioxane/water to obtain a compound of formula A4; and
  • a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4
  • a solvent such as dioxane/water
  • Step 4 Compound A4 is deprotected under the action of acid to obtain compound A5.
  • the compounds of the present invention can be synthesized by a method comprising the following steps:
  • Step 1 reacting a compound of formula B1 with an iodination reagent such as NIS in a solvent such as DMF under heating (e.g., 30° C.) to obtain a compound of formula B2;
  • Step 2 reacting the compound of formula B2 in the presence of a base such as Cs 2 CO 3 in a solvent such as DMF to obtain a compound of formula B3;
  • Step 3 reacting the compound of formula B3 with an amine in a solvent (such as NMP) under heating or microwave conditions to obtain a compound of formula B4;
  • a solvent such as NMP
  • Step 4 Compound B4 is reacted by Suzuki coupling in the presence of a coupling agent such as Pd(dppf)Cl 2 /H 3 PO 4 in a solvent such as dioxane/water with heating to obtain compound B5;
  • a coupling agent such as Pd(dppf)Cl 2 /H 3 PO 4
  • a solvent such as dioxane/water with heating
  • Step 5 heating the compound of formula B5 in the presence of a catalyst such as RuPhos-G2, a base such as Cs 2 CO 3 , and a solvent such as dioxane to obtain a compound of formula B6;
  • a catalyst such as RuPhos-G2
  • a base such as Cs 2 CO 3
  • a solvent such as dioxane
  • Step 6 Deprotecting the compound of formula B6 under the action of an acid such as HCl to obtain a compound of formula B7;
  • R 1 , X and p are as defined above for formula (I):
  • the compounds of the present invention can be synthesized by a method comprising the following steps:
  • Step 1 reacting a compound of formula C1 with an amine in the presence of a base such as DIPEA in a solvent such as NMP by heating to obtain a compound of formula C2;
  • Step 2 reacting the compound of formula C2 with an amine in the presence of a base such as DIEA in a solvent such as NMP with heating to obtain a compound of formula C3;
  • Step 3 reacting the compound of formula C3 with a cyanating agent such as Zn(CN) 2 in the presence of a catalyst such as Pd 2 (dba) 3 /DPPF and a solvent such as DMF by heating to obtain a compound of formula C4;
  • a cyanating agent such as Zn(CN) 2
  • a catalyst such as Pd 2 (dba) 3 /DPPF and a solvent such as DMF
  • Step 4 reacting the compound of formula C4 with a Grignard reagent to obtain a compound of formula C5;
  • Step 5 The compound of formula C5 is reacted by condensation reaction in the presence of a condensing agent such as HATU/DIEA in a solvent such as THF to obtain a compound of formula C6;
  • a condensing agent such as HATU/DIEA
  • a solvent such as THF
  • Step 6 The compound of formula C6 is heated in the presence of POCl 3 , such as at 100-150°C, to perform ring closure to obtain the compound of formula C7.
  • the compounds of the present invention can be synthesized by a method comprising the following steps:
  • Step 1 reacting a compound of formula D1 with a base such as DIPEA in a solvent such as THF at a temperature of 80° C. to obtain a compound of formula D2;
  • Step 2 Reaction of the compound of formula D2 with a base such as DIPEA in a solvent such as NMP at a temperature of, for example, 130° C. to obtain a compound of formula D3;
  • Step 3 Deprotecting the compound of formula D3 to obtain a compound of formula D4;
  • Step 3 The compound of formula E3 reacts with an amine in the presence of a base such as DIPEA and is heated in a solvent such as DMF (e.g., 80° C.) to obtain a compound of formula E4.
  • a base such as DIPEA
  • DMF e.g. 80° C.
  • Step 4 The compound of formula E4 is coupled with an amine in the presence of a coupling reagent such as Ruphos PdG2/ Cs2CO3 to obtain a compound of formula E5;
  • a coupling reagent such as Ruphos PdG2/ Cs2CO3
  • Step 6 Compound E6 is reacted with iodine in the presence of a base such as KOH to obtain compound E7;
  • Step 7 Compound E7 is subjected to Suzuki coupling or other coupling reaction to obtain compound E8-1; compound E7 is reacted with boronic acid or boronic acid ester to obtain compound E8-2;
  • Step 8 The compound of formula E8-1 is reacted with boronic acid or boronic ester to give a Chanlam reaction to obtain a compound of formula E9-1; or the compound of formula E8-2 is subjected to Suzuki coupling or other coupling reactions to obtain a compound of formula E9-2.
  • the experimental materials and reagents used in the following examples were obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application. Unless otherwise specified, the raw materials used in the present invention were commercially available and were used directly without further purification.
  • column chromatography uses silica gel (100-200 mesh) produced by Leyan Company; thin layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) uses Bruker AVANCE NEO-400 nuclear magnetic resonance instrument for determination; liquid chromatography-mass spectrometry (LC/MS) uses Agilent Technologi ESI 1260/1290 liquid chromatography-mass spectrometry instrument.
  • Method A Shim-pack Scepter C18-120, 3 ⁇ m, 4.5*50mm; mobile phase A: water/0.01% TFA, mobile phase B: ACN/0.01% TFA; flow rate: 1.8mL/min; gradient: 5-95% B in 1.3min, maintain 95% B in 1.7min, and finally drop to 5% B in 0.01min; detection wavelength 214,254nm, column temperature 45°C.
  • Method B Shim-pack Scepter C18-120, 3 ⁇ m, 3.0*33mm; mobile phase A: water/0.01% TFA, mobile phase B: ACN/0.01% TFA; flow rate: 1.8mL/min; gradient: 5% B to 95% B in 0.5min, hold 0.8min; detection wavelength 214,254nm, column temperature 45°C.
  • Method C Shimadzu LCMS-2020 column: YMC-Triart C18, 50*4.6mm, 5um; mobile phase A: water/0.1% FA, mobile phase B: acetonitrile; flow rate: 2.5mL/min; gradient: 0-0.01min maintain B phase at 20%, 0.01-1.80min B phase increases from 20% to 95%, 1.80-2.50min maintain B phase 95%, 2.50-2.51min within B phase decreases from 95% to 20%, 2.51-2.90min B phase maintains 20%; detection wavelength 254/220nm, column temperature 40°C.
  • Method D Shimadzu LC-2020; column: YMC-Triart C18, 50*4.6mm, 5um; mobile phase A: water/0.1% TFA, mobile phase B: acetonitrile/0.1% TFA; flow rate: 2.5mL/min; gradient: 20% B to 95% B in 3.4min, hold for 0.8min, then 20% B for 0.8min; detection wavelength 254/220nm, column temperature 40°C.
  • Method E Sepax GP-C18, 50 ⁇ 4.6mm, 5um; mobile phase A: water/0.1% TFA, mobile phase B: acetonitrile; flow rate: 2.5mL/min; gradient: 20% B in 0.01min, maintained to 95% B in 1.79min, and finally decreased to 20% B in 0.7min; detection wavelength 220,254nm, column temperature 40°C.
  • Method A (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IG_100x3.0mm_3 ⁇ m; mobile phase A: Supercritical CO2 , mobile phase B: MeOH (0.1% DEA), flow rate: 2.0ml/min; 5.0min; detection wavelength: 210nm, column temperature: 35°C.
  • Method B (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-ADHS150x4.6mm_5 ⁇ m, CN049; mobile phase A: Hexane, mobile phase B: EtOH, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35°C.
  • Method C (Waters UPCC system equipped with a PDA detector), column: RegisPack-IK_250x4.6mm_5 ⁇ m; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 6.0min; detection wavelength: 210nm, column temperature: 35°C.
  • Method D (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IG_100x3.0mm_3 ⁇ m; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 6.0min; detection wavelength: 210nm, column temperature: 35°C.
  • Method E (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-WHELK_150x4.6mm_5 ⁇ m; mobile phase A: Supercritical CO2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 5.0min; detection wavelength: 210nm, column temperature: 35°C.
  • Method F (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IES 150x4.6mm_5 ⁇ m, AS006; mobile phase A: n-hexane, mobile phase B: EtOH, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35°C.
  • Method G (SHIMADZY LC-20ADxr system equipped with a PDA detector), column: Daicel_ChiralPak-AD 4.6mmI.D.*150mm, 5 ⁇ m, CN049; mobile phase A: Hexane, mobile phase B: IPA, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35°C.
  • Step 4 Synthesis of 8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a)
  • Step 5 Synthesis of compound 8-(4-(cyclohex-1-en-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(4-(3-(fluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(4-(3-(fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(3-bromo-7-(3,3-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 3 Synthesis of 8-(7-(3,3-dimethylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(7-(3,3-dimethylmorpholinyl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 1-((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 2 Synthesis of 1-((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 2 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide
  • Step 4 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide
  • Step 5 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide
  • Step 2 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine
  • 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine (960 mg, 2.24 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. The reaction mixture was stirred at 25°C overnight. Saturated aqueous NaHCO3 was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2).
  • Step 4 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-bromo-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine
  • 6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine 200 mg, 0.58 mmol was dissolved in DMF (4 mL), and NBS (103 mg, 0.58 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. Saturated aqueous Na2SO3 was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 100° C. for 2 hrs. After the reaction mixture was cooled to room temperature, it was diluted with water and EA and extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (70 mg, 91.3% yield, yellow solid). LC-MS (ESI) m/z: 439.2 [M+H] + .
  • Step 7 8-(4-(3,3-dimethylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 8 8-(4-(3,3-dimethylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(4-((S)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 6-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine
  • Step 2 Synthesis of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8a)
  • 6-Fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine 23 g, 0.58 mmol was dissolved in NMP (200 mL), and DIPEA (43 g, 331 mmol) and 8-aza-3-oxabicyclo[3.2.1]octane (8.3 g, 73 mmol) were added. Under N2 protection, the reaction mixture was stirred at 25°C for 16 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (200 mL x 2).
  • Step 3 Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 3 Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 5 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 6 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 7 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((R)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Examples 16 and 17 ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1-trifluoropropan-2- yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol and ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3- yl)-3-((R,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol
  • Step 7 Synthesis of ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol
  • Step 3 Synthesis of 8-(3-iodo-7-((R)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(7-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 8 Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
  • Example 21 and Example 22 (S)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile and (R)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl )-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile
  • reaction mixture was stirred at 0°C for 2 hrs.
  • the reaction mixture was poured into a sufficient amount of water to quench the reaction mixture, followed by extraction with EA (50 mL x 2).
  • the combined organic phases were washed with water, dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography ( DCM:MeOH, 4% MeOH) to afford the title compound (2.8 g, 87.0% yield, yellow solid).
  • Step 2 Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one
  • Step 3 Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one
  • reaction mixture was stirred at 120° C. for 16 hrs under N 2 protection and then cooled to room temperature.
  • the reaction mixture was diluted with water and EA, and extracted with EA (20 mL x 2).
  • the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (DCM:MeOH, 5% MeOH) to obtain the crude product (550 mg, 51.2% yield, yellow solid).
  • Step 1 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(oxetan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propan-2-ol
  • Step 3 Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 5 Synthesis of 8-(4-(3,3-dimethylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 6 Synthesis of 8-(4-(3,3-dimethylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • the target compound (10 mg, white solid) was synthesized by referring to the synthesis method of Example 15.
  • the reaction mixture was stirred in an autoclave at 80°C under 15 atm CO2 for 16 hours and then cooled to room temperature.
  • the reaction mixture was diluted with water and EA, and extracted with EA (150 mL x 2).
  • the combined organic phases were washed with saturated brine (500 mL x 5), dried over anhydrous Na2SO4 , and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (1.40 g, yield 83.5%, brown solid).
  • Step 2 Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol
  • 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde 100 mg, 0.11 mmol was dissolved in THF (20 mL). Trimethyltrifluoromethylsilane (165 mg, 1.16 mmol) was slowly added dropwise, and the mixture was stirred at 25°C for 10 min. TBAF was then slowly added dropwise and stirred at 25°C for 30 min.
  • Example 36 and Example 37 (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazole-3-yl)- (R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3- (methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol
  • Example 39 and Example 40 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((R,2,2,2- trifluoro-1-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(1,2,2,2-tetrafluoroethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,2,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Example 42 and Example 43 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-1,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6 -yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-(((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(R)-1,2,2- tetrafluoroethyl )-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(3-(1-chloro-2,2,2-trifluoroethyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(3-(difluoromethyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetonitrile
  • Step 1 Synthesis of 8-(5-fluoro-4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(5-fluoro-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 3 Synthesis of 8-(5-fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of 8-(5-fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(3-methyl-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(3-methyl-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of (3S)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholine-3-carbaldehyde
  • Step 2 Synthesis of 8-(4-((S)-3-(difluoromethyl)morpholinyl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 5 Synthesis of 8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(3-(ethylsulfonyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • Step 2 Synthesis of 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

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Abstract

The present application relates to an organic compound having mTOR inhibitory activity, a preparation method therefor, a pharmaceutical composition comprising the organic compound, and a use thereof for the treatment or prevention of a disease responsive to mTOR inhibition. In particular, the compound of the present invention can be used in the treatment of a disease responsive to mTOR inhibition or a condition requiring mTOR inhibition, such as cancer, a nervous system disease, a metabolic disease, an autoimmune disease, or organ fibrosis, or can be used as an immunosuppressant.

Description

具有mTOR抑制活性的有机化合物及其用途Organic compounds with mTOR inhibitory activity and uses thereof 发明领域Field of the Invention

本申请涉及具有mTOR抑制活性的有机化合物、它们的制备方法、包含它们的药物组合物以及它们用于治疗或预防对mTOR抑制有响应的疾病或状况的用途。特别地，本发明的化合物可用于治疗或预防对mTOR抑制有响应的疾病或用于需要mTOR抑制的状况，例如癌症、神经系统疾病、代谢性疾病、自身免疫性疾病或器官纤维化或可用作免疫抑制剂。The present application relates to organic compounds having mTOR inhibitory activity, methods for their preparation, pharmaceutical compositions containing them, and their use for treating or preventing diseases or conditions responsive to mTOR inhibition. In particular, the compounds of the present invention can be used to treat or prevent diseases responsive to mTOR inhibition or conditions requiring mTOR inhibition, such as cancer, neurological diseases, metabolic diseases, autoimmune diseases, or organ fibrosis, or can be used as immunosuppressants.

发明背景Background of the Invention

哺乳动物雷帕霉素靶标(mTOR)是一种进化上高度保守的、非典型的丝氨酸-苏氨酸蛋白激酶，属于磷脂酰肌醇激酶相关激酶(PIKK)蛋白质家族成员。细胞内mTOR激酶可与不同蛋白结合形成两种结构与功能不同的复合物，即mTOR复合物1(mTORC1)和mTOR复合物2(mTORC2)。The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved, atypical serine-threonine protein kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family of proteins. Intracellularly, mTOR kinases can bind to different proteins to form two structurally and functionally distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

mTORC1核心复合物由mTOR、支架蛋白Raptor以及mLST8/GβL构成。此外，mTORC1还包含两种抑制性亚基PRAS40和DEPTOR，参与调节mTORC1的活性。mTORC1通过感应和整合外界信号，如生长因子、营养物质(氨基酸、葡糖糖等)、能量状态和含氧量等，调控细胞生长发育和细胞自噬等重要生命过程。具体地，受营养物质或激素等外界信号刺激，激活的mTORC1通过磷酸化核糖体蛋白S6激酶(S6K)β1(S6K1)和真核翻译起始因子4E结合蛋白(4E-BP)以及转录因子TFEB等不同底物来促进细胞的多种合成代谢途径，包括蛋白质、核糖体的生物合成，脂肪生成以及核苷酸的合成等或通过磷酸化unc-51样自噬激活激酶(ULK1)抑制自噬，限制分解代谢，促进细胞生长。The mTORC1 core complex is composed of mTOR, the scaffolding protein Raptor, and mLST8/GβL. mTORC1 also contains two inhibitory subunits, PRAS40 and DEPTOR, which participate in regulating mTORC1 activity. mTORC1 regulates important life processes such as cell growth and development and autophagy by sensing and integrating external signals, such as growth factors, nutrients (amino acids, glucose, etc.), energy status, and oxygen levels. Specifically, activated mTORC1, stimulated by external signals such as nutrients or hormones, promotes various cellular anabolic pathways, including protein and ribosome biogenesis, lipogenesis, and nucleotide synthesis, by phosphorylating various substrates, such as ribosomal protein S6 kinase (S6K) β1 (S6K1), eukaryotic translation initiation factor 4E binding protein (4E-BP), and the transcription factor TFEB. Alternatively, mTORC1 inhibits autophagy by phosphorylating the unc-51-like autophagy-activating kinase (ULK1), thereby limiting catabolism and promoting cell growth.

相对于mTORC1，mTORC2相关信号通路知之较少。mTORC2含有两个与mTORC1相同的核心单元，mTOR和mLST8，以及mTORC2特有的核心组分，主要为支架蛋白Rictor、mSin1、PRR5/Protor1/2以及负调控元件DEPTOR。与mTORC1不同，mTORC2主要作为胰岛素/PI3K信号传导的效应器，来调节细胞增殖、存活和细胞骨架的形成。胰岛素、胰岛素样生长因子1(IGF-1)和瘦素(Leptin)等胞外信号激活的PI3K-AKT通路，通过mTORC2来增强AKT激酶和胰岛素信号通路的其他下游效应子的活性。已确定的mTORC2主要磷酸化底物为AGC(PKA/PKG/PKC)家族的几个成员，包括激酶AKT、血清糖皮质激素调节激酶(SGK)和蛋白激酶Cα(PKCα)，但mTORC2最重要的作用可能是磷酸化激活AKT。AKT是胰岛素/PI3K信号传导的关键效应物,一旦活化，AKT通过磷酸化和抑制几种关键底物来促进细胞存活、增殖和生长，包括FoxO1/3a转录因子、GSK3b和TSC2。被mTORC2磷酸化激活的SGK1可调控离子转运以及细胞存活。Compared to mTORC1, less is known about the signaling pathways involved in mTORC2. mTORC2 contains two core units common to mTORC1: mTOR and mLST8, as well as core components unique to mTORC2, primarily the scaffolding proteins Rictor, mSin1, PRR5/Protor1/2, and the negative regulatory element DEPTOR. Unlike mTORC1, mTORC2 primarily functions as an effector of insulin/PI3K signaling, regulating cell proliferation, survival, and cytoskeletal organization. The PI3K-AKT pathway, activated by extracellular signals such as insulin, insulin-like growth factor 1 (IGF-1), and leptin, enhances the activity of AKT kinase and other downstream effectors of the insulin signaling pathway through mTORC2. The primary identified phosphorylation substrates of mTORC2 are several members of the AGC (PKA/PKG/PKC) family, including the kinase AKT, serum glucocorticoid-regulated kinase (SGK), and protein kinase Cα (PKCα). However, the most important role of mTORC2 may be phosphorylation and activation of AKT. AKT is a key effector of insulin/PI3K signaling. Once activated, AKT promotes cell survival, proliferation, and growth by phosphorylating and inhibiting several key substrates, including FoxO1/3a transcription factors, GSK3b, and TSC2. SGK1, activated by mTORC2 phosphorylation, regulates ion transport and cell survival.

细胞内两个mTOR复合物之间存在反馈调节作用。mTORC2通过磷酸化完全激活AKT，AKT可磷酸化mTORC1相互作用蛋白PRAS40以及mTORC1调节因子TSC2，解除TSC2的抑制作用，促进mTORC1活化。mTORC1及其直接效应子S6K在不同位置磷酸化IRS1，导致IRS1蛋白降解，蛋白水平降低，抑制胰岛素信号传导，从而影响mTORC2的活性。S6K1也可能通过RICTOR的磷酸化直接抑制mTORC2的活性。mTORC1还可直接磷酸化GRB10，GRB10是AKT和IGF-1受体上游信号的负调控因子，GRB10的磷酸化阻断了胰岛素/IGF与胰岛素受体的结合，进而抑制mTORC2通路。A feedback regulation exists between the two mTOR complexes within the cell. mTORC2 fully activates AKT through phosphorylation. AKT phosphorylates the mTORC1-interacting protein PRAS40 and the mTORC1 regulator TSC2, relieving the inhibitory effect of TSC2 and promoting mTORC1 activation. mTORC1 and its direct effector, S6K, phosphorylate IRS1 at various locations, leading to IRS1 protein degradation and reduced protein levels, inhibiting insulin signaling and thus affecting mTORC2 activity. S6K1 may also directly inhibit mTORC2 activity through phosphorylation of RICTOR. mTORC1 can also directly phosphorylate GRB10, a negative regulator of upstream signaling of AKT and the IGF-1 receptor. Phosphorylation of GRB10 blocks the binding of insulin/IGF to the insulin receptor, thereby inhibiting the mTORC2 pathway.

mTOR信号通路参与细胞内的多项生理活动。研究表明，mTOR信号通路异常与癌症、神经性退行性疾病、代谢性疾病和自身免疫性疾病等密切相关。通过调节mTOR信号通路能够对癌症、神经性退行性疾病、代谢性疾病和自身免疫性疾病等产生积极作用。具体地，通过调节、例如抑制mTOR信号通路，能够治疗或预防对mTOR抑制有响应的疾病，包括但不限于：癌症，例如黑色素瘤、乳腺癌，结直肠癌、肺癌、前列腺癌、胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食管癌、卵巢癌、胰腺癌、皮肤癌、甲状腺癌、子宫癌、宫颈癌或白血病(包括急性淋巴细胞白血病(ALL)和慢性髓性白细胞(CML))、多发性骨髓瘤、淋巴管肌瘤、室管膜下巨细胞星形细胞瘤、淋巴瘤、软组织肉瘤、肉瘤、脑膜瘤、胶质母细胞瘤、非霍奇金淋巴瘤、难治性中枢神经系统淋巴瘤、结节性硬化相关血管纤维瘤等；神经系统疾病，例如神经性退行性疾病，例如阿尔茨海默病、帕金森病、亨廷顿病等；代谢疾病，例如糖尿病、胰岛素抵抗、肥胖、衰老等；自身免疫性疾病，例如特异性皮炎、类风湿关节炎，系统性红斑狼疮、皮肌炎、多发性硬化病；或器官纤维化，例如特发性肺纤维化；以及用作免疫抑制剂，例如用于预防移植器官排斥反应或用于血管支架涂层。The mTOR signaling pathway is involved in many physiological activities in cells. Studies have shown that abnormalities in the mTOR signaling pathway are closely related to cancer, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. By regulating the mTOR signaling pathway, it is possible to have a positive effect on cancer, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. Specifically, by regulating, for example, inhibiting the mTOR signaling pathway, diseases that respond to mTOR inhibition can be treated or prevented, including but not limited to: cancers, such as melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, uterine cancer, cervical cancer or leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, lymphangioleiomyomas, subependymal giant cell astrocytomas, lymphomas, soft tissue sarcomas, Sarcoma, meningioma, glioblastoma, non-Hodgkin's lymphoma, refractory central nervous system lymphoma, tuberous sclerosis-associated angiofibroma, etc.; nervous system diseases, such as neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.; metabolic diseases, such as diabetes, insulin resistance, obesity, aging, etc.; autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis; or organ fibrosis, such as idiopathic pulmonary fibrosis; and as immunosuppressants, such as for preventing transplant organ rejection or for vascular stent coatings.

mTOR抑制剂已有广泛研究，mTOR抑制剂研究大致可分为三个阶段，第一代抑制剂为抗生素类变构mTOR抑制剂，主要是雷帕霉素(Rapamycin,1)及其衍生物(Rapalogs)，它仅部分抑制mTORC1信号途径，对mTORC2活性或通过S6K和mTORC2活性介导的PI3K/AKT信号反馈激活无抑制作用，临床上仅对于肾癌细胞有疗效，故治疗效果并不理想。第二代药物(Torin1，PP242，Ku-0063794，MLN0128，CC223，AZD2014)主要依靠与ATP竞争占据激酶活性位点抑制mTORC1和mTORC2底物发挥作用，早期临床数据表明mTOR抑制剂会出现耐药性。第三代mTOR抑制剂RapaLink主要将ATP竞争性抑制剂如Sapanisertib与Rapalogs的大环核偶联，以克服耐药。mTOR inhibitors have been extensively studied and can be broadly divided into three phases. The first generation of inhibitors are antibiotic allosteric mTOR inhibitors, primarily rapamycin (Rapamycin 1) and its derivatives (Rapalogs). They only partially inhibit the mTORC1 signaling pathway and have no inhibitory effect on mTORC2 activity or PI3K/AKT signaling feedback activation mediated by S6K and mTORC2 activity. Clinically, they are only effective against renal cancer cells, resulting in suboptimal therapeutic efficacy. Second-generation drugs (Torin 1, PP242, Ku-0063794, MLN0128, CC223, and AZD2014) primarily inhibit mTORC1 and mTORC2 substrates by competing with ATP for occupancy of the kinase active site. Early clinical data suggest that resistance to mTOR inhibitors can develop. The third-generation mTOR inhibitor, RapaLink, primarily couples ATP-competitive inhibitors such as sapanisertib to the macrocyclic core of Rapalogs to overcome resistance.

目前只有少数mTOR抑制剂正处于临床阶段，所有已批准的mTOR抑制剂均属于第一代mTOR抑制剂。因此，仍然需要另外的mTOR激酶抑制剂，特别是能够抑制mTORC1和/或mTORC2信号途径的mTOR激酶抑制剂。Currently, only a few mTOR inhibitors are in clinical trials, and all approved mTOR inhibitors belong to the first generation. Therefore, there is still a need for additional mTOR kinase inhibitors, especially those that can inhibit the mTORC1 and/or mTORC2 signaling pathways.

发明内容Summary of the Invention

发明简述Summary of the Invention

本发明人出人意料地发现：本发明的化合物具有令人满意的mTOR抑制活性，特别是良好的mTORC1和/或mTORC2抑制活性，显示出良好的抑制癌细胞增殖的活性，可用于治疗对mTOR抑制有响应的疾病如癌症、神经系统疾病、代谢性疾病、自身免疫性疾病和器官纤维化等，以及用于需要mTOR抑制的状况，可用作免疫抑制剂。The present inventors unexpectedly discovered that the compounds of the present invention have satisfactory mTOR inhibitory activity, in particular good mTORC1 and/or mTORC2 inhibitory activity, and show good activity in inhibiting cancer cell proliferation. They can be used to treat diseases responsive to mTOR inhibition, such as cancer, nervous system diseases, metabolic diseases, autoimmune diseases, and organ fibrosis, as well as conditions requiring mTOR inhibition, and can be used as immunosuppressants.

发明人还出人意料地发现，本发明的化合物还显示出良好的体内和/或体外药代动力学性质，例如良好的溶出和/或吸收、良好的代谢稳定性、改善的生物利用度、减少的副作用等。而且，本发明的化合物还具有良好的物理和/或化学稳定性，适合制备成符合药用的各种制剂。The inventors have also unexpectedly discovered that the compounds of the present invention exhibit favorable in vivo and/or in vitro pharmacokinetic properties, such as favorable dissolution and/or absorption, favorable metabolic stability, improved bioavailability, and reduced side effects. Furthermore, the compounds of the present invention possess favorable physical and/or chemical stability and are suitable for preparation into various pharmaceutical formulations.

因此，在第一方面，本发明提供了式(I)化合物或可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物。Thus, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg deuterated derivative) or solvate.

在第二方面，本发明提供了包含本发明的化合物，例如本发明的式(I)化合物或可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，以及可药用载体、稀释剂或赋形剂的药物组合物，In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, such as a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (e.g., deuterated derivative) or solvate, and a pharmaceutically acceptable carrier, diluent or excipient,

在第三方面，本发明提供了用于治疗或预防对mTOR抑制有响应的疾病或者用于需要mTOR抑制的状况的本发明的化合物。In a third aspect, the present invention provides a compound of the invention for use in the treatment or prevention of a disease responsive to mTOR inhibition or in a condition where mTOR inhibition is required.

在第四方面，本发明提供了在个体中治疗或预防对mTOR抑制有响应的疾病的方法，该方法包括给所述个体施用有效量的本发明的化合物。In a fourth aspect, the present invention provides a method of treating or preventing a disease responsive to mTOR inhibition in an individual, the method comprising administering to the individual an effective amount of a compound of the present invention.

在第五方面，本发明提供了本发明的化合物在制备药物中的用途，所述药物用于治疗或预防对mTOR抑制有响应的疾病。In a fifth aspect, the present invention provides the use of a compound of the present invention in the preparation of a medicament for treating or preventing a disease responsive to mTOR inhibition.

在第六方面，本发明提供了本发明的化合物与其它活性剂的组合。所述其它活性剂具有与本发明的化合物相同或不同的功效。In a sixth aspect, the present invention provides a combination of a compound of the present invention and another active agent having the same or different efficacy as the compound of the present invention.

在第七方面，本发明提供了本发明的化合物作为免疫抑制剂的用途，例如用于需要mTOR抑制的状况，例如用于预防移植器官排斥反应或用于血管支架涂层。In a seventh aspect, the present invention provides the use of a compound of the present invention as an immunosuppressant, for example for use in conditions where mTOR inhibition is required, such as for preventing transplant organ rejection or for use in vascular stent coatings.

在第八方面，本发明提供了本发明的化合物的制备方法。In an eighth aspect, the present invention provides a method for preparing the compound of the present invention.

本发明的上述和其它方面在下文进行了更详细的描述。These and other aspects of the invention are described in more detail below.

发明详述Detailed Description of the Invention

在一个方面，本发明提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative) or solvate thereof,

其中：in:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中至多三个、优选至多两个是N；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;

L表示价键、任选被一个或多个RL取代的C1-6亚烷基、-NRa-、-O-、-CO-、-SO-或-SO2-；L represents a valence bond, a C 1-6 alkylene group optionally substituted with one or more RL , -NR a -, -O-, -CO-, -SO- or -SO 2 -;

A表示C1-6烷基、C2-6链烯基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，表示C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；Ring B is connected to A 2 or A 3 and represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 3-10 membered heterocycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;

R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基、C1-6烷氧基、C1-6烷硫基、C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基-、3-10元杂环烷基-C1-6亚烷基-、C6-10芳基-C1-6亚烷基-或5-10元杂芳基-C1-6亚烷基-，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自卤素、氰基、羟基、C1-6烷基和NRaRb的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-； R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano , hydroxy , NRaRb, NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl ) -SO-, ( C1-6 alkyl) -SO2- , ( C1-6 alkyl )-SO(NH)-, ( C1-6 alkoxy)-CO- and C3-8 cycloalkyl; C3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene-, 3-10 membered heterocycloalkyl-C 1-6 alkylene-, C 6-10 aryl-C 1-6 alkylene-, or 5-10 membered heteroaryl-C 1-6 alkylene-, wherein said C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, and NR a R b ; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-;

R2是H、卤素、CN、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氰基烷基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-； R2 is H, halogen, CN, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, NRaRb , NRaRbCO-, NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl ) -CO-, ( C1-6 alkyl )-SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)-;

R3是氢、氘、卤素、氰基、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或C1-6氰基烷基；R 3 is hydrogen, deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl;

R4各自独立地是卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；each R 4 is independently halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy , C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基或C3-8环烷基-C1-6亚烷基-；R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-;

RL各自独立地是氢、卤素、CN、羟基、NH2和C1-3卤代烷基；和 RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ; and

表示所处的环是芳香性的。 Indicates that the ring is aromatic.

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中至多三个、优选至多两个是N；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;

L表示价键、任选被一个或多个RL取代的C1-6亚烷基、-NRa-、-O-、-CO-、-SO-或-SO2-；L represents a valence bond, a C 1-6 alkylene group optionally substituted with one or more RL , -NR a -, -O-, -CO-, -SO- or -SO 2 -;

A表示C1-6烷基、C2-6链烯基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，表示C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；Ring B is connected to A 2 or A 3 and represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 3-10 membered heterocycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;

R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基、C1-6烷氧基、C1-6烷硫基、C3-8环烷基、3-10元杂环烷基、C6-10芳基、或5-10元杂芳基，各自任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-； R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy , NRaRb , NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl)-SO-, ( C1-6 alkyl ) -SO2- , ( C1-6 alkyl)-SO(NH)-, ( C1-6 alkoxy)-CO-, and C3-8 cycloalkyl; ( C1-6 alkyl)-CO-; ( C1-6 alkyl)-SO-; ( C1-6 alkyl) -SO2- ; NR aRbCO- ; NRaRbSO- ; NRaRbSO2- ; or ( C1-3alkyl ) ( C1-3alkyl )-PO- ;

R2是H、卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氰基烷基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-； R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl , NRaRb , NRaRbCO- , NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl )-CO- , ( C1-6 alkyl ) -SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)-;

R3是氢、氘、卤素、氰基、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或C1-6氰基烷基；R 3 is hydrogen, deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl;

R4各自独立地是卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；each R 4 is independently halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy , C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基、或C3-8环烷基-C1-6亚烷基-；R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-;

RL各自独立地是氢、卤素、CN、羟基、NH2和C1-3卤代烷基；和 RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ; and

表示所处的环是芳香性的。 Indicates that the ring is aromatic.

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中至多三个、优选至多两个是N；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N;

L表示价键、任选被一个或多个RL取代的C1-6亚烷基、-NRa-、-O-、-CO-、-SO-或-SO2-；L represents a valence bond, a C 1-6 alkylene group optionally substituted with one or more RL , -NR a -, -O-, -CO-, -SO- or -SO 2 -;

A表示C1-6烷基、C2-6链烯基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，表示C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；Ring B is connected to A 2 or A 3 and represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 3-10 membered heterocycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;

R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基、C1-6烷氧基、C1-6烷硫基、C3-8环烷基、3-10元杂环烷基、C6-10芳基、或5-10元杂芳基，各自任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-； R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl, or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy , NRaRb , NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl)-SO-, ( C1-6 alkyl ) -SO2- , ( C1-6 alkyl)-SO(NH)-, ( C1-6 alkoxy)-CO-, and C3-8 cycloalkyl; ( C1-6 alkyl)-CO-; ( C1-6 alkyl)-SO-; ( C1-6 alkyl) -SO2- ; NR aRbCO- ; NRaRbSO- ; NRaRbSO2- ; or ( C1-3alkyl ) ( C1-3alkyl )-PO- ;

R2是H、卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氰基烷基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-； R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl , NRaRb , NRaRbCO- , NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl )-CO- , ( C1-6 alkyl ) -SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)-;

R3是氢、卤素、氰基、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或C1-6氰基烷基；R 3 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl;

R4各自独立地是卤素、氰基、羟基、氧代基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥； R4 is each independently halogen, cyano, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkoxy, C1-6 haloalkoxy, C1-6 cyanoalkoxy, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkylene-, NRaRb , NRaRb - CO- , NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl )-CO-, ( C1-6 alkyl ) -SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)- , or two R4 together form a C1-3 alkylene bridge ;

Ra和Rb各自独立地是氢、C1-6烷基、或C3-8环烷基-C1-6亚烷基-；R a and R b are each independently hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl-C 1-6 alkylene-;

RL各自独立地是氢、卤素、CN、羟基、NH2和C1-3卤代烷基；和 RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ; and

表示所处的环是芳香性的。 Indicates that the ring is aromatic.

在一些实施方案中，A1、A2、A3、A4和A5中的三个是N，且其它为C或CH。In some embodiments, three of A 1 , A 2 , A 3 , A 4 , and A 5 are N, and the others are C or CH.

在一些实施方案中，A1、A2、A3、A4和A5中的两个是N，且其它为C或CH。对于环部分而言，在一些实施方案中，A1是N，A3和A4之一为N，且其它环成员为C或CH。在另一些实施方案中，A2是N，A3、A4和A5之一为N，且其它环成员为C或CH。在另一些实施方案中，A3是N，A1、A2、A4和A5之一为N，且其它环成员为C或CH。在另一些实施方案中，A4是N，A1、A2、A3和A5之一为N，且其它环成员为C或CH。在另一些实施方案中，A5是N，A2、A3和A4之一为N，且其它环成员为C或CH。In some embodiments, two of A 1 , A 2 , A 3 , A 4 , and A 5 are N, and the others are C or CH. In some embodiments, A1 is N, one of A3 and A4 is N, and the other ring members are C or CH. In other embodiments, A2 is N, one of A3 , A4 and A5 is N, and the other ring members are C or CH. In other embodiments, A3 is N, one of A1 , A2 , A4 and A5 is N, and the other ring members are C or CH. In other embodiments, A4 is N, one of A1 , A2 , A3 and A5 is N, and the other ring members are C or CH. In other embodiments, A5 is N, one of A2 , A3 and A4 is N, and the other ring members are C or CH.

在一些实施方案中，选自 其中包含的环是芳香性的。在一些实施方案中，优选选自更优选选自 还更优选选自最优选是其中包含的环是芳香性的。In some embodiments, Selected from It contains The ring is aromatic. In some embodiments, Preferably selected from More preferably selected from Still more preferably selected from The most preferred It contains The ring is aromatic.

在一些实施方案中，本发明的式(I)化合物具有选自如下结构中的一种或多种：
In some embodiments, the compounds of formula (I) of the present invention have one or more structures selected from the following:

其中，包含的环是芳香性的，和其它符号如本文所定义。优选地，所述式(I)具有(Ia)、(Ic)、(If)或(Ih)任一者的结构，更优选具有(Ic)或(If)的结构，最优选具有(Ic)的结构Among them, The ring is aromatic, and other symbols are as defined herein. Preferably, the formula (I) has the structure of any one of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If), and most preferably has the structure of (Ic).

LL

在一些实施方案中，L表示价键、C1-6亚烷基、-NRa-、-O-、-CO-或-SO2-。在一些实施方案中，L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-或-SO2-。在一些实施方案中，L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-，优选价键、C1-6亚烷基或-N(C1-6烷基)-。In some embodiments, L represents a bond, C 1-6 alkylene, -NR a -, -O-, -CO-, or -SO 2 -. In some embodiments, L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -. In some embodiments, L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-, preferably a bond, C 1-6 alkylene, or -N(C 1-6 alkyl)-.

在一些实施方案中，L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-，优选表示价键、C1-6亚烷基、-NH-或-N(C1-6烷基)-。In some embodiments, L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-, preferably represents a bond, C 1-6 alkylene, -NH-, or -N(C 1-6 alkyl)-.

在一些实施方案中，L表示价键、-(CH2)-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)6-、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-、-SO-或-SO2-。在一些实施方案中，L是价键。在一些实施方案中，L是C1-6亚烷基。在一些实施方案中，L是-(CH2)-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、或-(CH2)6-。在一些实施方案中，L是-NH-、-N(C1-6烷基)-或-N(C3-8环烷基-C1-6亚烷基-)-(例如-N(环丙基-CH2-)-)。在一些实施方案中，L是-O-、-CO-、-SO-或-SO2-。在一些实施方案中，L表示价键、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-或-SO2-。In some embodiments, L represents a bond, -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, -SO-, or -SO 2 -. In some embodiments, L is a bond. In some embodiments, L is C 1-6 alkylene. In some embodiments, L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -. In some embodiments, L is -NH-, -N(C 1-6 alkyl)-, or -N(C 3-8 cycloalkyl-C 1-6 alkylene-)- (e.g., -N(cyclopropyl-CH 2 -)-). In some embodiments, L is -O-, -CO-, -SO-, or -SO 2 -. In some embodiments, L represents a bond, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -.

A和R4 A and R 4

在一些实施方案中，A表示C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，优选表示C1-6烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，更优选表示C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，还更优选表示3-10元杂环烷基或5-10元杂芳基，各自任选被一个或多个、例如一至三个独立选择的R4取代。在一些实施方案中，A表示C1-6烷基或3-10元杂环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, more preferably represents C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, still more preferably represents 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more, for example, one to three independently selected R 4. In some embodiments, A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl, each optionally substituted by one or more, for example, one to three independently selected R 4 .

在一些实施方案中，A表示C1-6烷基，例如C1-4烷基，如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents C 1-6 alkyl, for example C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, each optionally substituted by one or more, for example one to three independently selected R 4 .

在一些实施方案中，A表示C3-8环烷基，例如C3-6环烷基，如环丙基、环丁基、环戊基或环己基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents C 3-8 cycloalkyl, for example C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by one or more, for example one to three independently selected R 4 .

在一些实施方案中，A表示C3-8环烯基，例如C3-6环烯基，如环戊烯基、环己烯基或环己二烯基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents C 3-8 cycloalkenyl, for example C 3-6 cycloalkenyl, such as cyclopentenyl, cyclohexenyl or cyclohexadienyl, each optionally substituted by one or more, for example one to three independently selected R 4 .

在一些实施方案中，A表示含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代。在一些实施方案中，A表示含有1、2或3个、例如1或2个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基。例如，A表示哌啶基、四氢吡喃基、四氢噻喃基、六氢吡啶、六氢哒嗪基、六氢嘧啶基、哌嗪基、噁嗪烷、吗啉基、硫吗啉基、噻二嗪烷基、1,1-二氧硫代吗啉(thiomorpholine 1,1-dioxide)、四氢-2H(1,1-二氧)硫代吡喃(tetrahydro-2H-thiopyran 1,1-dioxide)、1-氧杂-8-氮杂螺[4.5]癸烷(1-oxa-8-azaspiro[4.5]decane)或氧杂氮杂环庚烷基(oxazepane)，优选哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫吗啉基、噻二嗪烷基、1-氧杂-8-氮杂螺[4.5]癸烷或氧杂氮杂环庚烷基，更优选哌啶基、四氢吡喃基、哌嗪基或吗啉基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents a 3-10 membered, for example, 6-10 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example, one to three independently selected R 4. In some embodiments, A represents a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3, for example, 1 or 2 heteroatoms independently selected from N, O or S. For example, A represents piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridine, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, oxazinane, morpholinyl, thiomorpholinyl, thiadiazinyl, 1,1-dioxothiomorpholine 1,1-dioxide, tetrahydro-2H(1,1-dioxo)thiopyranyl, tetrahydro-2H- ... 1,1-dioxide), 1-oxa-8-azaspiro[4.5]decane or oxazepane, preferably piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, 1-oxa-8-azaspiro[4.5]decane or oxazepane, more preferably piperidinyl, tetrahydropyranyl, piperazinyl or morpholinyl, each optionally substituted with one or more, e.g., one to three, independently selected R 4 .

在一些实施方案中，A表示 各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents Each is optionally substituted with one or more, eg, one to three, independently selected R 4 .

在一些实施方案中，A表示C6-10芳基，例如苯基或萘基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents C 6-10 aryl, such as phenyl or naphthyl, each optionally substituted with one or more, such as one to three, independently selected R 4 .

在一些实施方案中，A表示含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基，例如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡喃基、噻喃基或噁嗪基，优选吡唑基或吡啶基，各自任选被一个或多个、例如一至三个独立选择的R4取代。In some embodiments, A represents a 5-10 membered, preferably a 5-7 membered, heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, for example a 5- or 6-membered heteroaryl group, such as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl or oxazinyl, preferably pyrazolyl or pyridinyl, each optionally substituted by one or more, for example one to three independently selected R 4 .

在一些实施方案中，A表示其中，In some embodiments, A represents in,

X是O、-CH2-或-NH-；X is O, -CH 2 -, or -NH-;

Y是N或CH；Y is N or CH;

R4各自独立地位于相同或不同的环成员上，并且各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氘代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；R 4 is independently located on the same or different ring members and is independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 - or (C 1-6 alkyl)-SO(NH)-, or two R 4 together to form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基、或C3-8环烷基-C1-6亚烷基-，优选各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-, preferably each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy;

p是0、1、2、3或4，优选是0、1、2或3；p is 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3;

m和n各自独立地是0、1、2或3；和m and n are each independently 0, 1, 2 or 3; and

所述A通过Y与式(I)的其余部分连接。Said A is connected to the rest of the formula (I) through Y.

在一些实施方案中，X和Y均为碳。在进一步的实施方案中，X和Y均为碳，且m与n的总和小于等于4。In some embodiments, X and Y are both carbon. In further embodiments, X and Y are both carbon, and the sum of m and n is less than or equal to 4.

在另一些实施方案中，X和Y不同时为碳。在进一步的实施方案中，Y为N，且X为O、-NH-或-CH2-。在另一些进一步的实施方案中，Y为CH，且X为O或-NH-，优选为O。In other embodiments, X and Y are not both carbon. In further embodiments, Y is N, and X is O, -NH-, or -CH 2 -. In other further embodiments, Y is CH, and X is O or -NH-, preferably O.

在一些实施方案中，Y为N，且当存在一个以上的R4时，至少一个所述R4位于Y的邻位。In some embodiments, Y is N, and when more than one R 4 is present, at least one of said R 4 is located in an ortho position relative to Y.

在一些实施方案中，本发明的式(I)化合物具有式(Ii)：
In some embodiments, the compound of formula (I) of the present invention has formula (Ii):

其中各变量如本文所定义。wherein the variables are as defined herein.

在一些实施方案中，本发明的式(I)化合物具有式(Ij)：
In some embodiments, the compound of formula (I) of the present invention has formula (Ij):

在一些实施方案中，m为1且n为1。在另一些实施方案中，m为1且n为2。在另一些实施方案中，m为2且n为1。在另一些实施方案中，m为2且n为2。In some embodiments, m is 1 and n is 1. In other embodiments, m is 1 and n is 2. In other embodiments, m is 2 and n is 1. In other embodiments, m is 2 and n is 2.

在一些实施方案中，A表示在另一些实施方案中，A表示 In some embodiments, A represents In other embodiments, A represents

在一些实施方案中，可以存在0、1、2、3或4个R4。可以理解，当存在两个以上的R4时，R4各自可以是相同或不同的，并且可以位于相同或不同的位置上。在一些实施方案中，存在一个以上的R4，并且其中至少一个所述R4位于Y的邻位。在另一些实施方案中，存在两个以上的R4，并且其中两个R4可以一起形成C1-3亚烷基桥，例如如中所示。In some embodiments, there may be 0, 1, 2, 3, or 4 R 4 groups. It will be appreciated that when there are two or more R 4 groups, each R 4 group may be the same or different and may be located at the same or different positions. In some embodiments, there may be one or more R 4 groups , and at least one of the R 4 groups is located in an ortho position relative to Y. In other embodiments, there may be two or more R 4 groups, and two of the R 4 groups may together form a C 1-3 alkylene bridge, such as As shown in .

在一些实施方案中，R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥。In some embodiments, each R 4 is independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl , NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, and (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge.

在一些实施方案中，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥。In some embodiments, each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy , NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl )-CO-, and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge.

在一些实施方案中，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥。In some embodiments, each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge.

在一些实施方案中，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基和C1-6卤代烷氧基。In some embodiments, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

在一些实施方案中，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)和(C1-6烷基)-SO2-。In some embodiments, each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- (e.g., NH(C 1-6 alkyl)-CO-), and (C 1-6 alkyl)-SO 2 -.

在一些实施方案中，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥。In some embodiments, each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, and (C 1-6 alkyl )-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge.

在一些实施方案中，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、NRaRb-CO-和(C1-6烷基)-CO-，或者两个R4一起形成C1-3亚烷基桥。优选地，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基和NRaRb-CO-，或者两个R4一起形成C1-3亚烷基桥。更优选地，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基和C1-6卤代烷氧基，或者两个R4一起形成C1-3亚烷基桥。In some embodiments, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO- and (C 1-6 alkyl)-CO-, or two R 4 are taken together to form a C 1-3 alkylene bridge. Preferably, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b -CO-, or two R 4 are taken together to form a C 1-3 alkylene bridge. More preferably, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy, or two R 4 together form a C 1-3 alkylene bridge.

在一些实施方案中，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷氧基或C1-6卤代烷氧基。In some embodiments, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, or C 1-6 haloalkoxy.

在一些实施方案中，A表示C1-6烷基，例如C1-4烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4如本文所定义。优选地，R4各自独立地选自氰基、NRaRb、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，更优选是NRaRb，其中Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基。In some embodiments, A represents C 1-6 alkyl, such as C 1-4 alkyl, each optionally substituted by one or more, such as one to three, independently selected R 4 , wherein R 4 is as defined herein. Preferably, R 4 is each independently selected from cyano, NR a R b , (C 1-6 alkyl)-SO 2 - and (C 1-6 alkyl)-SO(NH)-, more preferably NR a R b , wherein R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy.

在一些实施方案中，A表示C1-6烷基，例如C1-4烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自卤素、氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、NRaRb-CO-、(C1-6烷基)-CO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，优选选自卤素、氰基、羟基、(C1-6烷基)-CO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，更优选选自氰基、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-。In some embodiments, A represents C 1-6 alkyl, such as C 1-4 alkyl, each optionally substituted by one or more, such as one to three, independently selected R 4 , wherein R 4 is each independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, preferably selected from halogen, cyano, hydroxy, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, more preferably selected from cyano, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)- 1-6 alkyl)-SO(NH)-.

在一些实施方案中，A表示C3-8环烷基，例如C3-6环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基和NRaRb，优选选自氰基、羟基和NH2，更优选是氰基。In some embodiments, A represents a C 3-8 cycloalkyl group, for example a C 3-6 cycloalkyl group, each optionally substituted by one or more, for example one to three, independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, hydroxyl and NH 2 , more preferably cyano.

在一些实施方案中，A表示C3-8环烷基，例如C3-6环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基和NRaRb，优选选自氰基、C1-6烷氧基、羟基和NH2，更优选是氰基和C1-6烷氧基。In some embodiments, A represents a C 3-8 cycloalkyl group, for example a C 3-6 cycloalkyl group, each optionally substituted by one or more, for example one to three, independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, C 1-6 alkoxy, hydroxy and NH 2 , more preferably cyano and C 1-6 alkoxy.

在一些实施方案中，A表示C3-8环烯基，例如C3-6环烯基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基和NRaRb，优选选自氰基、羟基、NH2。在一些实施方案中，A表示C3-8环烯基，例如C3-6环烯基，任选被一个或多个C1-6烷基如甲基取代。In some embodiments, A represents a C 3-8 cycloalkenyl group, such as a C 3-6 cycloalkenyl group, each optionally substituted with one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and NR a R b , preferably selected from cyano, hydroxyl, NH 2. In some embodiments, A represents a C 3-8 cycloalkenyl group, such as a C 3-6 cycloalkenyl group, optionally substituted with one or more C 1-6 alkyl groups such as methyl.

在一些实施方案中，A表示3-10元杂环烷基，例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10元杂环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，所述杂环烷基可以是单环或二环环状基团(包括螺环)，并且所述杂环烷基的任意N和S杂原子任选被氧化，例如为NO、SO、SO2的形式。优选地，R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。更优选地，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。另外优选地，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、NRaRb、NRaRb-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。In some embodiments, A represents a 3-10 membered heterocycloalkyl, for example a 3-10 membered, for example a 6-10 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example one to three independently selected R 4 , the heterocycloalkyl may be a monocyclic or bicyclic cyclic group (including spirocycles), and any N and S heteroatoms of the heterocycloalkyl are optionally oxidized, for example in the form of NO, SO, SO 2 . Preferably, R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl. More preferably, R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy , NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl. Also preferably, R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl.

在一些实施方案中，A表示含有1、2或3个、例如1或2个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-8环烷基和NRaRb，或者两个R4一起形成C1-3亚烷基桥；优选选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基和(C1-6烷基)-CO-，或者两个R4一起形成C1-3亚烷基桥；更优选选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷氧基和C1-6卤代烷氧基。In some embodiments, A represents a 3-10 membered, preferably a 3-8 membered, heterocycloalkyl group containing 1, 2 or 3, for example 1 or 2, heteroatoms independently selected from N, O or S, each optionally substituted by one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and N R a R b , or two R 4 together form a C 1-3 alkylene bridge; preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy and (C 1-6 alkyl)-CO-, or two R 4 together form a C 1-3 alkylene bridge; more preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy.

在一些实施方案中，A表示C6-10芳基，例如苯基或萘基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6羟基烷基、C1-6卤代烷基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-；优选选自NRaRb、NRaRb-CO-、(C1-6烷基)-CO-；更优选是NRaRb-CO-，例如NH2-CO-、NH(C1-6烷基)-CO-或N(C1-6烷基)(C1-6烷基)-CO-。在一些实施方案中，A表示C6-10芳基，任选被NH(C1-6烷基)-CO-取代。In some embodiments, A represents C 6-10 aryl, such as phenyl or naphthyl, each optionally substituted by one or more, for example one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-; preferably selected from NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO-; more preferably NR a R b -CO-, such as NH 2 -CO-, NH (C 1-6 alkyl) -CO- or N (C 1-6 alkyl) (C 1-6 alkyl) -CO-. In some embodiments, A represents C 6-10 aryl, optionally substituted by NH (C 1-6 alkyl) -CO-.

在一些实施方案中，A表示含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基，各自任选被一个或多个、例如一至三个独立选择的R4取代，其中R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6羟基烷基和C1-6卤代烷基；优选选自C1-6烷基、C1-6氘代烷基、C1-6羟基烷基和C1-6卤代烷基；更优选选自C1-6烷基和C1-6卤代烷基。In some embodiments, A represents a 5-10 membered, preferably a 5-7 membered, heteroaryl group, e.g., a 5- or 6 membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each optionally substituted by one or more, e.g., one to three independently selected R 4 , wherein R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl and C 1-6 haloalkyl; preferably selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl and C 1-6 haloalkyl; more preferably selected from C 1-6 alkyl and C 1-6 haloalkyl.

在一些实施方案中，A表示其中R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-或(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。优选地，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-或(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。更优选地，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基、C1-6卤代烷氧基。另外优选地，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、NRaRb、NRaRb-CO-或(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基。In some embodiments, A represents wherein R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl. Preferably, R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl ) -SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl. More preferably, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy. Also preferably, R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl.

在一些实施方案中，A表示其中R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-8环烷基、和NRaRb，或者两个R4一起形成C1-3亚烷基桥；优选选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、和(C1-6烷基)-CO-，或者两个R4一起形成C1-3亚烷基桥；更优选选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷氧基、和C1-6卤代烷氧基。In some embodiments, A represents wherein R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl , and NR a R b , or two R 4 together form a C 1-3 alkylene bridge; preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, and (C 1-6 alkyl)-CO-, or two R 4 together form a C 1-3 alkylene bridge; more preferably selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, and C 1-6 haloalkoxy.

在一些实施方案中，A表示其中Y为C或N，且当存在一个以上的R4时，至少一个所述R4位于Y的邻位。进一步地，所述位于Y邻位的R4选自卤素、氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NH2、NH(C1-6烷基)-CO-、(C1-6烷基)-CO-、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-，优选选自C1-6烷基、C1-6氘代烷基或C1-6卤代烷基，例如是甲基、氘代甲基或三氟甲基。In some embodiments, A represents wherein Y is C or N, and when there is more than one R 4 , at least one of said R 4 is located at an ortho position relative to Y. Further, said R 4 located at an ortho position relative to Y is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NH 2 , NH(C 1-6 alkyl)-CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - or (C 1-6 alkyl)-SO(NH)-, preferably selected from C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 haloalkyl, for example, methyl, deuterated methyl or trifluoromethyl.

在一些实施方案中，A选自：
In some embodiments, A is selected from:

在一些实施方案中，A选自：
In some embodiments, A is selected from:

B和R2 B and R 2

在一些实施方案中，环B与A2连接。在另一些实施方案中，环B与A3连接。In some embodiments, Ring B is attached to A 2. In other embodiments, Ring B is attached to A 3 .

在一些实施方案中，环B表示C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基。在另一些实施方案中，环B表示C6-10芳基或5-10元杂芳基。In some embodiments, Ring B represents C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl. In other embodiments, Ring B represents C 6-10 aryl, or 5-10 membered heteroaryl.

在一些实施方案中，环B表示C3-8环烷基，例如C3-6环烷基，如环丁烷、环戊基、或环己基。In some embodiments, ring B represents a C 3-8 cycloalkyl group, for example a C 3-6 cycloalkyl group, such as cyclobutane, cyclopentyl, or cyclohexyl.

在一些实施方案中，环B表示3-10元杂环烷基，例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如3-8元杂环烷基，例如吡咯烷基、四氢呋喃基、四氢噻喃基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基。在一些实施方案中，环B表示3-8元氧杂环烷基。In some embodiments, ring B represents a 3-10 membered heterocycloalkyl group, for example a 3-10 membered, for example a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, for example a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl. In some embodiments, ring B represents a 3-8 membered oxacycloalkyl group.

在一些实施方案中，环B表示C6-10芳基，例如苯基或萘基，优选苯基。In some embodiments, ring B represents a C 6-10 aryl group, such as phenyl or naphthyl, preferably phenyl.

在一些实施方案中，环B表示5-10元杂芳基，例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基，例如吡咯基、呋喃基、噻吩基、吡唑基、三唑基、四唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基或吡嗪基。在一些实施方案中，环B表示吡唑基、三唑基、咪唑基、噻唑基、异噻唑基或吡啶基。In some embodiments, ring B represents a 5-10 membered heteroaryl, for example a 5-10 membered, for example a 5-7 membered heteroaryl, for example a 5 or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S, for example pyrrolyl, furanyl, thienyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridonyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some embodiments, ring B represents a pyrazolyl, triazolyl, imidazolyl, thiazolyl, isothiazolyl or pyridinyl.

在一些实施方案中，环B表示苯基或含有1、2或3个独立地选自N、O或S的杂原子的5-7元、例如5或6元杂芳基。在一些实施方案中，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基或吡嗪基。优选地，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基或吡啶基。更优选地，环B表示苯基、吡唑基、咪唑基或吡啶基。在一些实施方案中，环B表示吡唑基、咪唑基或吡啶基，优选吡唑基或吡啶基，更优选吡唑基。In some embodiments, ring B represents phenyl or a 5-7 membered, for example, 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyridonyl, pyridazinyl, pyrimidinyl, or pyrazinyl. Preferably, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, or pyridinyl. More preferably, ring B represents phenyl, pyrazolyl, imidazolyl, or pyridinyl. In some embodiments, ring B represents pyrazolyl, imidazolyl, or pyridinyl, preferably pyrazolyl or pyridinyl, more preferably pyrazolyl.

在一些实施方案中，R2是H、卤素、CN、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-。在一些实施方案中，R2是H、卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-。在一些实施方案中，R2是H、卤素、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-。在另一些实施方案中，R2是H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-。在另一些实施方案中，R2是H、C1-6烷基或NH(C1-6烷基)CO-。在另一些实施方案中，R2是H或C1-6烷基。In some embodiments, R 2 is H, halogen, CN, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or NH(C 1-6 alkyl)CO-. In some embodiments, R 2 is H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or NH(C 1-6 alkyl)CO-. In some embodiments, R 2 is H, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or NH(C 1-6 alkyl)CO-. In other embodiments, R 2 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or NH(C 1-6 alkyl)CO-. In other embodiments, R 2 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or NH(C 1-6 alkyl)CO-. In other embodiments, R 2 is H, C 1-6 alkyl, or NH(C 1-6 alkyl)CO-. In other embodiments, R 2 is H or C 1-6 alkyl.

在一些实施方案中，B表示C6-10芳基或5-10元杂芳基，优选表示苯基或含有1、2或3个独立地选自N、O或S的杂原子的5-7元、例如5或6元杂芳基，且R2选自H、卤素、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-，优选选自H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-，更优选选自H、C1-6烷基或NH(C1-6烷基)CO-。In some embodiments, B represents C6-10 aryl or 5-10 membered heteroaryl, preferably represents phenyl or 5-7 membered, for example 5- or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and R2 is selected from H, halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-, preferably selected from H, C1-6 alkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-, more preferably selected from H, C1-6 alkyl or NH( C1-6 alkyl)CO-.

在一些实施方案中，B表示C6-10芳基(例如苯基或萘基)，且R2选自H、卤素、CN、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-，优选选自H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-，更优选是NH(C1-6烷基)CO-。In some embodiments, B represents a C6-10 aryl group (e.g., phenyl or naphthyl), and R2 is selected from H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, preferably selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, or NH( C1-6 alkyl)CO-, more preferably NH( C1-6 alkyl)CO-.

在另一些实施方案中，B表示5-10元杂芳基，例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元、还例如5或6元杂芳基(例如吡唑基、咪唑基、三唑基、噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基)，且R2选自H、卤素、氧代基、C1-6烷基或C1-6卤代烷基，优选选自H或C1-6烷基。In other embodiments, B represents a 5-10 membered heteroaryl, for example a 5-10 membered, for example a 5-7 membered, also for example a 5 or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S (for example pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl), and R 2 is selected from H, halogen, oxo, C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H or C 1-6 alkyl.

在一些实施方案中，B表示5-10元杂芳基，且R2选自H、卤素、CN、C1-6烷基、C1-6卤代烷基和C1-6羟基烷基，优选选自H、C1-6烷基、C1-6卤代烷基和C1-6羟基烷基，还优选选自H、C1-6烷基和C1-6羟基烷基。In some embodiments, B represents a 5-10 membered heteroaryl group, and R 2 is selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, preferably selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, further preferably selected from H, C 1-6 alkyl and C 1-6 hydroxyalkyl.

在一些实施方案中，选自：环戊基、氧杂环戊基、 In some embodiments, Selected from: cyclopentyl, oxacyclopentyl,

R1 R 1

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C1-6烷氧基；C1-6卤代烷氧基；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基、3-10元杂环烷基-C1-6亚烷基、C6-10芳基-C1-6亚烷基或5-10元杂芳基-C1-6亚烷基，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自C1-6烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy, (C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; C 1-6 alkoxy; C 1-6 haloalkoxy; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; C 3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene, 3-10 membered heterocycloalkyl-C 1-6 alkylene, C 6-10 aryl-C 1-6 alkylene, or 5-10 membered heteroaryl-C 1-6 alkylene, wherein said C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more substituents independently selected from C 1-6 alkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, the C 6-10 aryl is phenyl, or the 5-10 membered heteroaryl is a 5-10 membered, preferably 5-7, for example 5 or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C The 6-10 membered aryl group is phenyl, or the 5-10 membered heteroaryl group is a 5-10 membered, preferably 5-7, for example 5 or 6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl.

在一些实施方案中，R1是：卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2或C1-6烷氧基的取代基取代；或3-10元杂环烷基，其中所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，例如氧杂环丁烷基。In some embodiments, R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetanyl.

在一些实施方案中，R1是：氰基、C1-6烷基或C1-6卤代烷基，例如氰基、甲基或CF3。In some embodiments, R 1 is: cyano, C 1-6 alkyl, or C 1-6 haloalkyl, such as cyano, methyl, or CF 3 .

在一些实施方案中，R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基、C3-8环烷基、3-10元杂环烷基、C6-10芳基、或5-10元杂芳基，各自独立地任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb(如NH2)、NRaRbCO-、NRaRbSO-、NRaRbSO2-、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; hydroxy; C 1-6 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl , each independently optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NRaRb (such as NH2 ), NRaRbCO- , NRaRbSO- , NRaRbSO2- , C 1-6 alkoxy , (C 1-6 alkyl ) -CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO2-, (C 1-6 alkyl)-SO( NH )-, ( C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl )-SO-; (C 1-6 alkyl) -SO2- ; NRaRb CO-; NR a R b SO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb(如NH2)、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C3-8环烷基；3-10元杂环烷基；C6-10芳基(例如苯基)；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; hydroxy; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, (C 1-6 alkyl)-SO(NH)-, (C 1-6 alkoxy)-CO-, and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (such as phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO-; NR a R b SO 2 -; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb(如NH2)、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C3-8环烷基；3-10元杂环烷基；C6-10芳基(例如苯基)；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.

在一些实施方案中，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb(如NH2)、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C3-8环烷基；3-10元杂环烷基；C6-10芳基(例如苯基)；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-。In some embodiments, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (such as NH 2 ), C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.

在一些实施方案中，R1是：氢；卤素；氰基；C1-6烷基，任选被一个或多个、例如一个、两个或三个独立地选自卤素、氰基、羟基、NRaRb(如NH2)、C1-6烷氧基、和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基；3-10元杂环烷基；C6-10芳基(例如苯基)；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-。In some embodiments, R 1 is: hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more, e.g., one, two, or three, substituents independently selected from halogen, cyano, hydroxy, NR a R b (e.g., NH 2 ), C 1-6 alkoxy, and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 aryl (e.g., phenyl); (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-.

在一些实施方案中，R1是：卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb(如NH2)和C1-6烷氧基的取代基取代；C3-8环烷基；或3-10元杂环烷基。In some embodiments, R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NR a R b (eg, NH 2 ) and C 1-6 alkoxy; C 3-8 cycloalkyl; or 3-10 membered heterocycloalkyl.

在一些实施方案中，R1是C1-6烷基、C1-6氰基烷基、C1-6卤代烷基、被C1-6烷氧基取代的C1-6卤代烷基、被氨基取代的C1-6卤代烷基、或被羟基取代的C1-6卤代烷基。In some embodiments, R 1 is C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 haloalkyl substituted by C 1-6 alkoxy, C 1-6 haloalkyl substituted by amino, or C 1-6 haloalkyl substituted by hydroxy.

在一些实施方案中，R1是3-10元杂环烷基，例如含有1、2或3个、例如1或2个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基。在一些实施方案中，R1是氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环庚基、氧杂环庚基。优选地，R1是氮杂环丁基、氧杂环丁基，更优选R1是氧杂环丁基。In some embodiments, R is a 3-10 membered heterocycloalkyl, for example, a 3-10 membered, preferably a 3-8 membered, heterocycloalkyl containing 1, 2 or 3, for example 1 or 2 , heteroatoms independently selected from N, O or S. In some embodiments, R is azetidinyl, oxetanyl, azepanyl, oxolanyl, azepanyl, oxetanyl, azepanyl, oxepanyl. Preferably, R is azetidinyl, oxetanyl, more preferably R is oxetanyl.

在一些实施方案中，R1选自：不存在、氢、卤素(例如氟、氯、溴、碘)、氰基、甲基、CF2H-、CF3、(CF3)CH2-、(CF3)(CH3)CH-、(CF3)CHF-、(CF3)CF2-、氟丙基；CN-CH2-、(CN)(CH3)CH-、(CN)(CH3O)CH-、羟基丙基、(CF3)(OH)CH-、(CF3)(OH)2C-、(CF3)(NH2)CH-、(CF3)(CH3O)CH-、CH3O-C(O)-CH(CH3)-、环丙基-(CH2)-、环丙基、氧杂环丁烷基、苯基、CH3CO-、Et-SO2-、NH2CO-、(CH3)2-PO-、EtO-、CF3O-、环丁基-O-、氧杂环己烷-O-、吡啶基-O-、(N-甲基)吡唑基-O-、苄基和CH3-NH-SO2-。In some embodiments, R 1 is selected from the group consisting of: absent, hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, methyl, CF 2 H—, CF 3 , (CF 3 )CH 2 —, (CF 3 )(CH 3 )CH—, (CF 3 )CHF—, (CF 3 )CF 2 —, fluoropropyl; CN—CH 2 —, (CN)(CH 3 )CH—, (CN)(CH 3 O)CH—, hydroxypropyl, (CF 3 )(OH)CH—, (CF 3 )(OH) 2 C—, (CF 3 )(NH 2 )CH—, (CF 3 )(CH 3 O)CH—, CH 3 OC(O)—CH(CH 3 )—, cyclopropyl-(CH 2 )—, cyclopropyl, oxetanyl, phenyl, CH 3 CO—, Et—SO 2 —, NH 2 CO—, (CH 3 ) 2 -PO-, EtO-, CF 3 O-, cyclobutyl-O-, oxacyclohexane-O-, pyridyl-O-, (N-methyl)pyrazolyl-O-, benzyl and CH 3 -NH-SO 2 -.

W和R3 W and R 3

在一些实施方案中，W是N或CR3，且R3是氢、氘、卤素、氰基、C1-6烷基(如C1-4烷基)或C1-6卤代烷基(如C1-4卤代烷基)。优选地，R3是氢、氘、卤素、氰基或C1-6烷基(如C1-4烷基)。更优选地，R3是氢、氘、卤素或C1-6烷基(如C1-4烷基)。最优选地，R3是氢、氘或卤素，例如氢或卤素。In some embodiments, W is N or CR 3 , and R 3 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl (such as C 1-4 alkyl), or C 1-6 haloalkyl (such as C 1-4 haloalkyl). Preferably, R 3 is hydrogen, deuterium, halogen, cyano, or C 1-6 alkyl (such as C 1-4 alkyl). More preferably, R 3 is hydrogen, deuterium, halogen, or C 1-6 alkyl (such as C 1-4 alkyl). Most preferably, R 3 is hydrogen, deuterium, or halogen, for example, hydrogen or halogen.

在一些实施方案中，R3是氢、卤素、氰基或C1-3卤代烷基。在另一些实施方案中，R3是氢、卤素或氰基。在另一些实施方案中，R3是氢或卤素。In some embodiments, R 3 is hydrogen, halogen, cyano, or C 1-3 haloalkyl. In other embodiments, R 3 is hydrogen, halogen, or cyano. In other embodiments, R 3 is hydrogen or halogen.

在一些实施方案中，W是N或CR3，其中R3是H或卤素。在另一些实施方案中，W是N。在另一些实施方案中，W是CH。在一些实施方案中，W是CR3，其中R3是氘。在另一些实施方案中，W是CR3，其中R3是卤素。在一些实施方案中，W是CR3，其中R3是C1-6烷基(如C1-4烷基)。In some embodiments, W is N or CR 3 , wherein R 3 is H or halogen. In other embodiments, W is N. In other embodiments, W is CH. In some embodiments, W is CR 3 , wherein R 3 is deuterium. In other embodiments, W is CR 3 , wherein R 3 is halogen. In some embodiments, W is CR 3 , wherein R 3 is C 1-6 alkyl (such as C 1-4 alkyl).

Ra和Rb Ra and Rb

在一些实施方案中，Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基。在一些实施方案中，Ra和Rb均为氢。在一些实施方案中，Ra和Rb之一是氢，且另一个是任选被C1-6烷氧基取代的C1-6烷基。在一些实施方案中，Ra和Rb均为任选被C1-6烷氧基取代的C1-6烷基。例如，Ra为C1-6烷基且Rb为任选被C1-6烷氧基取代的C1-6烷基。In some embodiments, Ra and R are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy. In some embodiments, Ra and R are both hydrogen. In some embodiments, one of Ra and R is hydrogen, and the other is C 1-6 alkyl optionally substituted by C 1-6 alkoxy. In some embodiments, Ra and R are both C 1-6 alkyl optionally substituted by C 1-6 alkoxy. For example, Ra is C 1-6 alkyl and R is C 1-6 alkyl optionally substituted by C 1-6 alkoxy.

在一些实施方案中，Ra为氢，且Rb为C3-8环烷基-C1-6亚烷基-。In some embodiments, Ra is hydrogen, and Rb is C3-8cycloalkyl - C1-6alkylene- .

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-或-SO2-；L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -;

A表示C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基或吡嗪基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a pyridyl group, a pyridonyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group;

R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C1-6烷氧基；C1-6卤代烷氧基；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基、3-10元杂环烷基-C1-6亚烷基、C6-10芳基-C1-6亚烷基或5-10元杂芳基-C1-6亚烷基，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自C1-6烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 1-6 alkoxy; C 1-6 haloalkoxy; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; C 3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene, 3-10 membered heterocycloalkyl-C 1-6 alkylene, C 6-10 aryl-C 1-6 alkylene or 5-10 membered heteroaryl-C 1-6 alkylene, wherein said C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more substituents independently selected from C 1-6 alkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, the C 6-10 aryl is phenyl, or the 5-10 membered heteroaryl is a 5-10 membered, preferably 5-7, for example 5 or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

R2是H、卤素、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-； R2 is H, halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-;

R3是氢、氘、卤素或C1-6烷基(如C1-4烷基)；R 3 is hydrogen, deuterium, halogen or C 1-6 alkyl (such as C 1-4 alkyl);

R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO- (e.g. NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - and (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基、或C3-8环烷基-C1-6亚烷基-；和R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-；L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-;

A表示C1-6烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group or a pyridyl group;

R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C 6-10- membered aryl is phenyl, or the 5-10-membered heteroaryl is a 5-10-membered, preferably 5-7, for example 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;

R2是H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-;

R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen;

R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键、C1-6亚烷基或-N(C1-6烷基)-；L represents a valence bond, C 1-6 alkylene or -N(C 1-6 alkyl)-;

A表示C1-6烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group;

R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;

R2是H、C1-6烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;

R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen;

R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键、C1-6亚烷基或-N(C1-6烷基)-；L represents a valence bond, C 1-6 alkylene or -N(C 1-6 alkyl)-;

A表示C1-6烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group;

R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;

R2是H、C1-6烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;

R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen;

R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键；L represents a valence bond;

A表示3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，优选表示3-10元杂环烷基，各自任选被一个或多个独立选择的R4取代；A represents a 3-10 membered heterocycloalkyl group (e.g. a 3-10 membered, e.g. a 6-10 membered, heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S) or a 5-10 membered heteroaryl group (e.g. a 5-10 membered, preferably a 5-7 membered, e.g. a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S), preferably a 3-10 membered heterocycloalkyl group, each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示吡唑基；Ring B is connected to A 2 or A 3 , preferably connected to A 2 , and represents a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6 membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a pyrazolyl group;

R1是：卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2或C1-6烷氧基的取代基取代；或3-10元杂环烷基，其中所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，例如氧杂环丁烷基；R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetane;

R2是H或C1-6烷基； R2 is H or C1-6 alkyl;

R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen;

R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基和C1-6卤代烷氧基；和R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构，更优选具有(Ic)或(If)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-，优选表示价键、C1-6亚烷基、-NH-或-N(C1-6烷基)-；L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-, preferably a bond, C 1-6 alkylene, -NH-, or -N(C 1-6 alkyl)-;

A表示C1-6烷基或3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ;

环B与A2或A3连接，优选与A2连接，表示5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示吡唑基；Ring B is connected to A 2 or A 3 , preferably connected to A 2, and represents a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a pyrazolyl group;

R1是氰基、C1-6烷基或C1-6卤代烷基，例如氰基、甲基或CF3；R 1 is cyano, C 1-6 alkyl or C 1-6 haloalkyl, such as cyano, methyl or CF 3 ;

R2是H或C1-6烷基；优选地，R2是H；R 2 is H or C 1-6 alkyl; preferably, R 2 is H;

R3是氢、氘或卤素；优选地，R3是氢或氘；R 3 is hydrogen, deuterium or halogen; preferably, R 3 is hydrogen or deuterium;

R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、NRaRb、NRaRb-CO-和(C1-6烷基)-SO2-；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, NR a R b , NR a R b -CO- and (C 1-6 alkyl)-SO 2 -;

Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构，更优选具有(Ic)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic).

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物(例如氘代衍生物)或溶剂合物，其中：In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative (eg, deuterated derivative), or solvate thereof is provided, wherein:

W是N或CR3；W is N or CR 3 ;

A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH;

L表示价键；L represents a valence bond;

A表示C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R4 ;

环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基或吡啶基，更优选表示吡唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group, more preferably a pyrazolyl group or a pyridyl group;

R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl;

R2是H、C1-6烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-;

R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen;

R4各自独立地选自氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6羟基烷基、C1-6卤代烷基、C1-6氘代烷氧基、C1-6卤代烷氧基、NRaRb-CO-和(C1-6烷基)-CO-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, NR a R b -CO- and (C 1-6 alkyl)-CO-, or two R 4 together form a C 1-3 alkylene bridge;

Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and

表示所处的环是芳香性的。任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。 Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

特别地，本发明提供了实施例的化合物或其可药用的盐、互变异构体、立体异构体、氘代衍生物或溶剂合物。优选地，实施例的化合物选自：In particular, the present invention provides the compounds of the embodiments or pharmaceutically acceptable salts, tautomers, stereoisomers, deuterated derivatives or solvates thereof. Preferably, the compounds of the embodiments are selected from:

或其可药用的盐、互变异构体、立体异构体、氘代衍生物或溶剂合物。 or a pharmaceutically acceptable salt, tautomer, stereoisomer, deuterated derivative or solvate thereof.

需要说明，本发明的上述和其它方面以及上述和其它实施方案中的两个或多个方面或特征可以任意地进行组合，构成未直接描述的技术方案，这些未直接描述的技术方案也涵盖在本申请的公开范围内。It should be noted that the above and other aspects of the present invention and two or more aspects or features in the above and other embodiments can be arbitrarily combined to constitute technical solutions that are not directly described, and these technical solutions that are not directly described are also included in the scope of disclosure of this application.

定义definition

在本申请中，除非另有说明，否则本申请所用的术语具有下文定义的含义。本申请未明确定义的术语具有本领域技术人员通常理解的一般含义。In this application, unless otherwise specified, the terms used in this application have the meanings defined below. Terms not explicitly defined in this application have the general meanings commonly understood by those skilled in the art.

在本申请中使用的术语“一个”、“一种”、“该”和类似术语应理解为包括单数和复数，除非上下文另外特别指出或根据上下文明显矛盾。As used in this application, the terms “a,” “an,” “the” and similar referents are to be construed to cover both the singular and the plural, unless the context specifically indicates otherwise or clearly contradicted by context.

术语“卤素”或“卤代”指氟(F)、氯(Cl)、溴(Br)或碘(I)。优选的卤素是氟和氯。The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogens are fluorine and chlorine.

术语“烷基”单独或作为其它基团一部分表示由碳和氢原子组成的完全饱和的直链或支链烃基团。烷基优选是C1-6烷基(具有1-6个碳原子)，更优选是C1-4烷基或C1-3烷基。其代表性实例包括但不限于甲基(Me)、乙基(Et)、丙基(Pr)(包括正丙基和异丙基)、丁基(Bu)(包括正丁基、异丁基、仲丁基和叔丁基)、戊基(包括正戊基、异戊基、新戊基等)、己基、庚基、辛基等。The term "alkyl" alone or as part of another group refers to a fully saturated straight or branched hydrocarbon group consisting of carbon and hydrogen atoms. Alkyl is preferably a C1-6 alkyl (having 1 to 6 carbon atoms), more preferably a C1-4 alkyl or a C1-3 alkyl. Representative examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, etc.

术语“亚烷基”单独或作为其它基团一部分表示由碳和氢原子组成的完全饱和的直链或支链二价烃基团。亚烷基例如是C1-6亚烷基、优选是C1-3亚烷基、更优选是C1-2亚烷基。其代表性实例包括但不限于亚甲基、亚乙基、亚丙基等。The term "alkylene" alone or as part of another group refers to a fully saturated straight-chain or branched divalent hydrocarbon group composed of carbon and hydrogen atoms. Alkylene is, for example, C 1-6 alkylene, preferably C 1-3 alkylene, and more preferably C 1-2 alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, and the like.

术语“卤代烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素取代的如本文所定义的烷基。可以理解，当卤素取代基多于一个时，所述卤素取代基可以相同或不同，并且可以位于相同或不同的碳原子上。卤代烷基优选是C1-6卤代烷基，更优选是C1-4卤代烷基或C1-3卤代烷基。其代表性实例包括但不限于氟甲基、氯甲基、二氟甲基、二氯甲基、氟氯甲基、三氟甲基、三氯甲基、二氯氟甲基、二氟乙基、三氟乙基、三氯乙基、二氟氯乙基、二氟丙基和三氟丙基等。The term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by halogen. It will be understood that when there are more than one halogen substituent, the halogen substituents may be the same or different and may be located on the same or different carbon atoms. The haloalkyl group is preferably a C 1-6 haloalkyl group, more preferably a C 1-4 haloalkyl group or a C 1-3 haloalkyl group. Representative examples include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl and trifluoropropyl, and the like.

术语“羟基烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被羟基替代的如本文所定义的烷基。羟基烷基优选是C1-6羟基烷基，更优选是C1-4羟基烷基或C1-3羟基烷基。其代表性实例包括但不限于羟甲基、羟乙基、羟丙基等。The term "hydroxyalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, for example, 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, for example, 1, 2, or 3 hydrogen atoms, are replaced by hydroxy groups. Hydroxyalkyl is preferably a C 1-6 hydroxyalkyl, more preferably a C 1-4 hydroxyalkyl or a C 1-3 hydroxyalkyl. Representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

术语“氰基烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被氰基替代的如本文所定义的烷基。氰基烷基优选是C1-6氰基烷基，更优选是C1-4氰基烷基或C1-3氰基烷基。其代表性实例包括但不限于氰基甲基、氰基乙基、氰基丙基等。The term "cyanoalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, for example, 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, for example, 1, 2 or 3 hydrogen atoms, are replaced by a cyano group. The cyanoalkyl group is preferably a C 1-6 cyanoalkyl group, more preferably a C 1-4 cyanoalkyl group or a C 1-3 cyanoalkyl group. Representative examples include, but are not limited to, cyanomethyl, cyanoethyl, cyanopropyl, and the like.

术语“烷氧基”或“烷基氧基”可互换使用，表示通过氧桥连接的如上定义的烷基。烷氧基优选是C1-6烷氧基，更优选是C1-4烷氧基或C1-3烷氧基。其代表性实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基、异丙氧基)、丁氧基(包括正丁氧基、仲丁氧基、异丁氧基、叔丁氧基等)、戊氧基(包括正戊氧基、异戊氧基、新戊氧基等)、己氧基、庚氧基、辛氧基等。The terms "alkoxy" or "alkyloxy" are used interchangeably and refer to an alkyl group as defined above attached through an oxygen bridge. Alkoxy is preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group or a C 1-3 alkoxy group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentoxy (including n-pentoxy, isopentoxy, neopentoxy, etc.), hexyloxy, heptyloxy, octyloxy, and the like.

术语“烷硫基”或“烷基硫基”可互换使用，表示通过硫桥连接的如上定义的烷基。烷硫基优选是C1-6烷硫基，更优选是C1-4烷硫基或C1-3烷硫基。其代表性实例包括但不限于甲硫基、乙硫基、丙硫基(包括正丙硫基、异丙硫基)、丁硫基(包括正丁硫基、仲丁硫基、异丁硫基、叔丁硫基等)、戊硫基(包括正戊硫基、异戊硫基、新戊硫基等)、己硫基、庚硫基、辛硫基等。The terms "alkylthio" or "alkylthio" are used interchangeably and refer to an alkyl group as defined above connected through a sulfur bridge. Alkylthio is preferably a C 1-6 alkylthio, more preferably a C 1-4 alkylthio or a C 1-3 alkylthio. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, etc.), pentylthio (including n-pentylthio, isopentylthio, neopentylthio, etc.), hexylthio, heptylthio, octylthio, etc.

术语“卤代烷氧基”或“卤代烷基氧基”可互换使用，表示被一个或多个卤素取代的如上定义的烷氧基。卤代烷氧基优选是C1-6卤代烷氧基，更优选是C1-4卤代烷氧基或C1-3卤代烷氧基。The term "haloalkoxy" or "haloalkyloxy" is used interchangeably to refer to an alkoxy group as defined above that is substituted with one or more halogens. The haloalkoxy group is preferably a C 1-6 haloalkoxy group, more preferably a C 1-4 haloalkoxy group or a C 1-3 haloalkoxy group.

术语“羟基烷氧基”表示被一个或多个羟基取代的如上定义的烷氧基。羟基烷氧基优选是C1-6羟基烷氧基，更优选是C1-4羟基烷氧基或C1-3羟基烷氧基。The term "hydroxyalkoxy" refers to an alkoxy group as defined above substituted by one or more hydroxy groups. The hydroxyalkoxy group is preferably a C 1-6 hydroxyalkoxy group, more preferably a C 1-4 hydroxyalkoxy group or a C 1-3 hydroxyalkoxy group.

术语“氰基烷氧基”表示被一个或多个氰基取代的如上定义的烷氧基。氰基烷氧基优选是C1-6氰基烷氧基，更优选是C1-4氰基烷氧基或C1-3氰基烷氧基。The term "cyanoalkoxy" refers to an alkoxy group as defined above which is substituted by one or more cyano groups. The cyanoalkoxy group is preferably a C 1-6 cyanoalkoxy group, more preferably a C 1-4 cyanoalkoxy group or a C 1-3 cyanoalkoxy group.

术语“氘代”表示化合物或基团中的一个或多个H被氘(D)替换。可以理解，若无另外说明，本文所述的化合物或基团囊括其被氘代的形式(例如氘代衍生物)。The term "deuterated" means that one or more H in a compound or group is replaced by deuterium (D). It is understood that, unless otherwise indicated, the compounds or groups described herein encompass their deuterated forms (e.g., deuterated derivatives).

术语“氘代烷氧基”表示被一个或多个H被氘(D)替换的如上定义的烷氧基。氘代烷氧基优选是C1-6氘代烷氧基，更优选是C1-4氘代烷氧基或C1-3氘代烷氧基。The term "deuterated alkoxy" refers to an alkoxy group as defined above in which one or more H groups are replaced by deuterium (D). Deuterated alkoxy is preferably a C 1-6 deuterated alkoxy group, more preferably a C 1-4 deuterated alkoxy group or a C 1-3 deuterated alkoxy group.

术语“环烷基”表示由碳和氢原子组成的完全饱和的环状烃基团。环烷基优选是C3-8环烷基，更优选是C5-8环烷基。其代表性实例包括但不限于环丙基、环丁基、环戊基等。The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms. The cycloalkyl group is preferably a C 3-8 cycloalkyl group, more preferably a C 5-8 cycloalkyl group. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

术语“环烯基”表示由碳和氢原子组成的、含有一条或多条双键的部分不饱和的环状烃基团。环烯基优选是C3-8环烯基，更优选是C5-8环烯基。其代表性实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基等。The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group composed of carbon and hydrogen atoms and containing one or more double bonds. The cycloalkenyl group is preferably a C3-8 cycloalkenyl group, and more preferably a C5-8 cycloalkenyl group. Representative examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

术语“杂环烷基”表示具有一个或多个、优选1-6个、更优选1、2、3或4个、例如1、2或3个独立地选自N、O或S的杂原子且其余环成员为碳的饱和单环或二环环状基团，包括螺环。可以理解，杂环烷基可以被完全不饱和或部分不饱和的取代基取代。杂环的碳成员可以被-CO-代替，并且所述任意N和S杂原子可以任选被氧化(例如在NO、SO、SO2中)和所述任意N杂原子可以任选被季铵化(例如在[NR]+Cl-、[NR]+OH-中)。因此，本文对“杂环烷基”的称谓包括其中碳成员任选被-CO-代替的那些，其中任意N和S杂原子环成员任选被氧化的那些，和/或其中任意N杂原子环成员任选被季铵化的那些。杂环烷基优选是3-10元杂环烷基，更优选是3-8元杂环烷基或5-8元杂环烷基。杂环烷基可以通过碳原子或杂原子与分子的其余部分连接，只要化学上可行即可。杂环烷基的代表性实例包括但不限于吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、咪唑酮基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、哌啶基、哌啶酮基、六氢哒嗪基、六氢嘧啶基、哌嗪基、四氢吡喃基、四氢噻喃基、吗啉基、硫吗啉基、硫吗啉1-氧化物、硫吗啉1,1-二氧化物、氧杂环庚烷基、氮杂环庚烷基、氧杂氮杂环庚烷基等。杂环烷基可以通过碳原子或杂原子与分子的其余部分连接，只要化学上可行即可。当杂环烷基仅含有氧作为杂原子时，可以称为“氧杂环烷基”。The term "heterocycloalkyl" refers to a saturated monocyclic or bicyclic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4, for example 1, 2 or 3 heteroatoms independently selected from N, O or S and the remaining ring members being carbon, including spirocycles. It is understood that heterocycloalkyl can be substituted by completely unsaturated or partially unsaturated substituents. The carbon members of the heterocycle can be replaced by -CO-, and the arbitrary N and S heteroatoms can be optionally oxidized (e.g., in NO, SO, SO 2 ) and the arbitrary N heteroatoms can be optionally quaternized (e.g., in [NR] + Cl - , [NR] + OH - ). Therefore, the term "heterocycloalkyl" herein includes those in which the carbon members are optionally replaced by -CO-, those in which the arbitrary N and S heteroatom ring members are optionally oxidized, and/or those in which the arbitrary N heteroatom ring members are optionally quaternized. Heterocycloalkyl is preferably a 3-10 membered heterocycloalkyl, more preferably a 3-8 membered heterocycloalkyl or a 5-8 membered heterocycloalkyl. Heterocycloalkyl can be connected to the rest of the molecule by a carbon atom or a heteroatom, as long as it is chemically feasible. Representative examples of heterocycloalkyl include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, imidazolonyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperidonyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, oxepanyl, azepanyl, oxazazepanyl, etc. Heterocycloalkyl can be connected to the rest of the molecule by a carbon atom or a heteroatom, as long as it is chemically feasible. When a heterocycloalkyl contains only oxygen as a heteroatom, it can be referred to as an "oxepanyl".

术语“芳基”指具有一个或多个环、优选1或2个环的芳香族碳环。芳基优选是C6-10芳基。其代表性实例包括但不限于苯基(即C6芳基)、萘基等。The term "aryl" refers to an aromatic carbon ring having one or more rings, preferably 1 or 2 rings. Aryl is preferably a C 6-10 aryl. Representative examples include, but are not limited to, phenyl (i.e., C 6 aryl), naphthyl, and the like.

术语“杂芳基”指具有一个或多个、优选1-6个、更优选1、2、3或4个独立地选自N、O或S的杂原子且其余环成员为碳的环状基团。本文对“杂芳基”的称谓包括其中碳成员任选被-CO-代替的那些，其中任意N和S杂原子环成员任选被氧化的那些，和/或其中任意N杂原子环成员任选被季铵化的那些。杂芳基的任意N和S杂原子可以任选被氧化(例如在NO、SO、SO2中)和所述任意N杂原子可以任选被季铵化(例如在[NR]+Cl-、[NR]+OH-中)。杂芳基优选是5-10元杂芳基，更优选5-7元杂芳基，最优选5-或6-杂芳基。其代表性实例包括但不限于：吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噻唑基、噻唑基、异噻唑基、三唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基、吡嗪基、吡喃基、噻喃基、噁嗪基、噁二嗪基、吲哚基、异吲哚基、氮杂吲哚基(例如7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基)、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并噻唑基、吲唑基、苯并咪唑基、苯并噁唑基、喹啉基、异喹啉基、苯并吡喃基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、苯并三唑基、嘌呤基、中氮茚基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并吡嗪基、咪唑并吡啶基、咪唑并嘧啶基、吡唑并吡啶基、吡唑并哒嗪基、吡唑并嘧啶基、吡唑并吡嗪基、吡啶并吡嗪基、吡啶并嘧啶基、嘧啶并嘧啶基、吡嗪并吡嗪基、酞嗪、萘啶基等。杂芳基可以通过碳原子或杂原子与化合物的其余部分连接，只要化学上可行即可。The term "heteroaryl" refers to a cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4, heteroatoms independently selected from N, O or S, and the remaining ring members being carbon. The term "heteroaryl" herein includes those in which carbon members are optionally replaced by -CO-, those in which any N and S heteroatom ring members are optionally oxidized, and/or those in which any N heteroatom ring members are optionally quaternized. Any N and S heteroatoms of the heteroaryl group may be optionally oxidized (e.g., in NO, SO, SO 2 ) and any N heteroatom may be optionally quaternized (e.g., in [NR] + Cl - , [NR] + OH - ). The heteroaryl group is preferably a 5- to 10-membered heteroaryl group, more preferably a 5- to 7-membered heteroaryl group, and most preferably a 5- or 6-heteroaryl group. Representative examples include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, oxazinyl, oxadiazinyl, indolyl, isoindolyl, azaindolyl (e.g., 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl), benzofuranyl, isobenzofuranyl, benzothiophenyl, benzothiazole aryl, benzoxazolyl, benzoimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, benzotriazolyl, purinyl, indolizinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, pyrazinopyrazinyl, phthalazine, naphthyridinyl, etc. The heteroaryl group can be attached to the rest of the compound through a carbon atom or a heteroatom, as long as it is chemically feasible.

术语“氰基”表示CN。The term "cyano" refers to CN.

术语“羟基”表示OH。The term "hydroxy" refers to OH.

术语“NH2”表示氨基。术语“-NH(C1-6烷基)”表示被一个C1-6烷基取代的氨基。术语“-N(C1-6烷基)(C1-6烷基)”表示被两个相同或不同的C1-6烷基取代的氨基，例如二甲基氨基、(甲基)(乙基)氨基-等。The term " NH2 " represents an amino group. The term "-NH( C1-6alkyl )" represents an amino group substituted with one C1-6alkyl group. The term "-N( C1-6alkyl )( C1-6alkyl )" represents an amino group substituted with two identical or different C1-6alkyl groups, for example, dimethylamino, (methyl)(ethyl)amino-, etc.

术语“-CO-”或“-C(＝O)-”表示羰基。The term "-CO-" or "-C(=O)-" represents a carbonyl group.

术语“-SO-”表示亚磺酰基。The term "-SO-" represents a sulfinyl group.

术语“-SO2-”表示磺酰基。The term "-SO 2 -" represents a sulfonyl group.

术语“-PO-”表示磷酰基。The term "-PO-" represents a phosphoryl group.

术语“氧代基”表示＝O。The term "oxo" refers to =0.

不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-NRaRb表示该基团通过氮原子与分子的其余部分连接，-C1-3亚烷基-C3-8环烷基表示该基团的连接点在C1-3亚烷基上。当取代基的连接位点对本领域技术人员来说显而易见时(例如对于卤素、羟基、NRaRb等而言)，“-”可以省略。A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -NRaRb indicates that the group is attached to the rest of the molecule through the nitrogen atom, and -C1-3alkylene - C3-8cycloalkyl indicates that the point of attachment of the group is on the C1-3alkylene group. When the point of attachment of a substituent is obvious to one skilled in the art (e.g., for halogen, hydroxy, NRaRb , etc.), the "-" can be omitted.

当基团的价键带有波浪线时，表示所述基团通过该价键与分子其余部分连接。When the valence of a group is marked with a wavy line , it means that the group is connected to the rest of the molecule through this valence bond.

当价键穿过环时，例如在中，表示所述环通过环上任意可用的位置与其它部分连接。When the bond passes through the ring, e.g. In the embodiment, it means that the ring is connected to other parts through any available position on the ring.

表示所处的环是饱和的、部分不饱和的或芳香性的。 Indicates that the ring is saturated, partially unsaturated or aromatic.

表示所处的环是芳族环，即通式中A1至A5的选择使得所形成的环满足芳族环的价键理论，且在化学上可行及稳定。 It indicates that the ring is an aromatic ring, that is, the selection of A1 to A5 in the general formula makes the formed ring satisfy the valence bond theory of aromatic rings and is chemically feasible and stable.

结构式或结构片段中的表示存在立体异构体，且表示不对称中心的绝对构型，在本发明所提供的化合物或中间体的命名中通常以R或S表示。当存在于外消旋混合物中时，该实及虚锲形符号定义的是相对立体化学，而非绝对立体化学。In the structural formula or structural fragment Indicates the existence of stereoisomers and the absolute configuration of an asymmetric center, and is generally represented by R or S in the nomenclature of the compounds or intermediates provided herein. When present in a racemic mixture, the solid and dashed wedge symbols define the relative stereochemistry, not the absolute stereochemistry.

表述“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生，并且该表述包括所述事件发生的情形以及所述事件不发生的情形。例如，“任选被一个或多个R取代”包括未被取代的情形以及被一个或多个R取代的情形，并且其中所述R各自可以相同或不同。“任选的取代基”表明所述取代基可以存在或不存在。本领域技术人员可以理解，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。The expression "optional", "optionally" or "optionally" means that the subsequently described event may or may not occur, and that the expression includes instances where the event occurs as well as instances where the event does not occur. For example, "optionally substituted with one or more R" includes instances where the group is not substituted as well as instances where the group is substituted with one or more R, and wherein each of the Rs may be the same or different. "Optional substituent" indicates that the substituent may be present or absent. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution pattern that is sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable.

当任意变量在结构式中出现多于一次时，其在每次出现时是各自独立地定义的。例如，对于表述“任选被一个或多个R取代”中被多个R取代的情形，所述R各自可以相同或不同，并且所述R可以位于相同或不同的原子上。When any variable occurs more than once in a structural formula, it is independently defined at each occurrence. For example, in the expression "optionally substituted with one or more R" where multiple Rs are present, each of the Rs may be the same or different, and the Rs may be located on the same or different atoms.

表述“被一个或多个独立地选自A、B和C的取代基取代”表示被一个或多个各自独立地选自A、B和C的取代基取代的情形，例如被一个或多个A取代，被一个或多个B取代，被一个或多个C取代，被一个或多个A和一个或多个B取代，被一个或多个A和一个或多个C取代，被一个或多个B和一个或多个C取代，被一个或多个A、一个或多个B和一个或多个C取代，等。The expression "substituted by one or more substituents independently selected from A, B and C" refers to the case of being substituted by one or more substituents each independently selected from A, B and C, for example, substituted by one or more A, substituted by one or more B, substituted by one or more C, substituted by one or more A and one or more B, substituted by one or more A and one or more C, substituted by one or more B and one or more C, substituted by one or more A, one or more B and one or more C, etc.

取代基和/或变量的组合是允许的，只要这样的组成产生了稳定的化合物。Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

术语“包含”或“包括”指包括所述的要素、整数或步骤，但是不排除任意其它要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组合的情形。The term "comprise" or "include" refers to the inclusion of the elements, integers or steps described, but does not exclude any other elements, integers or steps. In this article, when the term "comprise" or "include" is used, unless otherwise indicated, the situation of combinations of the elements, integers or steps described is also covered.

术语“本发明的化合物”或“本申请的化合物”指符合式(I)或其亚式如式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、(Ig)、(Ih)、(Ii)和/或(Ij)的化合物或其盐、特别是可药用盐以及互变异构体、立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、代谢物、前药以及同位素衍生物(包括氘代衍生物)，包括多晶型物、溶剂合物和/或水合物，包括各实施方案以及实施例中定义的那些。在一些实施方案中，“本发明的化合物”特别指实施例的化合物或其盐、特别是可药用盐以及互变异构体、立体异构体、几何异构体、构象异构体、代谢物、前药以及同位素衍生物(例如氘代衍生物)，包括多晶型物、溶剂合物和/或水合物。The term "compound of the present invention" or "compound of the present application" refers to a compound according to formula (I) or its subformulae, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij), or a salt thereof, in particular a pharmaceutically acceptable salt, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformers (including rotamers and atropisomers), metabolites, prodrugs and isotopic derivatives (including deuterated derivatives), including polymorphs, solvates and/or hydrates, including those defined in the embodiments and examples. In some embodiments, "compound of the present invention" refers specifically to the compound of the examples or a salt thereof, in particular a pharmaceutically acceptable salt, as well as tautomers, stereoisomers, geometric isomers, conformers, metabolites, prodrugs and isotopic derivatives (e.g., deuterated derivatives), including polymorphs, solvates and/or hydrates.

在本文中，式(I)的称谓也包括其亚式，例如式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)(Ig)、(Ih)、(Ii)和/或(Ij)。Herein, references to formula (I) also include subformulas thereof, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and/or (Ij).

短语“可药用”指当施用于动物如人时不产生副反应、变态反应或其它不想要的反应的物质或组合物。The phrase "pharmaceutically acceptable" refers to substances or compositions that do not produce adverse, allergic or other undesirable reactions when administered to animals, such as humans.

本发明的化合物可以是盐、例如可药用盐的形式。“可药用盐”包括酸加成盐和碱加成盐。“可药用酸加成盐”指保留游离碱的生物学有效性和性质并且不是生物学或其它方面不期望的那些盐。酸加成盐可以用无机酸或有机酸形成，无机酸盐例如有盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、硝酸盐、碳酸盐、磷酸盐等，有机酸盐例如有甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、戊二酸盐、己二酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、天冬氨酸盐、昔萘酸盐、抗坏血酸盐、谷氨酸盐、邻氨基苯甲酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、双羟萘酸盐、苯乙酸盐、甲磺酸盐、乙磺酸盐、乙二磺酸盐、苯磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、三甲基苯磺酸盐(mesitylate)、羟乙磺酸盐、萘磺酸盐、萘二磺酸盐、樟脑磺酸盐、水杨酸盐、油酸盐、烟酸盐、糖精酸盐(saccharinate)、棕榈酸盐、硬脂酸盐、糠酸盐、马尿酸盐、乳清酸盐和扑酸盐等。盐还包括由无机碱衍生的那些，例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等；和由无毒有机碱衍生的那些：伯胺、仲胺和叔胺，被取代的胺、包括天然存在的被取代的胺，环胺和碱性离子交换树脂如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。盐可以通过常规方法由母体化合物进行合成。The compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. Acid addition salts can be formed with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, bisulfates, nitrates, carbonates, phosphates, and the like, and organic acid salts such as formates, acetates, trifluoroacetates, propionates, glycolates, gluconates, lactates, pyruvates, oxalates, malates, malonates, glutarates, adipates, succinates, fumarates, maleates, tartrates, citrates, aspartates, xinafoates, ascorbates, glutamates, o-aminobutyrates, thiazolinone ... aminobenzoate, benzoate, cinnamate, mandelate, pamoate, phenylacetate, methanesulfonate, ethanesulfonate, edisylate, benzenesulfonate, p-toluenesulfonate, xylenesulfonate, mesitylate, isethionate, naphthalenesulfonate, naphthalenedisulfonate, camphorsulfonate, salicylate, oleate, nicotinate, saccharinate, palmitate, stearate, furoate, hippurate, orotate, and pamoate, among others. Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like; and those derived from non-toxic organic bases: primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Salts can be synthesized from the parent compound by conventional methods.

可药用盐是优选的。然而，其它盐也可以是有用的，例如在分离或纯化步骤中，其可以在制备期间使用，因此被囊括在本公开的范围内。Pharmaceutically acceptable salts are preferred. However, other salts may also be useful, for example, in isolation or purification steps, which may be employed during preparation, and are therefore encompassed within the scope of this disclosure.

本发明的化合物可以含有一个或多个不对称碳原子。因此，化合物可以作为非对映异构体、对映异构体或其混合物存在。化合物的合成可以采用外消旋物、非对映异构体或异构体作为原料或作为中间体。可以通过色谱或结晶方法使特定非对映异构化合物的混合物分离或富含一种或多种特定非对映异构体。类似地，采用相同的技术或本领域已知的其它技术可以使对映异构混合物分离或对映异构体富含。非对称碳或氮原子各自可以是R或S构型，这两种构型都在本发明的范围内。在本文所示的结构中，当未指出任意特定手性原子的立体化学时，则所有立体异构体被包括在内作为本发明的化合物。本文使用的立体化学定义和约定遵循本领域的通常约定。The compounds of the present invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers, or isomers as starting materials or as intermediates. A mixture of specific diastereomeric compounds may be separated or enriched for one or more specific diastereomers by chromatography or crystallization methods. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques or other techniques known in the art. Asymmetric carbon or nitrogen atoms may each be in R or S configuration, both of which are within the scope of the present invention. In the structures shown herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers are included as compounds of the present invention. The stereochemical definitions and conventions used herein follow the common conventions in the art.

术语“非对映异构体”指具有两个或更多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和生物活性。非对映异构体的混合物可通过高分辨分析操作如电泳和色谱法如HPLC来进行分离。The term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and biological activities. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

术语“对映异构体”指互为不可重叠的镜像的化合物的两种立体异构体。The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

术语“互变异构体”指可通过低能垒互相转化的具有不同能量的结构异构体。例如，质子互变异构体(也称为质子移变互变异构体)包括通过质子迁移的互相转化，例如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组进行的互相转化。The term "tautomer" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

在存在手性中心时，本发明的化合物可以以单独的对映异构体或对映体混合物形式存在，本领域技术人员能够确定稳定和可行的本发明化合物的异构体形式。根据一个实施方案，提供了式(I)化合物或其药学上可接受的盐，其是对映体过量(％ee)＞95、＞98％或＞99％的单一对映体。优选地，单一对映异构体以＞99％的对映异构体过量(％ee)存在。When a chiral center is present, the compounds of the present invention may exist as individual enantiomers or mixtures of enantiomers, and those skilled in the art will be able to determine stable and viable isomeric forms of the compounds of the present invention. According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer with an enantiomeric excess (% ee) >95%, >98%, or >99%. Preferably, the single enantiomer is present in an enantiomeric excess (% ee) >99%.

本文所用的术语“同位素衍生物”指构成该化合物的一或多个原子上含有非天然比例同位素的化合物。本发明的化合物即可在构成化合物的一个或多个原子上包含非天然比例的原子同位素，从而形成同位素变化形式，其无论是否具有放射性，都旨在涵盖在本发明的范围内。可以掺入本发明化合物中的同位素及其可药用盐的实例包括但不限于氢的同位素(例如2H、3H)；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。应当理解，本发明化合物的同位素变化形式通常可以通过常规方法、使用适合试剂的适当同位素变化形式来制备。As used herein, the term "isotopic derivative" refers to a compound that contains an unnatural ratio of isotopes on one or more atoms constituting the compound. The compounds of the present invention may contain unnatural ratios of atomic isotopes on one or more atoms constituting the compound, thereby forming isotopic variations, which, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Examples of isotopes that can be incorporated into the compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of hydrogen (e.g., 2H , 3H ); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ). It will be appreciated that isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

术语“代谢物”指特定化合物或其盐经体内代谢产生的产物。这类产物可以产生于所施用化合物的例如氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂、酶裂解等。代谢物结构以常规方式来确定，例如通过MS、LC/MS或NMR分析。通常，代谢物分析以与本领域技术人员熟知的常规药物代谢研究相同的方式进行。代谢产物可用于本发明的化合物的治疗剂量的诊断分析，只要未在体内发现它们。The term "metabolite" refers to a product produced by the metabolism of a particular compound or its salt in vivo. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. The structure of the metabolite is determined in a conventional manner, for example, by MS, LC/MS or NMR analysis. Generally, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites can be used in diagnostic assays for therapeutic doses of the compounds of the present invention, as long as they are not found in vivo.

术语“前药”指被化学修饰的活性或非活性的化合物，其在施用于个体后经过体内生理作用(例如水解、新成代谢等)转化为本发明的化合物。制造和使用前药的技术是本领域技术人员熟知的。The term "prodrug" refers to a chemically modified active or inactive compound that, after administration to a subject, undergoes physiological action in vivo (e.g., hydrolysis, necrolysis, etc.) to convert into a compound of the present invention. The techniques for making and using prodrugs are well known to those skilled in the art.

术语“多晶型物”指具有相同的化学结构/组成、但是形成结晶的分子和/或离子的空间排列不同的结晶形式。本发明的化合物可以作为无定型固体或结晶固体来提供。本发明的范围意欲囊括所有这些物理形式。The term "polymorph" refers to crystalline forms having the same chemical structure/composition but differing in the spatial arrangement of the molecules and/or ions that form the crystals. The compounds of the present invention may be provided as amorphous solids or crystalline solids. The scope of the present invention is intended to encompass all such physical forms.

一些本发明的化合物可以以非溶剂化形式和溶剂化形式、包括水合形式存在。术语“溶剂合物”指一种或多种溶剂分子与本发明的化合物的缔合物或复合物。形成溶剂合物的溶剂的实例包括水、异丙醇、乙醇、MeOH、DMSO、EA、乙酸和乙醇胺。术语“水合物”指其中溶剂分子是水的复合物。溶剂化的方法是本领域公知的。Some compounds of the present invention may exist in unsolvated and solvated forms, including hydrated forms. The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, MeOH, DMSO, EA, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.

本发明化合物还涵盖可能存在的N-氧化物，本领域技术人员能够确定稳定和可行的本发明化合物的N-氧化物。本发明化合物还涵盖本发明化合物的代谢物，即给药本发明化合物时在体内通过氧化、还原、水解、酰胺化、酯化等形成的物质，其可通过本领域公知的技术进行鉴定。The compounds of the present invention also encompass N-oxides that may exist, and those skilled in the art will be able to determine stable and viable N-oxides of the compounds of the present invention. The compounds of the present invention also encompass metabolites of the compounds of the present invention, i.e., substances formed in vivo by oxidation, reduction, hydrolysis, amidation, esterification, etc., when the compounds of the present invention are administered, which can be identified by techniques well known in the art.

术语“个体”或“患者”指动物，优选是哺乳动物。个体的实例包括但不限于灵长类(例如人和非人灵长类动物如猴)、马、牛、羊、猫、狗、兔、兔以及啮齿类(例如小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。The term "subject" or "patient" refers to an animal, preferably a mammal. Examples of subjects include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), horses, cows, sheep, cats, dogs, rabbits, rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject is a human, including a child, adolescent, or adult.

术语“治疗”指(i)治疗或防止特定疾病、病症或障碍、(ii)减弱、改善或消除特定疾病、病症或障碍的一种或多种症状和任选地(iii)防止或延迟本文所述的特定疾病、病症或障碍的一种或多种症状的发作。在一些实施方案中，“治疗”指改善至少一种身体参数，其可能不为患者所察觉。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。The term "treating" refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, and optionally (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. In some embodiments, "treating" refers to improving at least one physical parameter, which may not be noticeable to the patient. In other embodiments, "treating" refers to modulating a disease or condition physically (e.g., stabilizing a noticeable symptom) or physiologically (e.g., stabilizing a physical parameter), or both.

术语“预防”指给具有易患所述疾病或病症的体质的个体施用一种或多种药物物质、特别是本发明的化合物和/或其可药用盐，用以防止个体罹患该疾病。The term "prevention" refers to the administration of one or more pharmaceutical substances, particularly compounds of the present invention and/or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease or condition in question, in order to prevent the individual from developing the disease.

术语“抑制”和“减轻”等指特定的病患、症状或病症或疾病的减轻或抑制，或者生物学活性或过程基线活性的显著降低。The terms "inhibit" and "alleviate" and the like refer to a reduction or suppression of a particular condition, symptom or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

术语“对mTOR抑制有响应的疾病”指mTOR信号通路异常对所述疾病的发生和发展起到促进作用，或抑制mTOR将降低疾病的发生率、减少或消除疾病病状的疾病。优选地，对mTOR抑制有响应的疾病包括但不限于癌症、神经系统疾病、代谢性疾病和自身免疫性疾病，它们与mTOR信号通路异常相关。The term "disease responsive to mTOR inhibition" refers to a disease in which abnormalities in the mTOR signaling pathway contribute to the onset and progression of the disease, or in which mTOR inhibition reduces the incidence, alleviates, or eliminates disease symptoms. Preferably, diseases responsive to mTOR inhibition include, but are not limited to, cancer, neurological diseases, metabolic diseases, and autoimmune diseases, which are associated with abnormalities in the mTOR signaling pathway.

术语“需要mTOR抑制的状况”指其中mTOR的抑制可产生有利作用或者可以减少或阻止不良作用的情况，所述情况可以是疾病或非疾病，例如需要免疫抑制的情况，例如移植器官排斥反应，或者可用于血管支架涂层发挥抗排异作用。The term "conditions requiring mTOR inhibition" refers to situations in which mTOR inhibition can produce beneficial effects or can reduce or prevent adverse effects, and the situations can be disease or non-disease, such as situations requiring immunosuppression, such as transplant organ rejection, or can be used for vascular stent coatings to exert anti-rejection effects.

术语“有效量”指以需要的剂量并持续需要的时间段有效实现所需治疗效果或预防效果的量。其可以由参与医师或兽医执业者来确定，并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。通常，“预防有效量”将小于“治疗有效量”。The term "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the required dosage and for the required period of time. It can be determined by the attending physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Generally, a "prophylactically effective amount" will be less than a "therapeutically effective amount."

术语“制剂”或“药物组合物”指适合于向动物、优选哺乳动物(包括人)施用的包含至少一种活性成分和至少一种非活性成分、例如可药用赋形剂的组合物。本发明的制剂可以是本领域适用的任意制剂，例如片剂、胶囊剂、液体制剂等。The term "preparation" or "pharmaceutical composition" refers to a composition suitable for administration to an animal, preferably a mammal (including a human) comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient. The preparation of the present invention can be any preparation suitable in the art, such as a tablet, capsule, liquid preparation, etc.

术语“可药用载体、稀释剂或赋形剂”指药物制剂中除活性成分以外的成分，其对个体是无毒的。可药用载体的实例包括但不限于粘合剂、崩解剂、润滑剂、溶剂、分散介质、缓冲剂、赋形剂、抗氧化剂、防腐剂或矫味剂等。The term "pharmaceutically acceptable carrier, diluent or excipient" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to a subject. Examples of pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

当涉及化学反应时，“处理”、“接触”和“反应”指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解，产生所示和/或所需产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一种或多种中间体，这些中间体最终导致了所示和/或所需产物的形成。When referring to a chemical reaction, "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and/or desired product.

表述A“和/或”B包括单独的A、单独的B以及A+B的情形。The expression A "and/or" B includes A alone, B alone, and the case of A+B.

一般而言，术语“约”与数值联合使用时表示该数值±20％、优选±10％、更优选±5％的范围。In general, the term "about" when used in conjunction with a numerical value means a range of ±20%, preferably ±10%, and more preferably ±5% of that numerical value.

功效effect

本发明的化合物具有良好的mTOR抑制活性，特别是良好的mTORC1和/或mTORC2抑制活性，显示出良好的抑制癌细胞增殖的活性。本发明的化合物还显示出良好的体内和/或体外药代动力学性质，例如良好的溶出和/或吸收、良好的代谢稳定性、改善的生物利用度、减少的副作用等。而且，本发明的化合物还具有良好的物理和/或化学稳定性。因此，本发明的化合物可用于需要mTOR抑制活性、特别是mTORC1和/或mTORC2抑制活性的多种应用中。The compounds of the present invention have good mTOR inhibitory activity, particularly good mTORC1 and/or mTORC2 inhibitory activity, and exhibit good activity in inhibiting cancer cell proliferation. The compounds of the present invention also exhibit good in vivo and/or in vitro pharmacokinetic properties, such as good dissolution and/or absorption, good metabolic stability, improved bioavailability, reduced side effects, etc. Furthermore, the compounds of the present invention also have good physical and/or chemical stability. Therefore, the compounds of the present invention can be used in a variety of applications requiring mTOR inhibitory activity, particularly mTORC1 and/or mTORC2 inhibitory activity.

在一些实施方案中，本发明的化合物可用于治疗或预防对mTOR抑制有响应的疾病，特别是对mTORC1和/或mTORC2抑制有响应的疾病，例如癌症、神经系统疾病、代谢性疾病、自身免疫性疾病或器官纤维化。In some embodiments, the compounds of the present invention are useful for treating or preventing diseases responsive to mTOR inhibition, particularly diseases responsive to mTORC1 and/or mTORC2 inhibition, such as cancer, neurological diseases, metabolic diseases, autoimmune diseases, or organ fibrosis.

在一些实施方案中，本发明的化合物可用于治疗或预防癌症，例如黑色素瘤、乳腺癌，结直肠癌、肺癌、前列腺癌、胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食管癌、卵巢癌、胰腺癌、皮肤癌、甲状腺癌、子宫癌、宫颈癌或白血病(包括急性淋巴细胞白血病(ALL)和慢性髓性白细胞(CML))、多发性骨髓瘤、淋巴管肌瘤、室管膜下巨细胞星形细胞瘤、淋巴瘤、软组织肉瘤、肉瘤、脑膜瘤、胶质母细胞瘤、非霍奇金淋巴瘤、难治性中枢神经系统淋巴瘤、结节性硬化相关血管纤维瘤等。In some embodiments, the compounds of the present invention can be used to treat or prevent cancer, such as melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, uterine cancer, cervical cancer or leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, lymphangioleiomyomas, subependymal giant cell astrocytomas, lymphomas, soft tissue sarcomas, sarcomas, meningiomas, glioblastomas, non-Hodgkin's lymphomas, refractory central nervous system lymphomas, tuberous sclerosis-associated angiofibromas, etc.

在一些实施方案中，本发明的化合物可用于治疗或预防神经系统疾病如神经性退行性疾病，例如阿尔茨海默病、帕金森病、亨廷顿病等。In some embodiments, the compounds of the present invention can be used to treat or prevent neurological diseases such as neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.

在一些实施方案中，本发明的化合物可用于治疗或预防代谢疾病，例如糖尿病、胰岛素抵抗、肥胖、衰老等。In some embodiments, the compounds of the present invention can be used to treat or prevent metabolic diseases, such as diabetes, insulin resistance, obesity, aging, and the like.

在一些实施方案中，本发明的化合物可用于治疗或预防自身免疫性疾病，例如特异性皮炎、类风湿关节炎，系统性红斑狼疮、皮肌炎、多发性硬化病等。In some embodiments, the compounds of the present invention can be used to treat or prevent autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, and the like.

在一些实施方案中，本发明的化合物可用于治疗器官纤维化，例如特发性肺纤维化。In some embodiments, the compounds of the invention are useful in treating organ fibrosis, such as idiopathic pulmonary fibrosis.

在一些实施方案中，本发明的化合物可用作免疫抑制药物，例如用于预防移植器官排斥反应。本发明的化合物还可用于血管支架涂层，发挥抗排异作用。In some embodiments, the compounds of the present invention can be used as immunosuppressive drugs, for example, to prevent transplant rejection. The compounds of the present invention can also be used in vascular stent coatings to exert anti-rejection effects.

药物组合物和施用Pharmaceutical compositions and administration

本发明的化合物可以以药物组合物的形式、通过任意适用的途径施用，例如但不限于口服(以片剂、包衣片剂、锭剂、硬和软明胶胶囊、溶液、乳剂或悬浮液的形式)、吸入(例如以喷雾剂形式)、直肠(例如以栓剂形式)或胃肠道外(例如以注射液形式，例如静脉内、肌内、皮下、腹膜内、颅内等)进行施用。特别优选口服、鼻内和肠胃外施用，例如静脉内施用。The compounds of the present invention can be administered in the form of pharmaceutical compositions by any suitable route, such as, but not limited to, oral administration (in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions), inhalation (e.g., in the form of sprays), rectal administration (e.g., in the form of suppositories) or parenteral administration (e.g., in the form of injections, such as intravenous, intramuscular, subcutaneous, intraperitoneal, intracranial, etc.). Oral, intranasal and parenteral administration, such as intravenous administration, are particularly preferred.

将本发明的化合物制备成药物组合物的技术是本领域熟知的。例如，可以使用一种或多种可药用载体、稀释剂或赋形剂将本发明的化合物加工成药物组合物的形式，例如片剂、包衣片剂、胶囊剂、液体制剂(例如注射液、输液、糖浆、乳剂、混悬剂等)、散剂、粉针剂、分散体、喷雾剂、栓剂、脂质体等。可药用载体、稀释剂或赋形剂是本领域熟知的，例如填充剂、崩解剂、溶媒、增溶剂、稳定剂、湿润剂、乳化剂、防腐剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂等。The technology of preparing the compound of the present invention into pharmaceutical compositions is well known in the art. For example, the compound of the present invention can be processed into the form of a pharmaceutical composition using one or more pharmaceutically acceptable carriers, diluents or excipients, such as tablets, coated tablets, capsules, liquid preparations (such as injections, infusions, syrups, emulsions, suspensions, etc.), powders, powder injections, dispersions, sprays, suppositories, liposomes, etc. Pharmaceutically acceptable carriers, diluents or excipients are well known in the art, such as fillers, disintegrants, solvents, solubilizers, stabilizers, wetting agents, emulsifiers, preservatives, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents or antioxidants, etc.

剂量可在宽范围内改变，并且当然必须根据每个具体病例中的个体需要进行调整。适宜剂量的确定可以由主治医师根据所治疗疾病的种类及其严重性、个体的健康状况和既往病史、共用药物、所施用的具体化合物和施用途径等酌情确定。70kg成人口服施用的日剂量典型地为约0.01mg至约1000mg本发明的化合物或相应量的可药用盐。根据需要，本发明的化合物的用量可以超出该剂量范围。日剂量可作为单剂量或以分次剂量施用。The dosage can vary over a wide range and must of course be adjusted according to the individual needs in each specific case. The determination of the appropriate dosage can be determined by the attending physician based on the type of disease being treated and its severity, individual health status and previous medical history, co-medication, the specific compound being administered, and the route of administration. The daily dosage for oral administration to a 70 kg adult is typically from about 0.01 mg to about 1000 mg of the compound of the present invention or a corresponding amount of pharmaceutically acceptable salt. As needed, the amount of the compound of the present invention can exceed this dosage range. The daily dosage can be administered as a single dose or in divided doses.

药物组合Drug combinations

本发明的化合物可以单独地或与一种或多种其它活性剂或疗法组合使用，所述其它活性剂或疗法可以具有与本发明的化合物相同或不同的药理学功效。本发明的化合物可以与所述其它活性剂或疗法同时、在其之前或在其之后施用。The compound of the present invention can be used alone or in combination with one or more other activating agents or therapies, and the other activating agents or therapies can have the same or different pharmacological effects as the compound of the present invention. The compound of the present invention can be used simultaneously with the other activating agents or therapies, before or after them.

当本发明的化合物与其它活性剂组合施用时，组合施用的活性剂的剂量当然将根据共用药物、待治疗病症、个体的一般健康状况、医师或兽医的判断等因素而变化。本发明的化合物可以与共用的其它活性剂通过相同或不同的施用途径同时、分别或依次施用。它们可以被包含在同一药物组合物中(固定组合物)，也可以是分开形式、例如药盒形式的组合产品。它们可以由相同或不同的制造商配制和/或供应。而且，本发明的化合物和其它活性剂可以(i)在将组合产品发送给医师之前(例如在包含本发明的化合物和其它活性剂的药盒的情形中)；(ii)在临施用前由医师自身(或在医师指导下)；或(iii)由患者自身、例如在本发明的化合物和其它活性剂的依次施用期间一起加入组合治疗中。When the compound of the present invention is used in combination with other active agents, the dosage of the active agent used in combination will of course vary according to factors such as the shared drug, the condition to be treated, the general health of the individual, the judgment of the physician or veterinarian. The compound of the present invention can be used simultaneously, separately or sequentially with other shared active agents by the same or different routes of administration. They can be included in the same pharmaceutical composition (fixed composition) or in a separate form, such as a combination product in the form of a kit. They can be formulated and/or supplied by the same or different manufacturers. Moreover, the compound of the present invention and other active agents can be (i) before the combination product is sent to the physician (e.g., in the case of a kit comprising the compound of the present invention and other active agents); (ii) by the physician himself (or under the guidance of a physician) before administration; or (iii) by the patient himself, such as during the sequential administration of the compound of the present invention and other active agents, added to the combination therapy.

在一些实施方案中，本申请提供了包含本发明的化合物以及一种或多种其它活性剂的药物组合物。任选地，药物组合物可以包含一种或多种可药用载体、稀释剂或赋形剂。In some embodiments, the present application provides a pharmaceutical composition comprising a compound of the present invention and one or more other active agents. Optionally, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents or excipients.

在一些实施方案中，本申请提供了药物组合产品如药盒，其包含两个或更多个单独的药物组合物，其中至少一个含有本发明的化合物。在一些实施方案中，药盒包括用于分别容纳所述组合物的器具，例如容器、分开的瓶或分开的箔袋。In some embodiments, the present application provides a pharmaceutical combination product such as a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In some embodiments, the kit includes appliances for separately containing the compositions, such as containers, separate bottles, or separate foil bags.

本申请的药盒可用于施用不同的剂型、例如口服和胃肠道外剂型，用于以不同的剂量间隔施用单独的组合物，或用于相对于另一种逐步增加单独的组合物。为了帮助顺应性，本申请的药盒通常包含施用说明书。The kit of the present application can be used to administer different dosage forms, such as oral and parenteral dosage forms, for administering separate compositions at different dosage intervals, or for gradually increasing a separate composition relative to another. To aid compliance, the kit of the present application typically includes instructions for administration.

本发明化合物的制备方法Preparation method of the compound of the present invention

本发明的化合物可以通过多种方法、包括下文流程中的方法、实施例中给出的方法或与之类似的方法来制备。对于各反应步骤而言，适当的反应条件是本领域技术人员已知的或者可以容易地确定。原料通常可购买获得，或者可以利用本领域公知的方法或本文所述的方法容易地制备。通式中的各变量具有本文定义的含义，另有说明除外。The compounds of the present invention can be prepared by a variety of methods, including the methods described in the following processes, the methods given in the examples, or methods similar thereto. For each reaction step, appropriate reaction conditions are known to those skilled in the art or can be readily determined. The starting materials are generally commercially available or can be readily prepared using methods known in the art or as described herein. The variables in the general formula have the meanings defined herein, unless otherwise indicated.

仅为解释目的，以下流程提供了合成本发明化合物的示例性途径。本领域技术人员理解，其它合成途径也是可利用的，并且通过下文所述方法制备的化合物可以根据本申请的内容、利用本领域技术人员熟知的常规化合物进行进一步改变。For illustrative purposes only, the following flow diagram provides an exemplary approach to synthesizing the compounds of the present invention. It will be appreciated by those skilled in the art that other synthetic approaches are also available, and the compounds prepared by the methods described below can be further modified according to the content of this application, utilizing conventional compounds well known to those skilled in the art.

在本发明的化合物的制备中，基团的保护(例如氨基保护基、羟基保护基)可能是需要的，这可以由本领域技术人员容易地决定。对于保护基的一般描述及其用途，参见T.W.Greene，Protective Groups in Organic Synthesis，John Wiley&Sons，纽约，1991。如果没有特别说明，在制备这些化合物中使用的原料和试剂通常可商购获得，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。In the preparation of the compounds of the present invention, protection of groups (e.g., amino protecting groups, hydroxy protecting groups) may be necessary, which can be readily determined by one skilled in the art. For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. Unless otherwise specified, the starting materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods described below, by methods analogous to those given below, or by methods known in the art.

如果需要，合成反应流程中的原料和中间体可以采用常规技术进行分离和纯化，所述技术包括但不限于过滤、蒸馏、结晶、色谱法等。所述材料可以采用包括物理常数和波谱数据在内的常规方法表征。If necessary, the starting materials and intermediates in the synthetic reaction schemes can be separated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The materials can be characterized by conventional methods including physical constants and spectral data.

合成方案A：
Synthesis Scheme A:

如方案A所示例，本发明化合物可通过包含以下步骤的方法合成：As illustrated in Scheme A, the compounds of the present invention can be synthesized by a method comprising the following steps:

步骤1：化合物A1与胺在碱如DIEA存在下、在溶剂如NMP中加热(例如于100℃)反应，得到式A2化合物；Step 1: Compound A1 reacts with an amine in the presence of a base such as DIEA and in a solvent such as NMP under heating (e.g., at 100° C.) to obtain a compound of formula A2;

步骤2：式A2化合物与胺在碱如DIEA存在下、在溶剂如NMP中加热(例如于130℃)反应，得到式A3化合物；Step 2: reacting a compound of formula A2 with an amine in the presence of a base such as DIEA in a solvent such as NMP with heating (e.g., at 130° C.) to obtain a compound of formula A3;

步骤3：式A3化合物与硼酸或者硼酸酯通过Suzuki偶联、在偶联剂如Pd(dtbpf)Cl2/H3PO4存在下、在溶剂如二噁烷/水中加热反应，得到式A4化合物；和Step 3: Suzuki coupling of the compound of formula A3 with boronic acid or boronic ester in the presence of a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4 and heating in a solvent such as dioxane/water to obtain a compound of formula A4; and

步骤4：式A4化合物在酸的作用下脱保护基，得到式A5化合物。Step 4: Compound A4 is deprotected under the action of acid to obtain compound A5.

合成方案B：
Synthesis Scheme B:

如方案B所示例，本发明化合物可通过包含以下步骤的方法合成：As illustrated in Scheme B, the compounds of the present invention can be synthesized by a method comprising the following steps:

步骤1：式B1化合物与碘化试剂如NIS存在下、在溶剂如DMF中加热(如30℃)反应，得到式B2化合物；Step 1: reacting a compound of formula B1 with an iodination reagent such as NIS in a solvent such as DMF under heating (e.g., 30° C.) to obtain a compound of formula B2;

步骤2：式B2化合物在碱如Cs2CO3存在下、在溶剂如DMF中反应，得到式B3化合物；Step 2: reacting the compound of formula B2 in the presence of a base such as Cs 2 CO 3 in a solvent such as DMF to obtain a compound of formula B3;

步骤3：式B3化合物与胺在溶剂(如NMP)中加热或微波条件下反应得到式B4化合物；Step 3: reacting the compound of formula B3 with an amine in a solvent (such as NMP) under heating or microwave conditions to obtain a compound of formula B4;

步骤4：式B4化合物通过Suzuki偶联、在偶联剂如Pd(dppf)Cl2/H3PO4存在下、在溶剂如二噁烷/水中加热反应，得到式B5化合物；Step 4: Compound B4 is reacted by Suzuki coupling in the presence of a coupling agent such as Pd(dppf)Cl 2 /H 3 PO 4 in a solvent such as dioxane/water with heating to obtain compound B5;

步骤5：式B5化合物在催化剂如RuPhos-G2作用下、在碱如Cs2CO3存在下、在溶剂如二噁烷中加热反应，得到式B6化合物；Step 5: heating the compound of formula B5 in the presence of a catalyst such as RuPhos-G2, a base such as Cs 2 CO 3 , and a solvent such as dioxane to obtain a compound of formula B6;

步骤6：式B6化合物在酸如HCl的作用下脱保护基，得到式B7化合物；Step 6: Deprotecting the compound of formula B6 under the action of an acid such as HCl to obtain a compound of formula B7;

合成方案C：
Synthesis Scheme C:

其中R1、X和p如上文对通式(I)所定义：wherein R 1 , X and p are as defined above for formula (I):

如方案C所示例，本发明化合物可通过包含以下步骤的方法合成：As illustrated in Scheme C, the compounds of the present invention can be synthesized by a method comprising the following steps:

步骤1：式C1化合物与胺在碱如DIPEA存在下、在溶剂如NMP中加热反应，得到式C2化合物；Step 1: reacting a compound of formula C1 with an amine in the presence of a base such as DIPEA in a solvent such as NMP by heating to obtain a compound of formula C2;

步骤2：式C2化合物与胺在碱如DIEA存在下、在溶剂如NMP中加热反应，得到式C3化合物；Step 2: reacting the compound of formula C2 with an amine in the presence of a base such as DIEA in a solvent such as NMP with heating to obtain a compound of formula C3;

步骤3：式C3化合物与氰化剂如Zn(CN)2、在催化剂如Pd2(dba)3/DPPF存在下、在溶剂如DMF存在下加热反应，得到式C4化合物；Step 3: reacting the compound of formula C3 with a cyanating agent such as Zn(CN) 2 in the presence of a catalyst such as Pd 2 (dba) 3 /DPPF and a solvent such as DMF by heating to obtain a compound of formula C4;

步骤4：式C4化合物与格式试剂反应，得到式C5化合物；Step 4: reacting the compound of formula C4 with a Grignard reagent to obtain a compound of formula C5;

步骤5：式C5化合物通过缩合反应、在缩合剂如HATU/DIEA存在下、在溶剂如THF中反应，得到式C6化合物；Step 5: The compound of formula C5 is reacted by condensation reaction in the presence of a condensing agent such as HATU/DIEA in a solvent such as THF to obtain a compound of formula C6;

步骤6：式C6化合物在POCl3存在下加热如在100-150℃关环，得到式C7化合物。Step 6: The compound of formula C6 is heated in the presence of POCl 3 , such as at 100-150°C, to perform ring closure to obtain the compound of formula C7.

合成方案D：
Synthesis Scheme D:

如方案D所示例，本发明化合物可通过包含以下步骤的方法合成As illustrated in Scheme D, the compounds of the present invention can be synthesized by a method comprising the following steps:

步骤1：式D1化合物在碱如DIPEA的作用下、在溶剂如THF中加热如80℃反应，得到式D2化合物；Step 1: reacting a compound of formula D1 with a base such as DIPEA in a solvent such as THF at a temperature of 80° C. to obtain a compound of formula D2;

步骤2：式D2化合物在碱如DIPEA的作用下、在溶剂如NMP中加热如130℃反应，得到式D3化合物；Step 2: Reaction of the compound of formula D2 with a base such as DIPEA in a solvent such as NMP at a temperature of, for example, 130° C. to obtain a compound of formula D3;

步骤3：式D3化合物脱保护基，得到式D4化合物；Step 3: Deprotecting the compound of formula D3 to obtain a compound of formula D4;

步骤4：式D4化合物上卤素得到式D5化合物；Step 4: Adding halogen to the compound of formula D4 to obtain a compound of formula D5;

步骤5：式D5化合物与合适试剂发生suzuki反应或者其他偶联得到式D6化合物；Step 5: The compound of formula D5 undergoes Suzuki reaction or other coupling with a suitable reagent to obtain a compound of formula D6;

步骤6：式D6化合物与碘代物或者硼酸/硼酸酯在偶联剂存在下偶联得到式D7化合物。Step 6: The compound of formula D6 is coupled with an iodide or boronic acid/boronic ester in the presence of a coupling agent to obtain a compound of formula D7.

合成方案E：
Synthesis Scheme E:

如方案E所示例，本发明化合物可通过包含以下步骤的方法合成：As illustrated in Scheme E, the compounds of the present invention can be synthesized by a method comprising the following steps:

步骤1：式E1化合物与水合肼在溶剂如乙醇中反应，得到式E2化合物；Step 1: reacting a compound of formula E1 with hydrazine hydrate in a solvent such as ethanol to obtain a compound of formula E2;

步骤2：式E2化合物在酸如TsOH的作用下、在溶剂如THP中反应，上保护基得到式E3化合物；Step 2: The compound of formula E2 is reacted with an acid such as TsOH in a solvent such as THP to obtain a compound of formula E3 by adding a protective group;

步骤3：式E3化合物与胺在碱如DIPEA作用，在溶剂如DMF中加热(比如80℃)，得到式E4化合物。；Step 3: The compound of formula E3 reacts with an amine in the presence of a base such as DIPEA and is heated in a solvent such as DMF (e.g., 80° C.) to obtain a compound of formula E4.

步骤4：式E4化合物与胺在偶联试剂比如Ruphos PdG2/Cs2CO3作用下偶联得到式E5化合物；Step 4: The compound of formula E4 is coupled with an amine in the presence of a coupling reagent such as Ruphos PdG2/ Cs2CO3 to obtain a compound of formula E5;

步骤5：式E5化合物在酸如HCl作用下脱保护得到E6化合物；Step 5: Deprotection of the compound of formula E5 under the action of an acid such as HCl to obtain the compound E6;

步骤6：式E6化合物与碘在碱如KOH作用下得到式E7化合物；Step 6: Compound E6 is reacted with iodine in the presence of a base such as KOH to obtain compound E7;

步骤7：式E7化合物通过Suzuki偶联或者其他偶联反应得到式E8-1化合物；式E7化合物通过与硼酸或者硼酸酯反生Chanlam反应得到式E8-2化合物；Step 7: Compound E7 is subjected to Suzuki coupling or other coupling reaction to obtain compound E8-1; compound E7 is reacted with boronic acid or boronic acid ester to obtain compound E8-2;

步骤8：式E8-1化合物通过与硼酸或者硼酸酯反生Chanlam反应得到式E9-1化合物；或者式E8-2化合物通过Suzuki偶联或者其他偶联反应得到式E9-2化合物。Step 8: The compound of formula E8-1 is reacted with boronic acid or boronic ester to give a Chanlam reaction to obtain a compound of formula E9-1; or the compound of formula E8-2 is subjected to Suzuki coupling or other coupling reactions to obtain a compound of formula E9-2.

实施例Example

提供以下实施例对本发明进行进一步说明。应当理解，其仅仅是为了能够更好的理解本发明，而不以任何方式限定本发明的范围。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。The following examples are provided to further illustrate the present invention. It should be understood that they are only for a better understanding of the present invention and are not intended to limit the scope of the present invention in any way. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

在本申请中，当化学名称和结构式不一致时，应当以结构式所示为准，除非根据上下文可以推断化学名称而非结构式是正确的。为简便，在本申请所给出的一些化合物结构式中并非所有氢原子均被明确地标示出来。当化合物中存在空余化合价时，表示存在未标示出的氢原子。In this application, when a chemical name and structural formula are inconsistent, the structural formula shall prevail unless the context indicates that the chemical name, rather than the structural formula, is correct. For simplicity, not all hydrogen atoms are explicitly labeled in some of the compound structural formulas presented in this application. When there are vacant valences in a compound, this indicates the presence of unlabeled hydrogen atoms.

下列实施例中未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。下列实施例中未注明手性中心构型时，意味着可以以单独的对映异构体或对映体混合物形式存在，且本领域技术人员能够确定化合物的稳定和可行的异构体形式。除非另外说明，否则百分比和份数分别是重量百分比和重量份数。除非另外说明，否则液体的比为体积比，本发明使用的温度均为摄氏度℃。下列实施例中，正相柱层析一般是用硅胶柱，反相一般用C18柱，除非特别注明。The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions for such reactions or under conditions recommended by the manufacturer. When the configuration of the chiral center is not specified in the following examples, it means that it can exist as a single enantiomer or a mixture of enantiomers, and those skilled in the art are able to determine the stable and feasible isomeric forms of the compound. Unless otherwise specified, percentages and parts are weight percentages and weight parts, respectively. Unless otherwise specified, the ratios of liquids are volume ratios, and the temperatures used in the present invention are all degrees Celsius. In the following examples, silica gel columns are generally used for normal phase column chromatography, and C18 columns are generally used for reverse phase chromatography, unless otherwise specified.

以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得、依据现有技术的方法制得或根据与本申请公开的类似的方法制得。除非另有说明，本发明使用的原料都是市售原料，无需进一步纯化可以直接使用。Unless otherwise specified, the experimental materials and reagents used in the following examples were obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application. Unless otherwise specified, the raw materials used in the present invention were commercially available and were used directly without further purification.

本申请使用的缩写具有本领域通常理解的含义，除非说明书中另外清楚定义。在下面列出说明书中使用的缩写的含义：

The abbreviations used in this application have the meanings generally understood in the art, unless otherwise clearly defined in the specification. The meanings of the abbreviations used in the specification are listed below:

合成实施例Synthesis Example

本发明提供的目标化合物制备方法中，本发明提供的目标化合物制备方法中，柱层析色谱采用乐研公司生产的硅胶(100-200目)；薄层色谱采用GF254(0.25毫米)；核磁共振色谱(NMR)使用Bruker AVANCE NEO-400核磁共振仪测定；液质联用(LC/MS)使用Agilent TechnologiESI 1260/1290液质联用仪。In the method for preparing the target compound provided by the present invention, column chromatography uses silica gel (100-200 mesh) produced by Leyan Company; thin layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) uses Bruker AVANCE NEO-400 nuclear magnetic resonance instrument for determination; liquid chromatography-mass spectrometry (LC/MS) uses Agilent Technologi ESI 1260/1290 liquid chromatography-mass spectrometry instrument.

此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。In addition, all operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection.

本发明中，LCMS使用的方法如下：In the present invention, the method used by LCMS is as follows:

方法A：Shim-pack Scepter C18-120,3μm,4.5*50mm；流动相A：水/0.01％ TFA，流动相B：ACN/0.01％TFA；流速：1.8mL/min；梯度：在1.3min内5-95％ B,在1.7min保持95％ B,最后在0.01min降至5％B；检测波长214,254nm，柱温45℃。Method A: Shim-pack Scepter C18-120, 3μm, 4.5*50mm; mobile phase A: water/0.01% TFA, mobile phase B: ACN/0.01% TFA; flow rate: 1.8mL/min; gradient: 5-95% B in 1.3min, maintain 95% B in 1.7min, and finally drop to 5% B in 0.01min; detection wavelength 214,254nm, column temperature 45℃.

方法B：Shim-pack Scepter C18-120,3μm,3.0*33mm；流动相A：水/0.01％ TFA，流动相B：ACN/0.01％TFA；流速：1.8mL/min；梯度：在0.5min内5％ B至95％ B,保持0.8min；检测波长214,254nm，柱温45℃。Method B: Shim-pack Scepter C18-120, 3μm, 3.0*33mm; mobile phase A: water/0.01% TFA, mobile phase B: ACN/0.01% TFA; flow rate: 1.8mL/min; gradient: 5% B to 95% B in 0.5min, hold 0.8min; detection wavelength 214,254nm, column temperature 45℃.

方法C：Shimadzu LCMS-2020柱：YMC-Triart C18,50*4.6mm,5um；流动相A：水/0.1％ FA，流动相B：乙腈；流速：2.5mL/min；梯度：0-0.01min保持B相为20％，0.01-1.80min B相由20％升至95％，1.80-2.50min保持B相95％，2.50-2.51min内B相由95％降至20％，2.51-2.90min B相保持20％；检测波长254/220nm，柱温40℃。Method C: Shimadzu LCMS-2020 column: YMC-Triart C18, 50*4.6mm, 5um; mobile phase A: water/0.1% FA, mobile phase B: acetonitrile; flow rate: 2.5mL/min; gradient: 0-0.01min maintain B phase at 20%, 0.01-1.80min B phase increases from 20% to 95%, 1.80-2.50min maintain B phase 95%, 2.50-2.51min within B phase decreases from 95% to 20%, 2.51-2.90min B phase maintains 20%; detection wavelength 254/220nm, column temperature 40℃.

方法D:Shimadzu LC-2020；柱：YMC-Triart C18,50*4.6mm,5um；流动相A：水/0.1％ TFA，流动相B：乙腈/0.1％TFA；流速：2.5mL/min；梯度：在3.4min内20％ B至95％ B,保持0.8min，然后0.8min20％ B；检测波长254/220nm，柱温40℃。Method D: Shimadzu LC-2020; column: YMC-Triart C18, 50*4.6mm, 5um; mobile phase A: water/0.1% TFA, mobile phase B: acetonitrile/0.1% TFA; flow rate: 2.5mL/min; gradient: 20% B to 95% B in 3.4min, hold for 0.8min, then 20% B for 0.8min; detection wavelength 254/220nm, column temperature 40℃.

方法E：Sepax GP-C18,50×4.6mm,5um；流动相A：水/0.1％ TFA，流动相B：乙腈；流速：2.5mL/min；梯度：在0.01min内20％ B,在1.79min保持至95％ B，最后在0.7min降至20％B；检测波长220,254nm，柱温40℃。Method E: Sepax GP-C18, 50×4.6mm, 5um; mobile phase A: water/0.1% TFA, mobile phase B: acetonitrile; flow rate: 2.5mL/min; gradient: 20% B in 0.01min, maintained to 95% B in 1.79min, and finally decreased to 20% B in 0.7min; detection wavelength 220,254nm, column temperature 40℃.

本发明中，手性分析(SFC)使用的方法如下：In the present invention, the method used for chiral analysis (SFC) is as follows:

方法A：(Waters UPCC system equipped with a PDA detector),柱：Daicel_ChiralPAK-IG_100x3.0mm_3μm；流动相A：Supercritical CO2，流动相B：MeOH(0.1％DEA)，流速：2.0ml/min；5.0min；检测波长210nm，柱温35℃。Method A: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IG_100x3.0mm_3μm; mobile phase A: Supercritical CO2 , mobile phase B: MeOH (0.1% DEA), flow rate: 2.0ml/min; 5.0min; detection wavelength: 210nm, column temperature: 35°C.

方法B：(SHIMADZU NEXERA XR-20ADXR),柱：Daicel Chiral PAK-ADHS150x4.6mm_5μm,CN049；流动相A：Hexane，流动相B：EtOH，流速：1.0ml/min；10.0min；检测波长254nm，柱温35℃。Method B: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-ADHS150x4.6mm_5μm, CN049; mobile phase A: Hexane, mobile phase B: EtOH, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35℃.

方法C：(Waters UPCC system equipped with a PDA detector),柱：RegisPack-IK_250x4.6mm_5μm；流动相A：Supercritical CO2,，流动相B：MeOH，流速：2.0ml/min；6.0min；检测波长210nm，柱温35℃。Method C: (Waters UPCC system equipped with a PDA detector), column: RegisPack-IK_250x4.6mm_5μm; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 6.0min; detection wavelength: 210nm, column temperature: 35°C.

方法D：(Waters UPCC system equipped with a PDA detector),柱：Daicel_ChiralPAK-IG_100x3.0mm_3μm；流动相A：Supercritical CO2，流动相B：MeOH，流速：2.0ml/min；6.0min；检测波长210nm，柱温35℃。Method D: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IG_100x3.0mm_3μm; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 6.0min; detection wavelength: 210nm, column temperature: 35°C.

方法E：(Waters UPCC system equipped with a PDA detector),柱：Daicel_ChiralPAK-WHELK_150x4.6mm_5μm；流动相A：Supercritical CO2，流动相B：MeOH，流速：2.0ml/min；5.0min；检测波长210nm，柱温35℃。Method E: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-WHELK_150x4.6mm_5μm; mobile phase A: Supercritical CO2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 5.0min; detection wavelength: 210nm, column temperature: 35°C.

方法F：(SHIMADZU NEXERA XR-20ADXR),柱：Daicel Chiral PAK-IES150x4.6mm_5μm,AS006；流动相A：正己烷,，流动相B：EtOH，流速：1.0ml/min；10.0min；检测波长254nm，柱温35℃。Method F: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IES 150x4.6mm_5μm, AS006; mobile phase A: n-hexane, mobile phase B: EtOH, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35℃.

方法G：(SHIMADZY LC-20ADxr system equipped with a PDA detector),柱：Daicel_ChiralPak-AD 4.6mmI.D.*150mm,5μm,CN049；流动相A：Hexane,，流动相B：IPA，流速：1.0ml/min；10.0min；检测波长254nm，柱温35℃。Method G: (SHIMADZY LC-20ADxr system equipped with a PDA detector), column: Daicel_ChiralPak-AD 4.6mmI.D.*150mm, 5μm, CN049; mobile phase A: Hexane, mobile phase B: IPA, flow rate: 1.0ml/min; 10.0min; detection wavelength 254nm, column temperature 35℃.

方法H：(SHIMADZU NEXERA XR-20ADXR),柱：Daicel Chiral PAK-IHS150x4.6mm_5μm,CN004；流动相A：正己烷，流动相B：EtOH，流速：1.0ml/min；15.0min；检测波长254nm，柱温35℃。Method H: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IHS150x4.6mm_5μm, CN004; mobile phase A: n-hexane, mobile phase B: EtOH, flow rate: 1.0ml/min; 15.0min; detection wavelength 254nm, column temperature 35℃.

方法I：(Waters UPCC system equipped with a PDA detector),柱：Daicel_ChiralPAK-IC_100x3.0mm_3μm；流动相A：Supercritical CO2，流动相B：MeOH，，流速：2.0ml/min；7.0min；检测波长210nm，柱温35℃。Method I: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IC_100x3.0mm_3μm; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH, flow rate: 2.0ml/min; 7.0min; detection wavelength: 210nm, column temperature: 35°C.

方法J：(SHIMADZU NEXERA XR-20ADXR),柱：Daicel Chiral PAK-IGS150x4.6mm_5μm,AV021；流动相A：正己烷，流动相B：ETOH，流速：1.0ml/min；20.0min；检测波长248nm，柱温35℃。Method J: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IGS150x4.6mm_5μm, AV021; mobile phase A: n-hexane, mobile phase B: ETOH, flow rate: 1.0ml/min; 20.0min; detection wavelength 248nm, column temperature 35℃.

方法K：Opti-Chiral IDH-3,100*4.6mm,3um；流动相A：CO2,流动相B:0.05％ DEA in EtOH；梯度：在0.1min，5％ B，在4min内5-40％ B，1min内保持至40％ B，最后在1min降至5％B；检测波长220nm,254nm，流速：2.5mL/min，柱温40℃。Method K: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO2 , mobile phase B: 0.05% DEA in EtOH; gradient: 5% B at 0.1 min, 5-40% B within 4 min, maintained at 40% B within 1 min, and finally reduced to 5% B within 1 min; detection wavelength 220 nm, 254 nm, flow rate: 2.5 mL/min, column temperature 40°C.

方法M：Opti-Chiral IDH-3,100*4.6mm,3um；流动相A：CO2,流动相B:0.05％ DEA in EtOH；梯度：在0.1min，5％ B，在3min内5-40％ B，2min内保持至40％ B，最后在1min降至5％B；检测波长220nm,254nm，流速：2.5mL/min，柱温40℃。Method M: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO2 , mobile phase B: 0.05% DEA in EtOH; gradient: 5% B at 0.1 min, 5-40% B within 3 min, maintained at 40% B within 2 min, and finally reduced to 5% B in 1 min; detection wavelength 220 nm, 254 nm, flow rate: 2.5 mL/min, column temperature 40°C.

方法N：Opti-Chiral IDH-3,100*4.6mm,3um；流动相A：CO2,流动相B:0.05％ DEA in EtOH；梯度：在0.1min，5％ B，在4min内5-40％ B，1min内保持至40％ B，最后在1min降至5％B；检测波长220nm,254nm，流速：2.5mL/min，柱温40℃。Method N: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO2 , mobile phase B: 0.05% DEA in EtOH; gradient: 5% B at 0.1 min, 5-40% B within 4 min, maintained at 40% B within 1 min, and finally reduced to 5% B within 1 min; detection wavelength 220 nm, 254 nm, flow rate: 2.5 mL/min, column temperature 40°C.

方法O：Opti-Chiral IDH-3,100*4.6mm,3um；流动相A：CO2,流动相B:甲醇；梯度：在0.1min，5％B，在4min内5-40％B，1min内保持至40％B，最后在1min降至5％B；检测波长220nm,254nm，流速：2.5mL/min，柱温40℃。Method O: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO 2 , mobile phase B: methanol; gradient: 5% B at 0.1 min, 5-40% B within 4 min, maintained at 40% B within 1 min, and finally reduced to 5% B within 1 min; detection wavelength 220 nm, 254 nm, flow rate: 2.5 mL/min, column temperature 40°C.

方法P：Opti-Chiral IDH-3,100*4.6mm,3um；流动相A：CO2,流动相B:氨水，甲醇；梯度：在0.1min，5％B，在4min内5-40％B，1min内保持至40％B，最后在1min降至5％B；检测波长220nm,254nm，流速：2.5mL/min，柱温40℃。Method P: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO2 , mobile phase B: ammonia water, methanol; gradient: 5% B at 0.1min, 5-40% B within 4min, maintained at 40% B within 1min, and finally reduced to 5% B within 1min; detection wavelength 220nm, 254nm, flow rate: 2.5mL/min, column temperature 40℃.

中间体3-(氟甲基)吗啉(2a)的合成Synthesis of Intermediate 3-(Fluoromethyl)morpholine (2a)

步骤1：4-苄基-3-(氟甲基)吗啉的合成
Step 1: Synthesis of 4-benzyl-3-(fluoromethyl)morpholine

向(4-苄基-吗啉-3-基)甲醇(207mg,0.10mmol)的DCM(4mL)溶液中加入DAST(1.27mL，9.64mmol)，反应混合物在0℃下搅拌2hrs，加入饱和NaHCO3水溶液终止反应。用EA(10mL×3)萃取。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，10％EA)，得到目标化合物(1.0g,收率99.1％，无色油状物)。LC-MS(ESI)m/z:210.2[M+H]+。To a solution of (4-benzylmorpholin-3-yl)methanol (207 mg, 0.10 mmol) in DCM (4 mL) was added DAST (1.27 mL, 9.64 mmol). The reaction mixture was stirred at 0°C for 2 hrs and quenched by addition of saturated aqueous NaHCO₃ . Extraction was performed with EA (10 mL x 3). The residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA, 10% EA) to afford the title compound (1.0 g, 99.1% yield, colorless oil). LC-MS (ESI) m/z: 210.2 [M+H] ⁺ .

步骤2：3-(氟甲基)吗啉的合成
Step 2: Synthesis of 3-(fluoromethyl)morpholine

在H2氛围下，向4-苄基-3-(氟甲基)吗啉(1.0g,4.78mmol)的MeOH(5mL)溶液中加入盐酸(0.008mL，0.27mmol)和Pd/C(200mg,10％ Pd)，并在室温下搅拌反应2hrs。过滤反应混合物，滤液减压浓缩得到目标化合物(530mg,收率93.1％，淡黄色油状物)。LC-MS(ESI)m/z:120.2[M+H]+。Under an H₂ atmosphere, hydrochloric acid (0.008 mL, 0.27 mmol) and Pd/C (200 mg, 10% Pd) were added to a solution of 4-benzyl-3-(fluoromethyl)morpholine (1.0 g, 4.78 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (530 mg, 93.1% yield, as a pale yellow oil). LC-MS (ESI) m/z: 120.2 [M+H] ⁺ .

中间体((1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(3a)的合成
Synthesis of the intermediate ((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (3a)

将3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(5000mg,25.77mmol)，3,4-二氢-2H-吡喃(3250mg,38.67mmol)和TFA(150mg,1.29mmol)依次加入到甲苯(50mL)中。N2保护下，所得反应混合物95℃下搅拌过夜，冷却至室温。反应混合物减压浓缩，残余物经反相柱(H2O：ACN＝20％：80％)分离纯化得到目标化合物(3.0g,收率59.4％，黄色固体)。LC-MS(ESI)m/z:199.2[M+H]+。3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5000 mg, 25.77 mmol), 3,4-dihydro-2H-pyran (3250 mg, 38.67 mmol), and TFA (150 mg, 1.29 mmol) were added sequentially to toluene (50 mL). Under N₂ protection, the resulting reaction mixture was stirred at 95°C overnight and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O :ACN = 20%:80%) to obtain the title compound (3.0 g, 59.4% yield, as a yellow solid). LC-MS (ESI) m/z: 199.2 [M+H] ⁺ .

中间体(R)-1-(3-甲基哌嗪-1-基)乙烷-1-酮(4a)的合成Synthesis of Intermediate (R)-1-(3-methylpiperazin-1-yl)ethan-1-one (4a)

步骤1：(R)-4-乙酰基-2-甲基哌嗪-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl (R)-4-acetyl-2-methylpiperazine-1-carboxylate

将(R)-2-甲基哌嗪-1-甲酸叔丁酯(2.00g,9.99mmol)、乙酰氯(860mg,10.98mmol)、TEA(2.40mL，14.09mmol)加入到DCM(20mL)中。N2保护下，所得反应混合物25℃搅拌6hrs。向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩得到目标化合物(1.50g,收率61.9％，黄色固体)。LC-MS(ESI)m/z:187.2[M-t-Bu+H]+。(R)-tert-Butyl 2-methylpiperazine-1-carboxylate (2.00 g, 9.99 mmol), acetyl chloride (860 mg, 10.98 mmol), and TEA (2.40 mL, 14.09 mmol) were added to DCM (20 mL). Under N₂ protection, the resulting reaction mixture was stirred at 25°C for 6 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to yield the title compound (1.50 g, 61.9% yield, as a yellow solid). LC-MS (ESI) m/z: 187.2 [Mt-Bu+H] ⁺ .

步骤2：(R)-1-(3-甲基哌嗪-1-基)乙烷-1-酮的合成
Step 2: Synthesis of (R)-1-(3-methylpiperazin-1-yl)ethan-1-one

将(R)-4-乙酰基-2-甲基哌嗪-1-甲酸叔丁酯(1.50g,6.19mmol)加入到DCM(24mL)中，然后加入4N盐酸/1,4-二氧六环溶液(24mL)，N2保护下，反应混合物室温下搅拌12hrs。将反应液减压浓缩得到目标化合物(880mg,粗品收率100％，黄色固体)。LC-MS(ESI)m/z:143.2[M+H]+。(R)-tert-Butyl 4-acetyl-2-methylpiperazine-1-carboxylate (1.50 g, 6.19 mmol) was added to DCM (24 mL), followed by a 4N hydrochloric acid/1,4-dioxane solution (24 mL). Under nitrogen , the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to yield the title compound (880 mg, 100% crude yield, as a yellow solid). LC-MS (ESI) m/z: 143.2 [M+H] + .

实施例1：8-(4-(环己-1-烯-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛 烷
Example 1: 8-(4-(cyclohex-1-en-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：2,6-二氟-4-碘烟醛的合成
Step 1: Synthesis of 2,6-difluoro-4-iodonicotinaldehyde

将2,6-二氟-4-碘吡啶(50.0g,207mmol)溶于THF(600mL)中，在N2氛围下，降温至-65℃，在此温度下缓慢加入LDA(124mL,53mmol)，反应混合物在-65℃下搅拌1hr。然后在-65℃向反应混合物中缓慢加入甲酸乙酯(25mL,311mmol)，滴加完毕后，反应混合物在-65℃搅拌1hr。向反应混合物中加入2N稀盐酸淬灭反应，用EA(500mL×2)萃取，合并有机相，用饱和食盐水(1L×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(55g,收率98.6％，淡黄色油状物)。2,6-Difluoro-4-iodopyridine (50.0 g, 207 mmol) was dissolved in THF (600 mL). Under a nitrogen atmosphere, the temperature was lowered to -65°C. LDA (124 mL, 53 mmol) was slowly added at this temperature, and the reaction mixture was stirred at -65°C for 1 hour. Ethyl formate (25 mL, 311 mmol) was then slowly added to the reaction mixture at -65°C. After the addition was complete, the reaction mixture was stirred at -65°C for 1 hour. 2N dilute hydrochloric acid was added to the reaction mixture to quench the reaction. The mixture was extracted with EA (500 mL x 2). The organic phases were combined, washed with saturated brine (1 L x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford the crude product (55 g, 98.6% yield, pale yellow oil).

步骤2：6-氟-4-碘-1H-吡唑并[3,4-b]吡啶的合成
Step 2: Synthesis of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine

将2,6-二氟-4-碘烟醛(55g,204mmol)溶于EtOH(500mL)中，加入水合肼(15mL)，反应混合物在80℃下搅拌16hrs，冷却至室温，反应混合物减压浓缩，残余物用纯水搅拌1hrs，浆化，过滤，收集固体，干燥得到粗品(45g,收率83.7％，黑色油状物)。LC-MS(ESI)m/z:264.0[M+H]+。2,6-Difluoro-4-iodonicotinaldehyde (55 g, 204 mmol) was dissolved in EtOH (500 mL), and hydrazine hydrate (15 mL) was added. The reaction mixture was stirred at 80°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was stirred with purified water for 1 hour, slurried, filtered, and the solid collected and dried to give the crude product (45 g, 83.7% yield, black oil). LC-MS (ESI) m/z: 264.0 [M+H] + .

步骤3：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1H-吡唑并[3,4-b]吡啶的合成
Step 3: Synthesis of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine

在N2保护下，向6-氟-4-碘-1H-吡唑并[3,4-b]吡啶(300mg,1.14mmol)的NMP(2mL)溶液中加入3-氧杂-8-氮杂双环[3.2.1]辛烷的盐酸盐(341mg,2.28mmol)和DIEA(590mg,4.56mmol)，反应混合物在150℃下搅拌3hrs，冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，70-90％EA)，得到目标化合物(100mg,收率24.6％，棕色固体)。LC-MS(ESI)m/z:357.0[M+H]+。Under N₂ protection, to a solution of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.14 mmol) in NMP (2 mL) were added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (341 mg, 2.28 mmol) and DIEA (590 mg, 4.56 mmol). The reaction mixture was stirred at 150°C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 70-90% EA) to obtain the title compound (100 mg, 24.6% yield, as a brown solid). LC-MS (ESI) m/z: 357.0 [M+H] + .

步骤4：8-(4-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1a)的合成
Step 4: Synthesis of 8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a)

向6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1H-吡唑并[3,4-b]吡啶(100mg,0.28mmol)的DMF(5mL)溶液中加入[1-(3,4,5,6-四氢-2H-吡唑-2-基)吡唑-3-基]硼二醇(55mg,0.28mmol)、吡啶(77mg,0.98mmol)和无水醋酸铜(112mg,0.56mmol)，反应混合物在O2氛围下50℃搅拌反应18hrs，冷却至室温，用EA和饱和NaCl溶液稀释，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(70mg,收率49.2％，棕色固体)。LC-MS(ESI)m/z:507.0[M+H]+。To a solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.28 mmol) in DMF (5 mL) were added [1-(3,4,5,6-tetrahydro-2H-pyrazol-2-yl)pyrazol-3-yl]boranediol (55 mg, 0.28 mmol), pyridine (77 mg, 0.98 mmol), and anhydrous copper acetate (112 mg, 0.56 mmol). The reaction mixture was stirred at 50°C under an O atmosphere for 18 hours, cooled to room temperature, diluted with EA and saturated NaCl solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to afford the title compound (70 mg, 49.2% yield, as a brown solid). LC-MS (ESI) m/z: 507.0 [M+H] + .

步骤5：化合物8-(4-(环己-1-烯-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of compound 8-(4-(cyclohex-1-en-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1a)(70mg,0.14mmol)的1,4-二氧六环(5mL)和H2O(1mL)的混合溶液中加入环己-1-烯基硼二醇(26mg,0.20mmol)和Cs2CO3(134mg,0.41mmol)，N2保护下，反应混合物在100℃搅拌12hrs，冷却至室温，用EA和饱和NaCl溶液稀释，有机相用水洗涤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)，得到目标化合物(40mg,收率62.8％，黄色固体)。LC-MS(ESI)m/z:461.2[M+H]+。To a mixed solution of 8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a) (70 mg, 0.14 mmol) in 1,4-dioxane (5 mL) and H₂O (1 mL) were added cyclohex-1-enylboranediol (26 mg, 0.20 mmol) and Cs₂CO₃ (134 mg , 0.41 mmol). Under N₂ protection, the reaction mixture was stirred at 100°C for 12 hrs, cooled to room temperature, diluted with EA and saturated NaCl solution, and the organic phase was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to give the title compound (40 mg, yield 62.8%, yellow solid). LC-MS(ESI)m/z:461.2[M+H] + .

步骤6：8-(4-(环己-1-烯-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(cyclohex-1-en-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

把8-(4-(环己-1-烯-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.09mmol)加入到THF(2mL)中，然后加入4N盐酸/1,4-二氧六环溶液(3mL)，反应混合物在50℃下搅拌12hrs，冷却至室温，减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,50*250mm,10um:0.1％FA；B％:50-80,流速：60mL/min，30min)分离纯化，得到目标化合物(10.0mg,收率31.2％，白色固体)。LC-MS(ESI)m/z:377.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.12(s,1H),7.82(s,1H),6.77(s,1H),6.66(s,1H),6.50(s,1H),4.63(s,2H),3.68(d,J＝10.7Hz,2H),3.57(d,J＝10.7Hz,2H),2.50–2.47(m,2H),2.32–2.25(m,2H),2.01–1.88(m,4H),1.81–1.73(m,2H),1.72–1.64(m,2H)。8-(4-(cyclohex-1-en-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.09 mmol) was added to THF (2 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (3 mL). The reaction mixture was stirred at 50°C for 12 hr, cooled to room temperature, and concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 50*250 mm, 10 μm: 0.1% FA; B%: 50-80, flow rate: 60 mL/min, 30 min) to afford the title compound (10.0 mg, 31.2% yield, as a white solid). LC-MS(ESI)m/z:377.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.79(s,1H),8.12(s,1H),7.82(s,1H),6.77(s,1H),6.66(s,1H),6.50(s,1H),4.63(s,2H),3.68(d,J＝10.7Hz,2H), 3.57(d,J＝10.7Hz,2H),2.50–2.47(m,2H),2.32–2.25(m,2H),2.01–1.88(m,4H),1.81–1.73(m,2H),1.72–1.64(m,2H).

实施例2：8-(4-(3-(氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1] 辛烷
Example 2: 8-(4-(3-(Fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：8-(4-(3-(氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(3-(fluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1a)(100mg,0.20mmol)的NMP(2mL)溶液中加入3-(氟甲基)吗啉(2a)(46mg,0.39mmol)、Cs2CO3(192mg,0.59mmol)和RuphosPdG2(15mg,0.02mmol)，反应混合物在120℃下搅拌3hrs，冷却至室温，用EA(10mL×3)萃取反应，合并有机相，减压浓缩，残余物经反相柱层析分离纯化(H2O:CH3CN，33％ CH3CN)得到目标化合物(10.0mg,收率10.2％，淡黄色固体)。LC-MS(ESI)m/z:498.20[M+H]+。To a solution of 8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a) (100 mg, 0.20 mmol) in NMP (2 mL) were added 3-(fluoromethyl)morpholine (2a) (46 mg, 0.39 mmol), Cs 2 CO 3 (192 mg, 0.59 mmol) and RuphosPdG2 (15 mg, 0.02 mmol). The reaction mixture was stirred at 120° C. for 3 hrs, cooled to room temperature, extracted with EA (10 mL×3), the organic phases were combined and concentrated under reduced pressure, and the residue was separated and purified by reverse phase column chromatography (H 2 O:CH 3 CN, 33% CH 3 CN) to give the title compound (10.0 mg, 10.2% yield, light yellow solid). LC-MS (ESI) m/z: 498.20 [M+H] + .

步骤2：8-(4-(3-(氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(3-(fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(3-(氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(15mg,0.03mmol)的THF(3mL)溶液中加入2N HCl/1,4-二氧六环溶液(5mL)，反应混合物在50℃下搅拌6hrs，冷却至室温，减压浓缩，残余物通过Prep-HPLC分离纯化，得到目标化合物(5.0mg,收率40.1％，白色固体)。LC-MS(ESI)m/z:414.2[M+H]+。1H NMR(400MHz,CD3OD)δ8.11(s,1H),7.70(s,1H),6.90(s,1H),5.86(s,1H),5.16–4.98(m,1H),4.55(s,2H),4.30–4.19(m,1H),4.12–3.96(m,4H),3.90–3.82(m,4H),3.82–3.69(m,1H),3.59(d,J＝11.0Hz,2H),2.10–1.97(m,4H).To a solution of 8-(4-(3-(fluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (15 mg, 0.03 mmol) in THF (3 mL) was added a 2N HCl/1,4-dioxane solution (5 mL). The reaction mixture was stirred at 50°C for 6 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC to obtain the title compound (5.0 mg, 40.1% yield, as a white solid). LC-MS (ESI) m/z: 414.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.11(s,1H),7.70(s,1H),6.90(s,1H),5.86(s,1H),5.16–4.98(m,1H),4.55(s,2H),4.30–4.19(m, 1H), 4.12–3.96 (m, 4H), 3.90–3.82 (m, 4H), 3.82–3.69 (m, 1H), 3.59 (d, J = 11.0Hz, 2H), 2.10–1.97 (m, 4H).

实施例3：8-(7-(3,3-二甲基吗啉基)-3-(1H-吡唑-3-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 3: 8-(7-(3,3-dimethylmorpholinyl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：4-(3-溴-5-氯吡唑并[1,5-a]嘧啶-7-基)-3,3-二甲基吗啉的合成
Step 1: Synthesis of 4-(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylmorpholine

将3-溴-5,7-二氯吡唑并[1,5-a]嘧啶(750mg,2.81mmol)、3,3-二甲基吗啉(323mg,2.81mmol)、DIEA(1.39mL，8.43mmol)加入到NMP(10mL)中，反应混合物在N2保护下100℃搅拌6hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，20％EA)得到目标化合物(600mg,收率61.8％，黄色固体)。LC-MS(ESI)m/z:345.0,347.0[M+H]+。3-Bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (750 mg, 2.81 mmol), 3,3-dimethylmorpholine (323 mg, 2.81 mmol), and DIEA (1.39 mL, 8.43 mmol) were added to NMP (10 mL). The reaction mixture was stirred at 100°C for 6 hr under N₂ protection. The mixture was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 20% EA) to obtain the title compound (600 mg, 61.8% yield, as a yellow solid). LC -MS (ESI) m/z: 345.0, 347.0 [M+H] ⁺ .

步骤2：8-(3-溴-7-(3,3-二甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-bromo-7-(3,3-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将4-(3-溴-5-氯吡唑并[1,5-a]嘧啶-7-基)-3,3-二甲基吗啉(600mg,1.74mmol)、3-氧杂-8-氮杂双环[3.2.1]辛烷的盐酸盐(393mg,3.47mmol)、DIEA(1.12g,8.68mmol)加入到NMP(8mL)中。反应混合物在N2保护下130℃下搅拌6hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和NaCl(30mL×2)水溶液洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，20％EA)得到目标化合物(400mg,收率54.6％，黄色固体)。LC-MS(ESI)m/z:422.2,424.0[M+H]+。4-(3-Bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylmorpholine (600 mg, 1.74 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (393 mg, 3.47 mmol), and DIEA (1.12 g, 8.68 mmol) were added to NMP (8 mL). The reaction mixture was stirred at 130°C for 6 hr under N₂ protection, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated aqueous NaCl (30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 20% EA) to obtain the title compound (400 mg, 54.6% yield) as a yellow solid. LC-MS(ESI)m/z:422.2,424.0[M+H] + .

步骤3：8-(7-(3,3-二甲基吗啉基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(7-(3,3-dimethylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-溴-7-(3,3-二甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(200mg,0.47mmol)、((1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(139mg,0.71mmol)、Pd(dtbpf)Cl2(31mg,0.047mmol)和K3PO4(301mg,1.42mmol)依次加入1,4-二氧六环/水(10mL，V/V＝5/1)中。反应混合物在100℃下反应12hrs，冷却至室温，向反应混合物中加入水(10mL)，用EA(15mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物直接用于下一步反应(210mg,黄色固体)。LC-MS(ESI)m/z:494.2[M+H]+。8-(3-Bromo-7-(3,3-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (200 mg, 0.47 mmol), ((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (139 mg, 0.71 mmol), Pd(dtbpf)Cl 2 (31 mg, 0.047 mmol) and K 3 PO 4 The 1,4-dioxane-2-ylpiperidin-2-ylpiperidin-2-ylpiperidin- 3 -ylpiperidin- 1 - ylpiperidin -2 ...

步骤4：8-(7-(3,3-二甲基吗啉基)-3-(1H-吡唑-3-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(7-(3,3-dimethylmorpholinyl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-溴-7-(3,3-二甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(210mg,0.43mmol)溶于MeOH(6mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物室温搅拌12hrs，减压浓缩，残余物经prep-HPLC分离纯化(柱:Xtimate C18 10um OBD 80*250mm；流动相:A-0.1％ FA,B％:32-62,180mL/min,30min)，得到目标化合物(40mg,收率23.0％,黄色固体)。LC-MS(ESI)m/z:410.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.21(s,1H),7.53(s,1H),6.67(s,1H),6.02(s,1H),4.69(s,2H),3.83(t,J＝4.8Hz,2H),3.71(d,J＝10.8Hz,2H),3.62(d,J＝10.4Hz,2H),3.58–3.51(m,2H),3.46(s,2H),2.03–1.90(m,4H),1.34(s,6H)。8-(3-Bromo-7-(3,3-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (210 mg, 0.43 mmol) was dissolved in MeOH (6 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was separated and purified by prep-HPLC (column: Xtimate C18 10 μm OBD 80*250 mm; mobile phase: A-0.1% FA, B%: 32-62, 180 mL/min, 30 min) to obtain the title compound (40 mg, 23.0% yield, as a yellow solid). LC-MS (ESI) m/z: 410.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.68(s,1H),8.21(s,1H),7.53(s,1H),6.67(s,1H),6.02(s,1H),4.69(s,2H),3.83(t,J＝4.8Hz,2H),3.7 1(d,J＝10.8Hz,2H),3.62(d,J＝10.4Hz,2H),3.58–3.51(m,2H),3.46(s,2H),2.03–1.90(m,4H),1.34(s,6H).

实施例4：1-((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲 基哌嗪-1-基)乙烷-1-酮
Example 4: 1-((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- methylpiperazin -1-yl)ethan-1-one

步骤1：1-((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-基)乙烷-1-酮的合成
Step 1: Synthesis of 1-((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

将8-(4-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1a)(350mg,0.69mmol)、(R)-1-(3-甲基哌嗪-1-基)乙烷-1-酮(196mg,1.38mmol)、Pd(OAc)2(16mg,0.069mmol)、BINAP(86.08mg,0.138mmol)和Cs2CO3(901mg,2.77mmol)依次加入到甲苯(20mL)中，反应混合物在N2保护下120℃下反应12hrs，冷却至室温后，向反应混合物中加入水(10mL)，用EA(15mL×3)萃取。合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(40mg,白色固体)，粗产品直接用于下一步反应。LC-MS(ESI)m/z:521.2[M+H]+。8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a) (350 mg, 0.69 mmol), (R)-1-(3-methylpiperazin-1-yl)ethan-1-one (196 mg, 1.38 mmol), Pd(OAc) 2 ( 16 mg, 0.069 mmol), BINAP (86.08 mg, 0.138 mmol) and Cs2CO3 (901 mg, 2.77 mmol) were added to toluene (20 mL) in sequence. The reaction mixture was reacted at 120°C under N2 protection for 12 hrs. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (15 mL×3). The organic phases were combined, washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (40 mg, white solid). The crude product was used directly in the next reaction. LC-MS (ESI) m/z: 521.2 [M+H] + .

步骤2：1-((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-基)乙烷-1-酮的合成
Step 2: Synthesis of 1-((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

将1-((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-基)乙烷-1-酮(40mg,0.07mmol)加入到MeOH(3mL)中，然后加入4N盐酸/1,4-二氧六环溶液(3mL)，反应混合物室温搅拌12hrs，减压浓缩，残余物经prep-HPLC分离纯化(柱:Xtimate C18 5um OBD 21.2*250mm；流动相：A-0.1％FA，B％:10-40，流速：20mL/min，18min)，得到目标化合物(10.0mg,收率10.0％,黄色固体)。LC-MS(ESI)m/z:437.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.15(s,1H),7.78(s,1H),6.77(s,1H),5.89(d,J＝3.5Hz,1H),4.54(s,2H),4.51–4.41(m,1H),4.34–4.14(m,1H),3.95–3.71(m,2H),3.69(d,J＝10.4Hz,2H),3.60(dd,J＝13.7,3.5Hz,1H),3.54(d,J＝10.7Hz,2H),3.46–3.38(m,1H),3.29–3.24(m,1H),3.16–2.96(m,1H),2.07(d,J＝22.3Hz,3H),1.99–1.81(m,4H),1.10(dd,J＝27.9,6.5Hz,3H)。1-((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one (40 mg, 0.07 mmol) was added to MeOH (3 mL), and then a 4N hydrochloric acid/1,4-dioxane solution (3 mL) was added. The reaction mixture was stirred at room temperature for 12 hrs and concentrated under reduced pressure. The residue was separated and purified by prep-HPLC (column: Xtimate C18 5um OBD 21.2*250mm; mobile phase: A-0.1% FA, B%: 10-40, flow rate: 20 mL/min, 18 min) to obtain the title compound (10.0 mg, yield 10.0%, yellow solid). LC-MS (ESI) m/z: 437.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 6.77 (s, 1H), 5.89 (d, J=3.5 Hz, 1H), 4.54 (s, 2H), 4.51–4.41 (m, 1H), 4.34–4.14 (m, 1H), 3.95–3.71 (m, 2H), 3.69 (d, J=10.4 Hz, 2H), 3.60 (dd,J＝13.7,3.5Hz,1H),3.54(d,J＝10.7Hz,2H),3.46–3.38(m,1H),3.29–3.24(m,1H),3. 16–2.96(m,1H),2.07(d,J＝22.3Hz,3H),1.99–1.81(m,4H),1.10(dd,J＝27.9,6.5Hz,3H).

实施例5：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯 甲酰胺
Example 5: 3-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N- methylbenzamide

步骤1：3-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺
Step 1: 3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

将4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(300mg,1.10mmol)、N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(229mg,0.88mmol)、Pd(dppf)Cl2(80mg,0.11mmol)、Cs2CO3(537mg,1.65mmol)依次加入到1,4-二氧六环/水(48mL，V/V＝5/1)中。N2保护下，反应混合物在50℃下搅拌3hrs。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，得到目标化合物(350mg,收率85.7％，黄色固体)。LC-MS(ESI)m/z:372.0[M+H]+。4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.10 mmol), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (229 mg, 0.88 mmol), Pd(dppf) Cl₂ (80 mg, 0.11 mmol), and Cs₂CO₃ (537 mg , 1.65 mmol) were added sequentially to 1,4-dioxane/water (48 mL, V/V = 5/1). Under N₂ protection, the reaction mixture was stirred at 50°C for 3 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 75% EA) to afford the title compound (350 mg, 85.7% yield, as a yellow solid). LC-MS(ESI)m/z:372.0[M+H] + .

步骤2：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺
Step 2: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

将3-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺(400mg,1.08mmol)溶于NMP(20mL)中，加入3-氧杂-8-氮杂双环[3.2.1]辛烷(183mg,1.61mmol)和DIPEA(694mg,5.38mmol)。N2保护下，反应混合物在110℃下搅拌16hrs。反应混合物冷却至室温后，向反应混合物中加入水(40.0mL)，用EA(40.0mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)，得到目标化合物(286mg,收率59.3％，黄色固体)。LC-MS(ESI)m/z:449.2[M+H]+。3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide (400 mg, 1.08 mmol) was dissolved in NMP (20 mL), and 3-oxa-8-azabicyclo[3.2.1]octane (183 mg, 1.61 mmol) and DIPEA (694 mg, 5.38 mmol) were added. Under N₂ protection, the reaction mixture was stirred at 110°C for 16 hrs. After cooling to room temperature, water (40.0 mL) was added to the reaction mixture, and the mixture was extracted with EA (40.0 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to obtain the title compound (286 mg, 59.3% yield, as a yellow solid). LC-MS(ESI)m/z:449.2[M+H] + .

步骤3：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺
Step 3: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

将3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺(186mg,0.42mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)。反应混合物在25℃下搅拌3hrs，减压浓缩，得到目标化合物(151mg,收率100.0％，黄色固体)。LC-MS(ESI)m/z:365.2[M+H]+。3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide (186 mg, 0.42 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 25°C for 3 hours and then concentrated under reduced pressure to obtain the title compound (151 mg, 100.0% yield, as a yellow solid). LC-MS (ESI) m/z: 365.2 [M+H] + .

步骤4：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺
Step 4: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

将3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺(71mg,0.20mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(65mg,0.23mmol)、甲基[(1S，2S)-2-(甲氨基)环己基]胺(28mg,0.20mmol)、Cs2CO3(159mg,0.50mmol)和CuI(37mg,0.20mmol)依次加入到NMP(15mL)中。反应混合物鼓N2 3mins，然后150℃下微波反应3hrs。反应混合物冷却至室温后，向反应混合物中加入水(30.0mL)，用EA(30.0mL×2)萃取，合并有机相，用饱和食盐水(80.0mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(100mg,粗品，黄色固体)。LC-MS(ESI)m/z:515.2[M+H]+。3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide (71 mg, 0.20 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (65 mg, 0.23 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (28 mg, 0.20 mmol), Cs 2 CO 3 (159 mg, 0.50 mmol) and CuI (37 mg, 0.20 mmol) were added sequentially to NMP (15 mL). The reaction mixture was bubbled with N 2 for 3 mins and then microwaved at 150° C. for 3 hrs. After the reaction mixture was cooled to room temperature, water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with EA (30.0 mL × 2). The organic phases were combined, washed with saturated brine (80.0 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (100 mg, crude product, yellow solid). LC-MS (ESI) m/z: 515.2 [M+H] + .

步骤5：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺
Step 5: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

将3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-N-甲基苯甲酰胺(95mg,0.19mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)。反应混合物在50℃下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:22-52,流速:20mL/min,20min)分离纯化得到目标化合物(21.2mg,收率26.7％，白色固体)。LC-MS(方法A)：RT＝1.11min，(ESI)m/z:431.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.70–8.65(m,1H),8.57(s,1H),8.56(t,J＝1.5Hz,1H),8.39–8.32(m,2H),8.08–8.04(m,1H),7.92–7.86(m,1H),7.71(t,J＝7.8Hz,1H),6.80(t,J＝2.1Hz,1H),4.99–4.58(m,2H),3.74–3.65(m,4H),2.85(d,J＝4.5Hz,3H),2.05–1.94(m,4H)。3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide (95 mg, 0.19 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 22-52, flow rate: 20 mL/min, 20 min) to obtain the title compound (21.2 mg, 26.7% yield, as a white solid). LC-MS (Method A): RT = 1.11 min, (ESI) m/z: 431.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.95(s,1H),8.70–8.65(m,1H),8.57(s,1H),8.56(t,J＝1.5Hz,1H),8.39–8.32(m,2H),8.08–8.04(m,1H),7.92–7.86(m,1H ),7.71(t,J＝7.8Hz,1H),6.80(t,J＝2.1Hz,1H),4.99–4.58(m,2H),3.74–3.65(m,4H),2.85(d,J＝4.5Hz,3H),2.05–1.94(m,4H).

实施例6：8-(4-(3,3-二甲基吗啉基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3- 氧杂-8-氮杂双环[3.2.1]辛烷
Example 6: 8-(4-(3,3-dimethylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3- oxa-8-azabicyclo[3.2.1]octane

步骤1：6-氯-4-(3,3-二甲基吗啉基)-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶
Step 1: 6-Chloro-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine

将4,6-二氯-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶(1.00g,3.66mmol)和3,3-二甲基吗啉(0.84g,7.32mmol)溶于THF(20mL)中，然后加入DIPEA(1.42g,10.98mmol)，反应混合物在80℃下搅拌3hrs。反应混合物冷却至室温后，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用水(50mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，38％EA)得到目标化合物(1.10g,收率85.4％，白色固体)。LC-MS(ESI)m/z:352.2[M+H]+。4,6-Dichloro-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine (1.00 g, 3.66 mmol) and 3,3-dimethylmorpholine (0.84 g, 7.32 mmol) were dissolved in THF (20 mL), followed by the addition of DIPEA (1.42 g, 10.98 mmol). The reaction mixture was stirred at 80°C for 3 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (20 mL x 2). The combined organic phases were washed with water (50 mL x 3 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 38% EA) to afford the title compound (1.10 g, 85.4% yield, as a white solid). LC-MS (ESI) m/z: 352.2 [M+H] ⁺ .

步骤2：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基吗啉基)-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶
Step 2: 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine

将6-氯-4-(3,3-二甲基吗啉基)-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶(1.10g,3.13mmol)和8-氮杂-3-氧杂双环[3.2.1]辛烷(0.71g,6.25mmol)溶于NMP(20mL)中，加入DIPEA(1.21g,9.38mmol)，反应混合物在130℃下搅拌16hrs，冷却至室温后，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相用水(50mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，25％EA)得到目标化合物(0.97g,收率72.4％，浅黄色固体)。LC-MS(ESI)m/z:429.3[M+H]+。6-Chloro-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine (1.10 g, 3.13 mmol) and 8-aza-3-oxabicyclo[3.2.1]octane (0.71 g, 6.25 mmol) were dissolved in NMP (20 mL), and DIPEA (1.21 g, 9.38 mmol) was added. The reaction mixture was stirred at 130°C for 16 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL×2). The combined organic phases were washed with water (50 mL× 3 ), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 25% EA) to obtain the title compound (0.97 g, yield 72.4%, light yellow solid). LC-MS(ESI)m/z:429.3[M+H] + .

步骤3：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶
Step 3: 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基吗啉基)-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶(960mg,2.24mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)。反应混合物在25℃下搅拌过夜。向反应混合物中加入饱和NaHCO3水溶液，用EA(20mL×2)萃取，合并有机相，用水(40mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，得到目标化合物(630mg,收率81.3％，黄色固体)。LC-MS(ESI)m/z:345.4[M+H]+。6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine (960 mg, 2.24 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. The reaction mixture was stirred at 25°C overnight. Saturated aqueous NaHCO₃ was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with water (40 mL x 3 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to yield the title compound (630 mg, 81.3% yield, as a yellow solid). LC-MS (ESI) m/z: 345.4 [M+H] ⁺ .

步骤4：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-溴-4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶
Step 4: 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-bromo-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶(200mg,0.58mmol)溶于DMF(4mL)中，加入NBS(103mg,0.58mmol)。反应混合物在25℃下搅拌2hrs。向反应混合物中加入饱和Na2SO3水溶液，用EA(10mL×2)萃取，合并有机相用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40-50％EA)，得到目标化合物(74mg,收率30.1％，橙色固体)。LC-MS(ESI)m/z:425.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.58 mmol) was dissolved in DMF (4 mL), and NBS (103 mg, 0.58 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. Saturated aqueous Na₂SO₃ was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40-50% EA) to obtain the title compound (74 mg, 30.1% yield, as an orange solid). LC-MS (ESI) m/z: 425.2 [M+H] ⁺ .

步骤5：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基吗啉基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-d]嘧啶
Step 5: 6-(8-aza-3-oxabicyclo[3.2.1]oct-8-yl)-4-(3,3-dimethylmorpholinyl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-溴-4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶(74mg,0.17mmol)和4,4,6-三甲基-2-(3,3,3-三氟丙基-1-烯-2-基)-1,3,2-二氧杂硼烷(116mg,0.52mmol)溶于1,4-二氧六环(4mL)和水(1mL)中，再加入Cs2CO3(171mg,0.52mmol)、Pd(dppf)Cl2(13mg,0.02mmol)。N2保护下，反应混合物在100℃下搅拌2hrs。反应混合物冷却至室温后，加入水和EA稀释，用EA(10mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)，得到目标化合物(70mg,收率91.3％，黄色固体)。LC-MS(ESI)m/z:439.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-bromo-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine (74 mg, 0.17 mmol) and 4,4,6-trimethyl-2-(3,3,3-trifluoropropyl-1-en-2-yl)-1,3,2-dioxaborolane (116 mg, 0.52 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and Cs 2 CO 3 (171 mg, 0.52 mmol) and Pd(dppf)Cl 2 (13 mg, 0.02 mmol) were added. Under N 2 protection, the reaction mixture was stirred at 100° C. for 2 hrs. After the reaction mixture was cooled to room temperature, it was diluted with water and EA and extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (70 mg, 91.3% yield, yellow solid). LC-MS (ESI) m/z: 439.2 [M+H] ⁺ .

步骤6：8-(4-(3,3-二甲基吗啉基)-3-(1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 6: 8-(4-(3,3-dimethylmorpholinyl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.18mmol)溶于MeOH(5mL)中，加入5％ Pd/C(100mg,wet，50％water)，反应混合物在H2氛围下置换两次，在25℃下搅拌16hrs。用硅藻土过滤，滤液减压浓缩，得到目标化合物(80mg,粗品，无色油状物)。LC-MS(ESI)m/z:441.2[M+H]+。8-(4-(3,3-dimethylmorpholinyl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.18 mmol) was dissolved in MeOH (5 mL). 5% Pd/C (100 mg, wet, 50% water) was added. The reaction mixture was purged twice under a H₂ atmosphere and stirred at 25°C for 16 hr. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (80 mg, crude, colorless oil). LC-MS (ESI) m/z: 441.2 [M+H] ⁺ .

步骤7：8-(4-(3,3-二甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 7: 8-(4-(3,3-dimethylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-3-(1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.18mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(76mg,0.27mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(26mg,0.18mmol)、Cs2CO3(148mg,0.45mmol)和CuI2(35mg,0.18mmol)依次加入到NMP(5mL)中。N2保护下，反应混合物120℃下搅拌16hrs。反应混合物冷却至室温后，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取。合并有机相用饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)，得到目标化合物(20mg,粗品，无色油状物)。LC-MS(ESI)m/z:591.2[M+H]+。8-(4-(3,3-Dimethylmorpholinyl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.18 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (76 mg, 0.27 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (26 mg, 0.18 mmol), Cs 2 CO 3 (148 mg, 0.45 mmol), and CuI 2 (35 mg, 0.18 mmol) were added sequentially to NMP (5 mL). Under N 2 protection, the reaction mixture was stirred at 120° C. for 16 hrs. After the reaction mixture was cooled to room temperature, water (20 mL) was added and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 5), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (20 mg, crude product, colorless oil). LC-MS (ESI) m/z: 591.2 [M+H] ⁺ .

步骤8：8-(4-(3,3-二甲基吗啉基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 8: 8-(4-(3,3-dimethylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(20mg,0.03mmol)溶于THF(5mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)。反应混合物在50℃下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18，21.2*250mm，5um：0.1％FA；B％：47-77，流速：20mL/min，20min)分离纯化得到目标化合物(2.0mg,收率11.5％，白色固体)。LC-MS(ESI)m/z:507.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.74(s,1H),6.84(s,1H),4.14–4.06(m,2H),3.98–3.94(m,1H),3.88–3.84(m,1H),3.84–3.79(m,2H),3.70–3.64(m,2H),3.54–3.50(m,2H),3.47–3.43(m,2H),2.12–2.08(m,2H),1.67(d,J＝7.2Hz,2H),1.63–1.58(m,4H),0.92–0.88(m,6H).8-(4-(3,3-dimethylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20 mg, 0.03 mmol) was dissolved in THF (5 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 47-77, flow rate: 20 mL/min, 20 min) to obtain the title compound (2.0 mg, 11.5% yield) as a white solid. LC-MS(ESI)m/z:507.2[M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.74(s,1H),6.84(s,1H),4.14–4.06(m,2H),3.98–3.94(m,1H),3.88–3.84(m,1H),3.84–3.79(m,2H),3.70–3.64(m,2 H),3.54–3.50(m,2H),3.47–3.43(m,2H),2.12–2.08(m,2H),1.67(d,J＝7.2Hz,2H),1.63–1.58(m,4H),0.92–0.88(m,6H).

实施例7：8-(4-((S)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1] 辛烷
Example 7: 8-(4-((S)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：8-(4-((S)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((S)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1a)(100mg,0.20mmol)，(S)-3-甲基吗啉(40mg,0.40mmol)，Pd(OAc)2(4mg,0.02mmol)，1,1'-联萘-2,2'-双二苯膦(24mg,0.04mmol)和Cs2CO3(193mg,0.60mmol)依次加入到甲苯(3mL)中。N2保护下，反应混合物120℃下搅拌过夜。反应混合物冷却至室温后，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝11：9)得到目标化合物(40mg,收率42.2％，棕色油状物)。LC-MS(ESI)m/z:480.2[M+H]+。8-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1a) (100 mg, 0.20 mmol), (S)-3-methylmorpholine (40 mg, 0.40 mmol), Pd(OAc) 2 (4 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (24 mg, 0.04 mmol), and Cs2CO3 (193 mg, 0.60 mmol) were added sequentially to toluene (3 mL). Under N2 protection, the reaction mixture was stirred at 120°C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=11:9) to obtain the title compound (40 mg, 42.2% yield, brown oil). LC-MS (ESI) m/z: 480.2 [M+H] + .

步骤2：8-(4-((S)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Step 2: 8-(4-((S)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((S)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.08mmol)溶解到4N盐酸/1,4-二氧六环溶液(3mL)中。N2保护下，反应混合物室温搅拌过夜。减压浓缩，残余物经pre-HPLC(柱：Shimadzu LC-20AP；Xtimate C18，21.2*250mm，5um；流动相A：0.1％ FA/水，流动相B：ACN；梯度：12-42％B；检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(5.4mg,收率16.4％，白色固体)。LC-MS(ESI)m/z:396.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),8.15(s,1H),7.79(s,1H),6.78(s,1H),5.90(s,1H),4.53(s,2H),4.37–4.29(m,1H),3.96(dd,J＝10.9,3.4Hz,1H),3.80–3.66(m,4H),3.64–3.56(m,2H),3.53(d,J＝10.8Hz,2H),3.30–3.28(m,1H),1.97–1.92(m,2H),1.90–1.84(m,2H),1.16(d,J＝6.6Hz,3H)。Dissolve 8-(4-((S)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.08 mmol) in a 4N hydrochloric acid/1,4-dioxane solution (3 mL). Under N₂ protection, the reaction mixture was stirred at room temperature overnight. The residue was concentrated under reduced pressure, and purified by pre-HPLC (Shimadzu LC-20AP; Xtimate C18, 21.2 x 250 mm, 5 μm column; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 12-42% B; detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to afford the title compound (5.4 mg, 16.4% yield, white solid). LC-MS (ESI) m/z: 396.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.73(s,1H),8.15(s,1H),7.79(s,1H),6.78(s,1H),5.90(s,1H),4.53(s,2H),4.37–4.29(m,1H),3.96(dd,J＝10.9,3.4Hz,1H),3.80 –3.66(m,4H),3.64–3.56(m,2H),3.53(d,J＝10.8Hz,2H),3.30–3.28(m,1H),1.97–1.92(m,2H),1.90–1.84(m,2H),1.16(d,J＝6.6Hz,3H).

实施例8：8-(4-(3,3-二甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1] 辛烷
Example 8: 8-(4-(3,3-dimethylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：6-氟-4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶的合成
Step 1: Synthesis of 6-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

将6-氟-4-碘-1H-吡唑并[3,4-b]吡啶(55g,209mmol)溶于THF(500mL)中，加入甲磺酸(55g,209mmol)和3.4-二氢-2H-吡喃(38mL，418mmol)。反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA＝15/1)得到目标化合物(23g,收率66.2％，白色固体)。LC-MS(ESI)m/z:717.0[2M+Na]+。Dissolve 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (55 g, 209 mmol) in THF (500 mL), add methanesulfonic acid (55 g, 209 mmol) and 3,4-dihydro-2H-pyran (38 mL, 418 mmol). The reaction mixture is stirred at 25°C for 16 hours. The residue is concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA = 15/1) to afford the title compound (23 g, 66.2% yield, as a white solid). LC-MS (ESI) m/z: 717.0 [2M+Na] + .

步骤2：8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(8a)的合成
Step 2: Synthesis of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8a)

将6-氟-4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶(23g,0.58mmol)溶于NMP(200mL)中，加入DIPEA(43g,331mmol)和8-氮杂-3-氧杂双环[3.2.1]辛烷(8.3g,73mmol)。N2保护下，反应混合物在25℃下搅拌16hrs。向反应混合物中加入水(200mL)，用EA(200mL×2)萃取，合并有机相，用饱和NaCl(500mL×5)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，30％EA)得到目标化合物(21g,收率72.0％，白色固体)。LC-MS(ESI)m/z:441.2[M+H]+。6-Fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (23 g, 0.58 mmol) was dissolved in NMP (200 mL), and DIPEA (43 g, 331 mmol) and 8-aza-3-oxabicyclo[3.2.1]octane (8.3 g, 73 mmol) were added. Under N₂ protection, the reaction mixture was stirred at 25°C for 16 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (200 mL x 2). The combined organic phases were washed with saturated NaCl (500 mL x 5 ), dried over anhydrous Na₂SO₄ , and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (21 g, 72.0% yield, as a white solid). LC-MS(ESI)m/z:441.2[M+H] + .

步骤3：8-(4-(3,3-二甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(500mg,1.13mmol)溶解在甲苯(15mL)中，依次加入3.3-二甲基吗啉(261mg,2.27mmol)、叔丁醇钠(273mg,2.84mmol)，Xphos(108mg,0.22mmol)和Pd2(dba)3(104mg,0.11mmol)，反应混合物在120℃下搅拌反应6hrs，冷却至室温，加入水(20mL)，用EA(20mL×3)萃取，减压浓缩，残余物经反相柱层析纯化(H2O:CH3CN，35％ CH3CN)得到目标化合物(30mg,收率6.2％，淡黄色油状物)。LC-MS(ESI)m/z:428.2[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (500 mg, 1.13 mmol) was dissolved in toluene (15 mL), and 3.3-dimethylmorpholine (261 mg, 2.27 mmol), sodium tert-butoxide (273 mg, 2.84 mmol), Xphos (108 mg, 0.22 mmol) and Pd 2 (dba) 3 (104 mg, 0.11 mmol) were added in sequence. The reaction mixture was stirred at 120° C. for 6 hrs, cooled to room temperature, added with water (20 mL), extracted with EA (20 mL×3), and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (H 2 O:CH 3 CN, 35% CH 3 CN) to give the title compound (30 mg, 6.2% yield, light yellow oil). LC-MS (ESI) m/z: 428.2 [M+H] + .

步骤4：8-(4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(3,3-二甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(35mg,0.08mmol)的THF(5mL)溶液中加入4N盐酸/1,4-二氧六环溶液(5mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，得到目标化合物(18mg,收率64.0％，灰黄色油状物)。LC-MS(ESI)m/z:344.2[M+H]+。To a solution of 8-(4-(3,3-dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (35 mg, 0.08 mmol) in THF (5 mL) was added a 4N hydrochloric acid/1,4-dioxane solution (5 mL). The reaction mixture was stirred at 25°C for 16 hours and then concentrated under reduced pressure to obtain the title compound (18 mg, 64.0% yield, pale yellow oil). LC-MS (ESI) m/z: 344.2 [M+H] + .

步骤5：8-(4-(3,3-二甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.08mmol)溶解于NMP(2mL)中,然后加入3-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(24mg,0.08mmol)、Cs2CO3(85mg,0.26mmol)、甲基[(1S，2S)-2-(甲氨基)环己基]胺(12mg,0.08mmol)和CuI2(33mg,0.18mmol)，N2保护下，反应混合物在120℃下搅拌3hrs。冷却至室温后，用EA(50mL)和H2O(20mL)稀释，用EA(10mL×3)萃取，合并有机相，减压浓缩，残余物用硅胶柱层析分离纯化(PE:EA，70％ EA)得到目标化合物(15mg,收率34.8％，棕黄色固体)。LC-MS(ESI)m/z:494.2[M+H]+。8-(4-(3,3-Dimethylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.08 mmol) was dissolved in NMP (2 mL), and then 3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (24 mg, 0.08 mmol), Cs 2 CO 3 (85 mg, 0.26 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (12 mg, 0.08 mmol) and CuI 2 (33 mg, 0.18 mmol) were added. Under N 2 protection, the reaction mixture was stirred at 120° C. for 3 hrs. After cooling to room temperature, the mixture was diluted with EA (50 mL) and H 2 O (20 mL), extracted with EA (10 mL×3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 70% EA) to obtain the title compound (15 mg, 34.8% yield, brown-yellow solid). LC-MS (ESI) m/z: 494.2 [M+H] + .

步骤6：8-(4-(3,3-二甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-(3,3-二甲基-吗啉基)-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]吡唑并[3,4-b]吡啶(15mg,0.03mmol)的THF(3mL)溶液中加入4N盐酸/1,4-二氧六环溶液(5mL)中，反应混合物在50℃下搅拌12hrs，冷却至室温，反应混合物减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:25-55,流速：20mL/min，20min)分离纯化得到目标化合物(4.0mg,收率32.1％，类白色固体)。LC-MS(ESI)m/z:410.2[M+H]+。1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.76–7.53(m,1H),7.07(s,1H),6.41–6.23(m,1H),4.63–4.53(m,2H),3.94–3.89(m,2H),3.87–3.83(m,2H),3.64(d,J＝10.8Hz,2H),3.56–3.54(m,2H),3.53–3.49(m,2H),2.16–2.01(m,4H),1.32(s,6H).To a solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (15 mg, 0.03 mmol) in THF (3 mL) was added 4N hydrochloric acid/1,4-dioxane solution (5 mL). The reaction mixture was stirred at 50° C. for 12 hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 25-55, flow rate: 20 mL/min, 20 min) to give the title compound (4.0 mg, yield 32.1%, off-white solid). LC-MS(ESI)m/z:410.2[M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.09(s,1H),7.76–7.53(m,1H),7.07(s,1H),6.41–6.23(m,1H),4.63–4.53(m,2H),3.94–3.89(m,2H),3. 87–3.83(m,2H),3.64(d,J＝10.8Hz,2H),3.56–3.54(m,2H),3.53–3.49(m,2H),2.16–2.01(m,4H),1.32(s,6H).

实施例9：8-(5-环丙基-4-((R)-3-甲基吗啉基)-7-(1H-吡唑-3-基)咪唑并[1,5-b]哒嗪-2-基)-3-氧杂-8-氮杂双环 [3.2.1]辛烷
Example 9: 8-(5-cyclopropyl-4-((R)-3-methylmorpholinyl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-oxa-8-azabicyclo [3.2.1]octane

步骤1：(R)-4-(3,6-二氯哒嗪-4-基)-3-甲基吗啉的合成
Step 1: Synthesis of (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylmorpholine

将3,4,6-三氯哒嗪(6.00g,33mmol)溶于NMP(50mL)中，加入DIPEA(16.88g,131mmol)和(R)-3-甲基吗啉(3.97g,39mmol)，N2保护下，反应混合物在80℃下搅拌5hrs，冷却至室温。向反应混合物中加入水(80mL)，用EA(100mL×2)萃取。合并有机相用饱和食盐水(300mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(3.84g,收率47.3％，黄色固体)。LC-MS(ESI)m/z:248.0[M+H]+。1H NMR(400MHz,CDCl3)δ6.87(s,1H),4.19–4.12(m,1H),4.00(dt,J＝11.5,3.0Hz,1H),3.90(dd,J＝11.5,2.9Hz,1H),3.81–3.74(m,1H),3.70(dd,J＝11.5,2.6Hz,1H),3.59–3.52(m,1H),3.02(dt,J＝12.4,2.5Hz,1H),1.22(d,J＝6.7Hz,3H)。3,4,6-Trichloropyridazine (6.00 g, 33 mmol) was dissolved in NMP (50 mL), and DIPEA (16.88 g, 131 mmol) and (R)-3-methylmorpholine (3.97 g, 39 mmol) were added. Under N₂ protection, the reaction mixture was stirred at 80°C for 5 hrs and then cooled to room temperature. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL x 2). The combined organic phases were washed with saturated brine (300 mL x 5 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (3.84 g, 47.3% yield, as a yellow solid). LC-MS (ESI) m/z: 248.0 [M+H] ⁺ . 1 H NMR (400MHz, CDCl 3 )δ6.87(s,1H),4.19–4.12(m,1H),4.00(dt,J＝11.5,3.0Hz,1H),3.90(dd,J＝11.5,2.9Hz,1H),3.81–3.74(m ,1H),3.70(dd,J＝11.5,2.6Hz,1H),3.59–3.52(m,1H),3.02(dt,J＝12.4,2.5Hz,1H),1.22(d,J＝6.7Hz,3H).

步骤2：8-(6-氯-5-((R)-3-甲基吗啉基)哒嗪-3-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(6-chloro-5-((R)-3-methylmorpholinyl)pyridazin-3-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(R)-4-(3,6-二氯哒嗪-4-基)-3-甲基吗啉(1.20g,4.84mmol)溶于NMP(30mL)中，加入3-氧杂-8-氮杂双环[3.2.1]辛烷(1.45g,9.67mmol)和DIPEA(3.12g,24.18mmol)。N2保护下，反应混合物微波200℃反应3hrs，冷却至室温。向反应混合物中加入水(80mL)，用EA(80mL×2)萃取。合并有机相用饱和食盐水(200mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，68％EA)得到目标化合物(1.25g,收率79.6％，黄色固体)。LC-MS(ESI)m/z:325.2[M+H]+。(R)-4-(3,6-Dichloropyridazin-4-yl)-3-methylmorpholine (1.20 g, 4.84 mmol) was dissolved in NMP (30 mL), and 3-oxa-8-azabicyclo[3.2.1]octane (1.45 g, 9.67 mmol) and DIPEA (3.12 g, 24.18 mmol) were added. Under N₂ protection, the reaction mixture was microwaved at 200°C for 3 hr and cooled to room temperature. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with EA (80 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 5 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 68% EA) to afford the title compound (1.25 g, 79.6% yield, as a yellow solid). LC-MS(ESI)m/z:325.2[M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-碳腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazine-3-carbonitrile

将8-(6-氯-5-((R)-3-甲基吗啉基)哒嗪-3-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.10g,3.39mmol)、Zn(CN)2(155mg,1.32mmol)、dppf(375mg,0.68mmol)、Pd2(dba)3(310mg,0.34mmol)依次加入到DMF(30mL)中。N2鼓气2mins，然后反应混合物在微波140℃反应4hrs，冷却至室温。向反应混合物中加入水(30mL)，用EA(60mL×2)萃取。合并有机相用饱和食盐水(80mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80-90％EA)得到目标化合物(1.04g,收率97.4％，棕色固体)。LC-MS(ESI)m/z:316.2[M+H]+。8-(6-chloro-5-((R)-3-methylmorpholinyl)pyridazin-3-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.10 g, 3.39 mmol), Zn(CN) (155 mg, 1.32 mmol ), dppf (375 mg, 0.68 mmol), and Pd (dba) ( 310 mg, 0.34 mmol) were added sequentially to DMF (30 mL). N2 was bubbled for 2 minutes, and the reaction mixture was then microwaved at 140°C for 4 hours before cooling to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (60 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 5), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 80-90% EA) to obtain the title compound (1.04 g, 97.4% yield, brown solid). LC-MS (ESI) m/z: 316.2 [M+H] + .

步骤4：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-基)(环丙基)甲胺的合成
Step 4: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazin-3-yl)(cyclopropyl)methanamine

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-碳腈(450mg,1.43mmol)溶于甲苯(10mL)中，50℃下，慢慢滴加环丙基溴化镁(5.55mL，5.55mmol)，N2保护下，反应混合物在110℃下搅拌2hrs，冷却至0℃，在此温度下缓慢加入NaBH4(108mg,2.85mmol)的MeOH(3mL)溶液，滴加完后升温到25℃，搅拌30mins。减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，10％MeOH)，得到目标化合物(450mg,收率87.7％，棕色固体)。LC-MS，(ESI)m/z:360.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazine-3-carbonitrile (450 mg, 1.43 mmol) was dissolved in toluene (10 mL). Cyclopropylmagnesium bromide (5.55 mL, 5.55 mmol) was slowly added dropwise at 50°C. Under nitrogen protection, the reaction mixture was stirred at 110°C for 2 hours, cooled to 0°C, and a solution of NaBH₄ (108 mg, 2.85 mmol) in MeOH (3 mL) was slowly added at this temperature. After the addition was complete, the temperature was raised to 25°C and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (450 mg, 87.7% yield, brown solid). LC-MS, (ESI) m/z: 360.2 [M+H] ⁺ .

步骤5：N-((6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-基)(环丙基)甲基)-1H-吡唑-5-甲酰胺的合成
Step 5: Synthesis of N-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazin-3-yl)(cyclopropyl)methyl)-1H-pyrazole-5-carboxamide

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-基)(环丙基)甲胺(200mg,0.56mmol)溶于THF(12mL)中，加入1H-吡唑-5-羧酸(62mg,0.56mmol)、HATU(254mg,0.67mmol)和DIPEA(215mg,1.67mmol)。反应混合物在25℃搅拌2hrs，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，10％MeOH)，得到目标化合物(336mg,收率90.5％，淡黄色油状物)。LC-MS(ESI)m/z:454.2[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazin-3-yl)(cyclopropyl)methanamine (200 mg, 0.56 mmol) was dissolved in THF (12 mL), and 1H-pyrazole-5-carboxylic acid (62 mg, 0.56 mmol), HATU (254 mg, 0.67 mmol), and DIPEA (215 mg, 1.67 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (336 mg, 90.5% yield, light yellow oil). LC-MS (ESI) m/z: 454.2 [M+H] + .

步骤6：8-(5-环丙基-4-((R)-3-甲基吗啉基)-7-(1H-吡唑-3-基)咪唑并[1,5-b]哒嗪-2-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(5-cyclopropyl-4-((R)-3-methylmorpholinyl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将N-((6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)哒嗪-3-基)(环丙基)甲基)-1H-吡唑-5-甲酰胺(200mg,4.41mmol)溶于ACN(12mL)中，加入POCl3(676mg,0.56mmol)。反应混合物在100℃下搅拌2hrs，冷却至室温，向反应混合物中加入饱和NaHCO3溶液(30mL)，用EA(80mL×2)萃取。合并有机相用饱和NaHCO3(200mL×2)水溶液洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)得到目标化合物(52mg,收率27.1％，淡黄色固体)。LC-MS(ESI)m/z:436.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),7.67(s,1H),7.09–6.89(m,1H),5.98(s,1H),4.59–4.31(m,2H),4.01–3.91(m,1H),3.92–3.81(m,2H),3.78(d,J＝10.8Hz,1H),3.76–3.68(m,2H),3.62–3.53(m,3H),3.53–3.45(m,1H),2.86(d,J＝12.6Hz,1H),2.38–2.27(m,1H),2.05–1.85(m,4H),1.43–1.26(m,1H),1.03(d,J＝6.4Hz,3H),0.98–0.88(m,2H),0.74–0.64(m,1H).N-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazin-3-yl)(cyclopropyl)methyl)-1H-pyrazole-5-carboxamide (200 mg, 4.41 mmol) was dissolved in ACN (12 mL), and POCl₃ (676 mg, 0.56 mmol) was added. The reaction mixture was stirred at 100°C for 2 hrs, cooled to room temperature, and saturated NaHCO₃ solution (30 mL) was added to the reaction mixture, followed by extraction with EA (80 mL x 2). The combined organic phases were washed with saturated NaHCO₃ aqueous solution (200 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 60% EA) to afford the title compound (52 mg, 27.1% yield, as a pale yellow solid). LC-MS(ESI)m/z:436.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.05(s,1H),7.67(s,1H),7.09–6.89(m,1H),5.98(s,1H),4.59–4.31(m,2H),4.0 1–3.91(m,1H),3.92–3.81(m,2H),3.78(d,J＝10.8Hz,1H),3.76–3.68(m,2H),3.62–3. 53(m,3H),3.53–3.45(m,1H),2.86(d,J＝12.6Hz,1H),2.38–2.27(m,1H),2.05–1.85(m ,4H),1.43–1.26(m,1H),1.03(d,J＝6.4Hz,3H),0.98–0.88(m,2H),0.74–0.64(m,1H).

实施例10：(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基) 甲醇
Example 10: (4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl) methanol

实施例11：[(3S)-4-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)吡唑并[3,4-b]吡啶-4-基]-吗啉-3-Example 11: [(3S)-4-[6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]-morpholine-3-yl 基]甲醇和Methanol and

实施例12：[(3R)-4-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)吡唑并[3,4-b]吡啶-4-基]-吗啉-3- 基]甲醇
Example 12: [(3R)-4-[6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]-morpholin-3- yl]methanol

步骤1：4-苄基-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉的合成
Step 1: Synthesis of 4-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

将(4-苄基-1,4-恶嗪-3-基)甲醇(2.00g,9.65mmol)和TBSCl(2.18g,14.47mmol)溶于DMF(20mL)中，加入咪唑(1.64g,24.12mmol)，反应混合物在25℃下搅拌过夜。向反应混合物中加入水(50mL)，用EA(50mL×2)萃取。合并有机相用饱和食盐水(100mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，36％EA)，得到目标化合物(2.77g,收率89.3％，白色固体)。LC-MS(ESI)m/z:322.4[M+H]+。(4-Benzyl-1,4-oxazin-3-yl)methanol (2.00 g, 9.65 mmol) and TBSCl (2.18 g, 14.47 mmol) were dissolved in DMF (20 mL). Imidazole (1.64 g, 24.12 mmol) was added, and the reaction mixture was stirred at 25°C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 36% EA) to obtain the title compound (2.77 g, 89.3% yield, as a white solid). LC-MS (ESI) m/z: 322.4 [M+H] ⁺ .

步骤2：3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉的合成
Step 2: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

将4-苄基-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉(2.77g,8.62mmol)溶于MeOH(30mL)中，加入10％ Pd/C(0.92g)。反应混合物在H2氛围下置换两次，然后在室温条件下搅拌16hrs。将反应液通过硅藻土过滤，滤液减压浓缩，得到目标化合物(1.93g,收率97.0％，无色液体)。LC-MS(ESI)m/z:232.2[M+H]+。4-Benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (2.77 g, 8.62 mmol) was dissolved in MeOH (30 mL), and 10% Pd/C (0.92 g) was added. The reaction mixture was purged twice with H₂ and then stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.93 g, 97.0% yield, colorless liquid). LC-MS (ESI) m/z: 232.2 [M+H] ⁺ .

步骤3：8-(4-(3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(3-((tert-butyldimethylsilyl)oxy)methyl)morpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(8a)(1.00g,2.27mmol)和3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉(0.63g,2.72mmol)溶于甲苯(20mL)，然后依次加入Cs2CO3(2.22g,6.81mmol)、rac-BINAP(0.21g,0.34mmol)、Pd(OAc)2(0.05g,0.23mmol)。反应混合物N2保护下在120℃下搅拌2hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(50mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，33％EA)得到目标化合物(0.58g,收率46.8％，黄色固体)。LC-MS(ESI)m/z:544.3[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8a) (1.00 g, 2.27 mmol) and 3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (0.63 g, 2.72 mmol) were dissolved in toluene (20 mL), and then Cs 2 CO 3 (2.22 g, 6.81 mmol), rac-BINAP (0.21 g, 0.34 mmol), and Pd(OAc) 2 (0.05 g, 0.23 mmol) were added in sequence. The reaction mixture was stirred at 120° C. under N 2 protection for 2 hrs and then cooled to room temperature. The reaction mixture was diluted with water and EA, then extracted with EA (50 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 33% EA) to obtain the title compound (0.58 g, 46.8% yield, as a yellow solid). LC-MS (ESI) m/z: 544.3 [M+H] ⁺ .

步骤4：(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 4: Synthesis of (4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将8-(4-(3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(530mg,0.44mmol)溶于MeOH(10mL)中，加入4N盐酸/1,4-二氧六环溶液。反应混合物在室温下搅拌16hrs。减压浓缩，向反应混合物中加入过量饱和Na2CO3水溶液至碱性，用EA(20mL×2)萃取。合并有机相用水洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到目标化合物(292mg,收率86.7％，白色固体)。LC-MS(ESI)m/z:346.3[M+H]+。8-(4-(3-((tert-Butyldimethylsilyl)oxy)methyl)morpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (530 mg, 0.44 mmol) was dissolved in MeOH (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. An excess of saturated aqueous Na₂CO₃ was added to the reaction mixture until basic, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (292 mg, 86.7% yield, as a white solid). LC-MS (ESI) m/z: 346.3 [M+H] ⁺ .

步骤5：(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 5: Synthesis of (4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(192mg,0.56mmol)和3-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(186mg,0.67mmol)溶于NMP(10mL)中，再依次加入Cs2CO3(543mg,1.67mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(79mg,0.56mmol)、CuI(106mg,0.56mmol)，N2保护下，反应混合物在120℃下搅拌2hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(20mL×2)萃取。合并有机相用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。滤液减压浓缩得到粗产品(150mg,收率54.5％，黄色固体)。LC-MS(ESI)m/z:496.2[M+H]+。(4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (192 mg, 0.56 mmol) and 3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (186 mg, 0.67 mmol) were dissolved in NMP (10 mL). Cs 2 CO 3 (543 mg, 1.67 mmol), (1S,2S)-N1,N 2 -dimethylcyclohexane-1,2-diamine (79 mg, 0.56 mmol), and CuI (106 mg, 0.56 mmol) were added sequentially. Under N 2 protection, the reaction mixture was stirred at 120°C for 2 hrs and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (20 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give a crude product (150 mg, yield 54.5%, yellow solid). LC-MS (ESI) m/z: 496.2 [M+H] + .

步骤6：(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 6: Synthesis of (4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(150mg,0.30mmol)溶于MeOH(3mL)中，加入4N盐酸/1,4-二氧六环。反应混合物在室温下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:10-40,流速：20mL/min，20min)分离纯化，得到目标化合物消旋体(50mg,40.1％，白色固体)。LC-MS(ESI)m/z:412.2[M+H]+。(4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (150 mg, 0.30 mmol) was dissolved in MeOH (3 mL), and 4N hydrochloric acid/1,4-dioxane was added. The reaction mixture was stirred at room temperature for 16 hours. It was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 10-40, flow rate: 20 mL/min, 20 min) to obtain the racemate of the title compound (50 mg, 40.1%, white solid). LC-MS(ESI)m/z:412.2[M+H] + .

步骤7：[(3R)-4-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)吡唑并[3,4-b]吡啶-4-基]-吗啉-3-基]甲醇和[(3S)-4-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)吡唑并[3,4-b]吡啶-4-基]-吗啉-3-基]甲醇的合成
Step 7: Synthesis of [(3R)-4-[6-(8-aza-3-oxabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]-morpholin-3-yl]methanol and [(3S)-4-[6-(8-aza-3-oxabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]-morpholin-3-yl]methanol

将(4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(50mg,0.12mmol)经Prep-SFC(column:Daical ChiralPak IG,40*250mm,10um:A相：Supercritical CO2；B相：0.1％ NH3H2O in MeOH,梯度:50,流速：120mL/min，7.24min)分离，得到目标化合物P1(6.4mg,收率5.1％，白色固体)。LC-MS(ESI)m/z:412.2[M+H]+。SFC(方法A)：RT＝1.490min。1H NMR(400MHz,Methanol-d4)δ8.17(s,1H),7.74(s,1H),6.94(s,1H),5.96(s,1H),4.60(s,2H),4.25–4.19(m,1H),4.19–4.11(m,1H),4.10–3.97(m,2H),3.94–3.87(m,2H),3.87–3.75(m,2H),3.75–3.66(m,2H),3.66–3.61(m,3H),3.57–3.47(m,1H),2.14–2.03(m,4H)。(4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (50 mg, 0.12 mmol) was separated by Prep-SFC (column: Daical ChiralPak IG, 40*250 mm, 10 μm; Phase A: Supercritical CO 2 ; Phase B: 0.1% NH 3 H 2 O in MeOH, gradient: 50, flow rate: 120 mL/min, 7.24 min) to afford the title compound P1 (6.4 mg, 5.1% yield, white solid). LC-MS (ESI) m/z: 412.2 [M+H] + . SFC (Method A): RT = 1.490 min. 1 H NMR (400MHz, Methanol-d 4 )δ8.17(s,1H),7.74(s,1H),6.94(s,1H),5.96(s,1H),4.60(s,2H),4.25–4.19(m,1H),4.19–4.11(m,1H),4.10–3.97(m ,2H),3.94–3.87(m,2H),3.87–3.75(m,2H),3.75–3.66(m,2H),3.66–3.61(m,3H),3.57–3.47(m,1H),2.14–2.03(m,4H).

和P2(10.1mg,收率8.1％，白色固体)。LC-MS(ESI)m/z:412.2[M+H]+。SFC(方法A)：RT＝2.397min。1H NMR(400MHz,Methanol-d4)δ8.17(s,1H),7.75(s,1H),6.94(s,1H),5.97(s,1H),4.61(s,2H),4.23(d,J＝11.7Hz,1H),4.15(s,1H),4.12–3.97(m,2H),3.95–3.88(m,2H),3.88–3.76(m,2H),3.76–3.67(m,2H),3.67–3.61(m,2H),3.58–3.48(m,1H),2.16–2.04(m,4H)。and P2 (10.1 mg, yield 8.1%, white solid). LC-MS (ESI) m/z: 412.2 [M+H] + . SFC (Method A): RT = 2.397 min. 1 H NMR (400MHz, Methanol-d4) δ8.17(s,1H),7.75(s,1H),6.94(s,1H),5.97(s,1H),4.61(s,2H),4.23(d,J＝11.7Hz,1H),4.15(s,1H),4 .12–3.97(m,2H),3.95–3.88(m,2H),3.88–3.76(m,2H),3.76–3.67(m,2H),3.67–3.61(m,2H),3.58–3.48(m,1H),2.16–2.04(m,4H).

实施例13:8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((R)-1,1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-b]吡啶-6-Example 13: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((R)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-yl 基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和1-(2-(2-nitro-3-oxa-8-azabicyclo[3.2.1]octane) and

实施例14:8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((S)-1,1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-b]吡啶-6- 基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 14: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2氛围下，把6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3，4-b]吡啶(8a)(2.00g,4.54mmol)溶解于NMP(100mL)中，并加入(R)-3-甲基吗啉盐酸盐(0.94g,6.81mmol)、Cs2CO3(4.44g,13.63mmol)和Ruphos Pd G2(0.35g,0.45mmol)。反应混合物在N2保护下130℃下搅拌12hrs，冷却至室温。加入水，用EA(10mL×3)萃取，收集有机相。减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA，78％ EA)得到目标化合物(900mg,收率47.9％，淡黄色固体)。LC-MS(ESI)m/z:414.2[M+H]+。Under a nitrogen atmosphere, 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (8a) (2.00 g, 4.54 mmol) was dissolved in NMP (100 mL), and (R)-3-methylmorpholine hydrochloride (0.94 g, 6.81 mmol), Cs₂CO₃ (4.44 g, 13.63 mmol), and Ruphos Pd G₂ (0.35 g, 0.45 mmol) were added. The reaction mixture was stirred at 130°C for 12 hours under nitrogen protection and then cooled to room temperature. Water was added, the mixture was extracted with EA (10 mL x 3), and the organic phase was collected. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA, 78% EA) to afford the title compound (900 mg, 47.9% yield, light yellow solid). LC-MS (ESI) m/z: 414.2 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(900mg,2.18mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(20mL)。反应混合物在25℃搅拌12hrs，减压浓缩，加入饱和NaHCO3水溶液中和至弱碱性，用EA(10mL×3)萃取，合并有机相，减压浓缩，残余物经反相柱层析分离纯化(H2O:CH3CN，35％ CH3CN)得到目标化合物(450mg,收率62.8％，淡黄色固体)。LC-MS(ESI)m/z:330.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (900 mg, 2.18 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (20 mL) was added. The reaction mixture was stirred at 25°C for 12 hours, concentrated under reduced pressure, and neutralized to a weakly alkaline state by adding saturated aqueous NaHCO₃ . The mixture was extracted with EA (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography ( H₂O : CH₃CN , 35% CH₃CN ) to afford the title compound (450 mg, 62.8% yield, as a pale yellow solid). LC-MS (ESI) m/z: 330.2 [M+H] ⁺ .

步骤3：8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(350mg,0.85mmol)、KOH(298mg,5.31mmol)加入到DMF(20mL)中，反应混合物在25℃下搅拌5mins，然后缓慢加入I2(539mg,2.13mmol)。反应混合物在N2保护下在25℃下搅拌2hrs。向反应混合物中加入过量饱和Na2SO3水溶液，用EA(40mL×2)萃取，合并有机相用饱和食盐水洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(289mg,收率59.7％，黄色固体)。LC-MS(ESI)m/z:456.0[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (350 mg, 0.85 mmol) and KOH (298 mg, 5.31 mmol) were added to DMF (20 mL). The reaction mixture was stirred at 25°C for 5 minutes, followed by the slow addition of I₂ (539 mg, 2.13 mmol). The reaction mixture was stirred at 25°C for 2 hours under N₂ protection. An excess of saturated aqueous Na₂SO₃ was added to the reaction mixture, which was then extracted with EA (40 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 50% EA) to afford the title compound (289 mg, 59.7% yield) as a yellow solid. LC-MS(ESI)m/z:456.0[M+H] + .

步骤4：8-(4-((R)-3-甲基吗啉基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(270mg,0.59mmol)溶于1,4-二氧六环(10mL)和水(1mL)中，加入4,4,6-三甲基-2-(3,3,3-三氟丙-1-烯-2-基)-1,3,2-二氧杂硼烷(527mg,2.37mmol)，Na2CO3(157mg,1.48mmol)和Pd(dppf)Cl2(43mg,0.06mmol)。N2保护下，反应混合物在100℃下搅拌16hrs，冷却至室温，减压浓缩，残余物经反相硅胶柱层析分离纯化(H2O：CH3CN，42％CH3CN)得到目标化合物(184mg,收率73.3％，淡黄色固体)。LC-MS(ESI)m/z:424.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (270 mg, 0.59 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborolane (527 mg, 2.37 mmol), Na 2 CO 3 (157 mg, 1.48 mmol) and Pd(dppf)Cl 2 (43 mg, 0.06 mmol) were added. Under N 2 protection, the reaction mixture was stirred at 100°C for 16 hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H 2 O:CH 3 CN, 42% CH 3 CN) to obtain the title compound (184 mg, 73.3% yield, light yellow solid). LC-MS (ESI) m/z: 424.2 [M+H] + .

步骤5：8-(4-((R)-3-甲基吗啉基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(184mg,0.44mmol)溶于MeOH(5mL)中，加入5％ Pd/C(210mg)，反应混合物在H2氛围下置换三次，然后在25℃下搅拌16hrs。用硅藻土过滤，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，30％EA)，得到目标化合物(126mg,收率68.2％，白色固体)。LC-MS(ESI)m/z:426.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (184 mg, 0.44 mmol) was dissolved in MeOH (5 mL) and 5% Pd/C (210 mg) was added. The reaction mixture was purged three times under an H₂ atmosphere and then stirred at 25°C for 16 hours. The mixture was filtered through Celite, and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (126 mg, 68.2% yield, as a white solid). LC-MS (ESI) m/z: 426.2 [M+H] ⁺ .

步骤6：8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(120mg,0.28mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(118mg,0.42mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(40mg,0.28mmol)、Cs2CO3(230mg,0.71mmol)和CuI(54mg,0.28mmol)依次加入到NMP(10mL)中。N2保护下，反应混合物120℃下搅拌16hrs。向反应混合物中加入水，用EA(20mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(162mg,黄色油状物)。LC-MS(ESI)m/z:576.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-3-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.28 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (118 mg, 0.42 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40 mg, 0.28 mmol), Cs2CO3 (230 mg, 0.71 mmol), and CuI (54 mg, 0.28 mmol) were added sequentially to NMP ( 10 mL). Under N2 protection, the reaction mixture was stirred at 120°C for 16 hrs. Water was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give a crude product (162 mg, yellow oil). LC-MS (ESI) m/z: 576.2 [M+H] + .

步骤7：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((R)-1,1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((S)-1,1,1,1-三氟丙-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((R)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(95mg,0.19mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)。反应混合物在50℃下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18，21.2*250mm，5um：0.1％FA；B％：38-68，流速：20mL/min，20min)分离纯化，得到目标化合物P1(22.6mg,收率16.4％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),7.82(s,1H),6.74(s,1H),6.48(s,1H),4.60(d,J＝13.0Hz,2H),4.36–4.27(m,1H),3.87(dd,J＝11.1,2.9Hz,1H),3.80–3.63(m,4H),3.58–3.53(m,2H),3.52–3.46(m,1H),3.39–3.33(m,1H),3.26–3.20(m,1H),2.79–2.73(m,1H),2.01–1.88(m,4H),1.61(d,J＝7.2Hz,3H),0.89(d,J＝6.1Hz,3H)。8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropyl-2-yl)-1-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (95 mg, 0.19 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 50° C. for 3 hrs. The residue was concentrated under reduced pressure and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um: 0.1% FA; B%: 38-68, flow rate: 20mL/min, 20min) to obtain the target compound P1 (22.6mg, yield 16.4%, white solid). LC-MS (ESI) m/z: 492.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.80(s,1H),7.82(s,1H),6.74(s,1H),6.48(s,1H),4.60(d,J＝13.0Hz,2 H),4.36–4.27(m,1H),3.87(dd,J＝11.1,2.9Hz,1H),3.80–3.63(m,4H),3.58– 3.53(m,2H),3.52–3.46(m,1H),3.39–3.33(m,1H),3.26–3.20(m,1H),2.79– 2.73(m,1H),2.01–1.88(m,4H),1.61(d,J＝7.2Hz,3H),0.89(d,J＝6.1Hz,3H).

和P2(13.4mg,收率9.7％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.82(s,1H),6.74(s,1H),6.62(s,1H),4.65–4.53(m,3H),3.90–3.83(m,2H),3.70–3.64(m,3H),3.59–3.54(m,2H),3.46–3.40(m,1H),3.39–3.33(m,1H),3.09(d,J＝12.5Hz,1H),2.89(t,J＝9.3Hz,1H),2.00–1.89(m,4H),1.54(d,J＝7.2Hz,3H),0.85(d,J＝6.0Hz,3H)。and P2 (13.4 mg, yield 9.7%, white solid). LC-MS (ESI) m/z: 492.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.81(s,1H),7.82(s,1H),6.74(s,1H),6.62(s,1H),4.65–4.53(m, 3H),3.90–3.83(m,2H),3.70–3.64(m,3H),3.59–3.54(m,2H),3.46–3. 40(m,1H),3.39–3.33(m,1H),3.09(d,J＝12.5Hz,1H),2.89(t,J＝9.3Hz,1H),2.00–1.89(m,4H),1.54(d,J＝7.2Hz,3H),0.85(d,J＝6.0Hz,3H).

实施例15:((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑 并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇
Example 15: ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo [3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

实施例16和17：((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-((S)-1,1,1-三氟丙烷-2- 基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇和((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3- 基)-3-((R,1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇
Examples 16 and 17: ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1-trifluoropropan-2- yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol and ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3- yl)-3-((R,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

步骤1：(S)-4-苄基-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉的合成
Step 1: Synthesis of (S)-4-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

将(R)-(4-苄基吗啉-3-基)甲醇(2.00g,9.65mmol)和TBSCl(2.18g,14.47mmol)溶于DMF(20mL)中，加入咪唑(1.64g,24.12mmol)，反应混合物在室温下搅拌过夜。向反应混合物中加入水(50mL)，用EA(50mL×2)萃取，合并有机相，用水(100mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，36％EA)得到目标化合物(2.2g,收率71.0％，白色固体)。LC-MS(ESI)m/z:322.4[M+H]+。(R)-(4-Benzylmorpholin-3-yl)methanol (2.00 g, 9.65 mmol) and TBSCl (2.18 g, 14.47 mmol) were dissolved in DMF (20 mL). Imidazole (1.64 g, 24.12 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with water (100 mL x 3 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 36% EA) to obtain the title compound (2.2 g, 71.0% yield, as a white solid). LC-MS (ESI) m/z: 322.4 [M+H] + .

步骤2：(S)-3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉的合成
Step 2: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)methyl)morpholine

将(S)-4-苄基-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉(2.2g,6.84mmol)溶于MeOH(30mL)中，加入10％ Pd/C(0.73g,6.84mmol)。反应混合物在H2氛围下置换两次，然后在室温条件下搅拌过夜。反应液混合物用硅藻土过滤，滤液减压浓缩，得到目标化合物(1.5g,收率94.7％，无色液体)。LC-MS(ESI)m/z:232.3[M+H]+。(S)-4-Benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (2.2 g, 6.84 mmol) was dissolved in MeOH (30 mL), and 10% Pd/C (0.73 g, 6.84 mmol) was added. The reaction mixture was purged twice under an H₂ atmosphere and then stirred at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g, 94.7% yield, colorless liquid). LC-MS (ESI) m/z: 232.3 [M+H] ⁺ .

步骤3：8-(4-((S)-3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((S)-3-((tert-butyldimethylsilyl)oxy)methyl)morpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(8a)(1.80g,4.09mmol)和(S)-3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉(1.14g,4.91mmol)溶于甲苯(20mL)，然后依次加入Cs2CO3(4.00g,12.26mmol)、rac-BINAP(0.38g,0.61mmol)、Pd(OAc)2(0.09g,0.41mmol)。反应混合物在N2保护下在120℃下搅拌2hrs。向反应混合物中加入水和EA稀释，用EA(50mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相柱层析分离纯化(PE:EA，27％EA)得到目标化合物(1.26g,收率56.7％，黄色固体)。LC-MS(ESI)m/z:544.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (8a) (1.80 g, 4.09 mmol) and (S)-3-((tert-butyldimethylsilyl)oxy)methyl)morpholine (1.14 g, 4.91 mmol) were dissolved in toluene (20 mL), and then Cs 2 CO 3 (4.00 g, 12.26 mmol), rac-BINAP (0.38 g, 0.61 mmol), and Pd(OAc) 2 (0.09 g, 0.41 mmol) were added in sequence. The reaction mixture was stirred at 120° C. for 2 hrs under N 2 protection. The reaction mixture was diluted with water and EA, extracted with EA (50 mL x 2), and the combined organic phases were washed three times with saturated brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (PE:EA, 27% EA) to obtain the title compound (1.26 g, 56.7% yield, yellow solid). LC-MS (ESI) m/z: 544.2 [M+H] + .

步骤4：((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 4: Synthesis of ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将8-(4-((S)-3-((叔丁基二甲基甲硅烷基)氧基)甲基)吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.26g,0.11mmol)溶于MeOH(10mL)中，加入4M盐酸/1,4-二氧六环溶液(10mL)，所得反应混合物N2保护下室温搅拌过夜。减压浓缩得到粗产品(900mg,粗品，黄色固体)。LC-MS(ESI)m/z:346.2[M+H]+。8-(4-((S)-3-((tert-butyldimethylsilyl)oxy)methyl)morpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.26 g, 0.11 mmol) was dissolved in MeOH (10 mL), and a 4M hydrochloric acid/1,4-dioxane solution (10 mL) was added. The resulting reaction mixture was stirred at room temperature overnight under N protection. The mixture was concentrated under reduced pressure to give the crude product (900 mg, crude, yellow solid). LC-MS (ESI) m/z: 346.2 [M+H] + .

步骤5：((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 5: Synthesis of ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(800mg,2.32mmol)和KOH(325mg,5.79mmol)溶解于DMF(40mL)中，再缓慢加入I2(1175mg,4.63mmol)。反应混合物在N2保护下在室温下搅拌2hrs。加入饱和Na2SO3水溶液淬灭反应，用EA(50mL×3)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA，50％ EA)，得到目标化合物(425mg,收率38.9％，淡黄色固体)。LC-MS(ESI)m/z:472.0[M+H]+。((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (800 mg, 2.32 mmol) and KOH (325 mg, 5.79 mmol) were dissolved in DMF (40 mL), and I₂ (1175 mg, 4.63 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hr under N₂ protection. The reaction was quenched by the addition of saturated aqueous Na₂SO₃ solution and extracted with EA (50 mL x 3). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (425 mg, 38.9% yield, as a pale yellow solid). LC-MS(ESI)m/z:472.0[M+H] + .

步骤6：((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 6: Synthesis of ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(400mg,0.85mmol)和4,4,6-三甲基-2-(3,3,3-三氟丙基-1-烯-2-基)-1,3,2-二氧杂硼烷(565mg,2.55mmol)溶于1,4-二氧六环(10mL)和水(2mL)的混合溶剂中，再加入Na2CO3(225mg,2.12mmol)、Pd(dppf)Cl2(62mg,0.08mmol)。N2保护下，反应混合物在100℃下搅拌2hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(50mL×2)萃取，合并有机相，饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(150mg,收率40.2％，黄色固体)。LC-MS(ESI)m/z:440.2[M+H]+。((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (400 mg, 0.85 mmol) and 4,4,6-trimethyl-2-(3,3,3-trifluoropropyl-1-en-2-yl)-1,3,2-dioxaborolane (565 mg, 2.55 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL ). Na₂CO₃ (225 mg, 2.12 mmol) and Pd(dppf) Cl₂ (62 mg, 0.08 mmol) were then added. Under N₂ protection, the reaction mixture was stirred at 100°C for 2 hrs and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (150 mg, 40.2% yield, yellow solid). LC-MS (ESI) m/z: 440.2 [M+H] + .

步骤7：((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 7: Synthesis of ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-(3,3,3-三氟丙基-1-烯-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(150mg,0.34mmol)溶于MeOH(5mL)中，加入10％ Pd/C(36mg,0.34mmol)。反应混合物在H2氛围下室温下搅拌过夜。反应混合物用硅藻土过滤，滤液减压浓缩，得到目标化合物(126mg,收率83.6％，黄色固体)。LC-MS(ESI)m/z:442.2[M+H]+。((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(3,3,3-trifluoropropyl-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (150 mg, 0.34 mmol) was dissolved in MeOH (5 mL), and 10% Pd/C (36 mg, 0.34 mmol) was added. The reaction mixture was stirred at room temperature overnight under an H₂ atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (126 mg, 83.6% yield, as a yellow solid). LC-MS (ESI) m/z: 442.2 [M+H] ⁺ .

步骤8：((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 8: Synthesis of ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(100mg,0.23mmol)和3-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(126mg,0.45mmol)溶于NMP(5mL)中，再依次加入Cs2CO3(222mg,0.68mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(32mg,0.23mmol)、CuI(43mg,0.23mmol)，反应混合物在N2保护下在120℃下搅拌3hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(20mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(140mg,收粗品，黄色固体)。LC-MS(ESI)m/z:592.2[M+H]+。((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (100 mg, 0.23 mmol) and 3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (126 mg, 0.45 mmol) were dissolved in NMP (5 mL), and Cs2CO3 (222 mg , 0.68 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32 mg, 0.23 mmol) and CuI (43 mg, 0.23 mmol) were added in sequence. The reaction mixture was stirred at 120°C for 3 hrs under N2 protection and cooled to room temperature. The reaction mixture was diluted with water and EA, extracted with EA (20 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (140 mg, crude product, yellow solid). LC-MS (ESI) m/z: 592.2 [M+H] + .

步骤9：((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 9: Synthesis of ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(1,1,1-三氟丙-2-基)-1-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(160mg,0.27mmol)溶于MeOH(4mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在N2保护下室温下搅拌过夜。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18，21.2*250mm，5um；流动相A：0.1％TFA/H2O；流动相B：ACN，梯度：15-45％B，流速：20mL/min，18min)分离纯化，得到目标化合物(40mg,收率29.1％，白色固体)。LC-MS(ESI)m/z:508.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.82(s,1H),9.41(s,1H),9.21(s,1H),7.81(d,J＝2.2Hz,1H),6.74(d,J＝2.3Hz,1H),6.31(s,1H),4.63(s,2H),4.56–4.33(m,3H),4.19–4.06(m,1H),4.02–3.90(m,1H),3.87–3.77(m,1H),3.77–3.65(m,4H),3.61–3.57(m,2H),3.30–3.20(m,2H),2.03–1.89(m,4H),1.63–1.53(m,3H).((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (160 mg, 0.27 mmol) was dissolved in MeOH (4 mL), and 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at room temperature overnight under N2 protection. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% TFA/H 2 O; mobile phase B: ACN, gradient: 15-45% B, flow rate: 20 mL/min, 18 min) to obtain the title compound (40 mg, yield 29.1%, white solid). LC-MS (ESI) m/z: 508.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.82(s,1H),9.41(s,1H),9.21(s,1H),7.81(d,J=2.2Hz,1H),6.74( d,J＝2.3Hz,1H),6.31(s,1H),4.63(s,2H),4.56–4.33(m,3H),4.19–4.0 6(m,1H),4.02–3.90(m,1H),3.87–3.77(m,1H),3.77–3.65(m,4H),3.61 –3.57(m,2H),3.30–3.20(m,2H),2.03–1.89(m,4H),1.63–1.53(m,3H).

步骤10：((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-((S)-1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇和((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-((R,1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 10: Synthesis of ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-3-((S)-1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol and ((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-3-((R,1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

化合物((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(40mg,0.08mmol)经SFC(Daicel DhiralPak AD，40.0*250mm，10um A％：n-hexane；B(Ethanol)％：15，流速：80mL/min，6min)分离纯化，得到目标化合物P1(10mg,收率25.0％，白色固体)，LC-MS(ESI)m/z:508.2[M+H]+。SFC(方法B)RT＝4.363min。1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),7.88(s,1H),6.80(s,1H),6.35(s,1H),4.68(s,2H),4.58–4.25(m,3H),4.13–3.82(m,2H),3.78–3.71(m,2H),3.67–3.55(m,4H),3.21–3.12(m,1H),3.01–2.96(m,3H),2.09–1.98(m,4H),1.65(d,J＝7.1Hz,3H)。和P2(17mg,收率42.5％，白色固体)，LC-MS(ESI)m/z:508.2[M+H]+。SFC(方法B)RT＝5.230min。1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),7.87(s,1H),6.81(s,1H),6.32(s,1H),4.67(s,2H),4.42–4.32(m,1H),4.24–4.11(m,2H),3.94(d,J＝10.8Hz,1H),3.81–3.70(m,3H),3.63(d,J＝10.6Hz,2H),3.55–3.40(m,3H),3.33–3.22(m,1H),3.01–2.87(m,2H),2.06–1.95(m,4H),1.64(d,J＝7.2Hz,3H)。The compound ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (40 mg, 0.08 mmol) was separated and purified by SFC (Daicel DhiralPak AD, 40.0*250 mm, 10 μm A%: n-hexane; B (Ethanol)%: 15, flow rate: 80 mL/min, 6 min) to obtain the title compound P1 (10 mg, 25.0% yield, white solid). LC-MS (ESI) m/z: 508.2 [M+H] + . SFC (Method B) RT = 4.363 min. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 7.88 (s, 1H), 6.80 (s, 1H), 6.35 (s, 1H), 4.68 (s, 2H), 4.58–4.25 (m, 3H), 4.13–3.82 (m, 2H), 3.78–3.71 (m, 2H), 3.67–3.55 (m, 4H), 3.21–3.12 (m, 1H), 3.01–2.96 (m, 3H), 2.09–1.98 (m, 4H), 1.65 (d, J=7.1 Hz, 3H). P2 (17 mg, yield 42.5%, white solid) was obtained. LC-MS (ESI) m/z: 508.2 [M+H] + . SFC (Method B) RT=5.230min. 1 H NMR (400MHz, DMSO-d 6 )δ12.86(s,1H),7.87(s,1H),6.81(s,1H),6.32(s,1H),4.67(s,2H),4.42–4.32(m,1H),4.24–4.11(m,2H),3.94(d,J＝10.8Hz,1H),3.81 –3.70(m,3H),3.63(d,J＝10.6Hz,2H),3.55–3.40(m,3H),3.33–3.22(m,1H),3.01–2.87(m,2H),2.06–1.95(m,4H),1.64(d,J＝7.2Hz,3H).

实施例18:6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 18: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(参考实施列16合成方法)(130mg,0.28mmol)、Zn(CN)2(97mg,0.83mmol)、锌粉(54mg,0.83mmol)、Pd2(dba)3(25mg,0.028mmol)和Pd(dppf)Cl2(40mg,0.055mmol)依次加入到有DMA(10mL)的微波管中。在N2氛围下鼓气2mins，然后反应混合物在微波下150℃搅拌1hr，冷却至室温。向反应混合物中加入水(30mL)，用EA(30mL×2)萃取。合并有机相用饱和食盐水(120mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，12％MeOH)，得到目标化合物(66mg,粗品，黄色油状物)。LC-MS(ESI)m/z:371.2[M+H]+。((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (synthesized by reference to Example 16) (130 mg, 0.28 mmol), Zn(CN) ₂ (97 mg, 0.83 mmol), zinc powder (54 mg, 0.83 mmol), Pd₂ (dba) ₃ (25 mg, 0.028 mmol), and Pd(dppf) Cl₂ (40 mg, 0.055 mmol) were sequentially added to a microwave tube containing DMA (10 mL). After bubbling under a N₂ atmosphere for 2 minutes, the reaction mixture was stirred at 150°C in a microwave for 1 hour and then cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with saturated brine (120 mL x 5), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 12% MeOH) to obtain the title compound (66 mg, crude product, yellow oil). LC-MS (ESI) m/z: 371.2 [M+H] ⁺ .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(66mg,0.18mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(99mg,0.36mmol)、甲基[(1S，2S)-2-(甲氨基)环己基]胺(51mg,0.36mmol)、Cs2CO3(174mg,0.54mmol)和CuI(68mg,0.36mmol)依次加入到NMP(10mL)中。在N2氛围下鼓气2mins，然后反应混合物在微波仪器中150℃搅拌3hrs。向反应混合物中加入水(40mL)，用EA(50mL×2)萃取。合并有机相用饱和食盐水(80mL×5)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，35％EA)，得到粗产品化合物(23.4mg,粗品，无色油状物)。LC-MS(ESI)m/z:521.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (66 mg, 0.18 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (99 mg, 0.36 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (51 mg, 0.36 mmol), Cs 2 CO 3 (174 mg, 0.54 mmol), and CuI (68 mg, 0.36 mmol) were added sequentially to NMP (10 mL). After bubbling under a N 2 atmosphere for 2 minutes, the reaction mixture was stirred at 150° C. in a microwave apparatus for 3 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL×2). The combined organic phases were washed with saturated brine (80 mL x 5), dried over anhydrous Na 2 SO 4 , and filtered. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA, 35% EA) to obtain the crude product compound (23.4 mg, crude product, colorless oil). LC-MS (ESI) m/z: 521.2 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(羟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(23.4mg)溶于THF(5mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)。混合物在50℃下搅拌16hrs，冷却至室温。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:22-52,流速：20mL/min，30min)分离纯化，得到目标化合物P1(1.87mg,收率9.5％，白色固体),LC-MS(ESI)m/z:437.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝2.0Hz,1H),6.96(d,J＝2.4Hz,1H),6.17(s,1H),4.61(s,2H),4.05(s,2H),4.04–3.98(m,2H),3.95–3.87(m,1H),3.85–3.75(m,3H),3.72–3.66(m,1H),3.62(d,J＝10.3Hz,2H),3.58–3.53(m,1H),3.11(d,J＝12.2Hz,1H),2.14–2.01(m,4H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-(hydroxymethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (23.4 mg) was dissolved in THF (5 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The mixture was stirred at 50° C. for 16 hours and then cooled to room temperature. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 22-52, flow rate: 20 mL/min, 30 min) to give the title compound P1 (1.87 mg, 9.5% yield, white solid). LC-MS (ESI) m/z: 437.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.76(d,J＝2.0Hz,1H),6.96(d,J＝2.4Hz,1H),6.17(s,1H),4.61(s,2H),4.05(s,2H),4.04–3.98(m,2H),3.95–3.87(m,1H) ,3.85–3.75(m,3H),3.72–3.66(m,1H),3.62(d,J＝10.3Hz,2H),3.58–3.53(m,1H),3.11(d,J＝12.2Hz,1H),2.14–2.01(m,4H).

实施例19：8-(7-((R)-3-甲基吗啉)-3-(1H-吡唑-3-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 19: 8-(7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(R)-4-(5-氯吡唑并[1,5-a]嘧啶-7-基)-3-甲基吗啉的合成
Step 1: Synthesis of (R)-4-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylmorpholine

将5,7-二氯吡唑并[1,5-a]嘧啶(500mg,2.7mmol)、(R)-3-甲基吗啉盐酸盐(1.1g,8.0mmol)、DIEA(1.0g,8.0mmol)加入到NMP(15mL)中。反应混合物在微波仪内100℃反应0.5hr，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝35％:65％)得到目标化合物(573mg,收率84.0％,白色固体)。5,7-Dichloropyrazolo[1,5-a]pyrimidine (500 mg, 2.7 mmol), (R)-3-methylmorpholine hydrochloride (1.1 g, 8.0 mmol), and DIEA (1.0 g, 8.0 mmol) were added to NMP (15 mL). The reaction mixture was reacted in a microwave at 100°C for 0.5 hr, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 35%:65%) to obtain the title compound (573 mg, 84.0% yield, as a white solid).

步骤2：8-(7-((R)-3-甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(7-((R)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(R)-4-(5-氯吡唑并[1,5-a]嘧啶-7-基)-3-甲基吗啉(240mg,0.9mmol)、3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐(200mg,1.8mmol)、DIEA(348mg,2.7mmol)依次加入到NMP(10mL)中。反应混合物在微波仪内170℃下反应5hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，用无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标化合物(139mg,收率47.0％,白色固体)。(R)-4-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylmorpholine (240 mg, 0.9 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (200 mg, 1.8 mmol), and DIEA (348 mg, 2.7 mmol) were added sequentially to NMP (10 mL). The reaction mixture was reacted in a microwave at 170°C for 5 hr. After cooling to room temperature, water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (139 mg, 47.0% yield, as a white solid).

步骤3：8-(3-碘-7-((R)-3-甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(3-iodo-7-((R)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(7-((R)-3-甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(139mg,0.4mmol)、N-碘代丁二酰亚胺(95mg,0.4mmol)加入到ACN(5mL)中，室温搅拌0.5hr，减压浓缩，残余物经硅胶柱层析(PE:EA＝1:1)分离纯化得到目标化合物(130mg,收率71.4％,白色固体)。8-(7-((R)-3-Methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (139 mg, 0.4 mmol) and N-iodosuccinimide (95 mg, 0.4 mmol) were added to ACN (5 mL), stirred at room temperature for 0.5 hr, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA=1:1) to obtain the title compound (130 mg, yield 71.4%), as a white solid.

步骤4：8-(7-((R)-3-甲基吗啉基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(7-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-7-((R)-3-甲基吗啉基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(130mg,0.3mmol)、1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-1H-吡唑(119mg,0.45mmol)、K3PO4(182mg,0.9mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(19mg,0.03mmol)依次加入到二氧六环/水(10mL/2mL)中。反应混合物在80℃下反应1hr，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE:EA＝1:4)分离纯化得到目标化合物(81mg,收率56.3％,白色固体)。LC-MS(ESI)m/z:479.9[M+H]+。8-(3-iodo-7-((R)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (130 mg, 0.3 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H-pyrazole (119 mg, 0.45 mmol), K 3 PO 4 (182 mg, 0.9 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.03 mmol) were added sequentially to dioxane/water (10 mL/2 mL). The reaction mixture was reacted at 80°C for 1 hour, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (81 mg, 56.3% yield, as a white solid). LC-MS (ESI) m/z: 479.9 [M+H] + .

步骤5：8-(7-((R)-3-甲基吗啉)-3-(1H-吡唑-3-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(7-((R)-3-甲基吗啉基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)吡唑并[1,5-a]嘧啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(81mg,0.2mmol)加入到6M盐酸水溶液/THF(2mL/4mL)，反应混合物在50℃下搅拌1hr，冷却至室温，用饱和NaHCO3水溶液调pH>8，用EA(20mL×3)萃取，合并有机层，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM/MeOH＝30/1)得到目标化合物(30mg,收率38.0％,白色固体)。LC-MS(ESI)m/z:396.10[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.58(s,1H),8.22(s,1H),7.55(s,1H),6.69(s,1H),5.84(s,1H),5.14-5.06(m,1H),4.74-4.65(m,2H),3.93(d,J＝10.8Hz,1H),3.86-3.79(m,1H),3.75-3.48(m,7H),3.38-3.34(m,1H),2.01-1.91(m,4H),1.11(d,J＝6.8Hz,3H)。8-(7-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (81 mg, 0.2 mmol) was added to 6 M aqueous hydrochloric acid/THF (2 mL/4 mL). The reaction mixture was stirred at 50°C for 1 hr, cooled to room temperature, adjusted to pH>8 with saturated aqueous NaHCO₃ , and extracted with EA (20 mL×3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=30/1) to give the title compound (30 mg, yield 38.0%) as a white solid. LC-MS(ESI)m/z:396.10[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.22(s,1H),7.55(s,1H),6.69(s,1H),5.84(s,1H),5.14-5.06(m,1H),4.74-4.65(m,2 H),3.93(d,J＝10.8Hz,1H),3.86-3.79(m,1H),3.75-3.48(m,7H),3.38-3.34(m,1H),2.01-1.91(m,4H),1.11(d,J＝6.8Hz,3H).

实施例20:6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡 啶-3-腈
Example 20: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine - 3-carbonitrile

步骤1：8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-氟-4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶(27.84g,80.20mmol)溶于DMSO(300mL)中，加入K3PO4(18.73g,88.22mmol)和8-氮杂-3-氧杂双环[3.2.1]辛烷(9.98g,88.22mmol)。反应混合物在N2保护下60℃下搅拌16hrs，冷却至室温。向反应混合物中加入水(200mL)，用EA(200mL×2)萃取，合并有机相，用饱和食盐水(500mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经(PE/EA＝5/1)浆化，过滤，收集固体，得到目标化合物(21g,收率59.5％，黄色固体)。LC-MS(ESI)m/z:441.0[M+H]+。1H NMR(400MHz,Chloroform-d)δ7.58(s,1H),6.83(s,1H),5.75(dd,J＝10.5,2.5Hz,1H),4.44(d,J＝15.3Hz,2H),4.06–4.01(m,1H),3.77(dd,J＝10.8,2.9Hz,2H),3.69–3.63(m,1H),3.57(d,J＝10.9Hz,2H),2.54–2.46(m,1H),2.09–2.02(m,3H),1.98–1.93(m,2H),1.88–1.83(m,1H),1.73–1.66(m,2H),1.54–1.50(m,1H).6-Fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo [ 3,4-b]pyridine (27.84 g, 80.20 mmol) was dissolved in DMSO (300 mL), and K₃PO₄ (18.73 g, 88.22 mmol) and 8-aza-3-oxabicyclo[3.2.1]octane (9.98 g, 88.22 mmol) were added. The reaction mixture was stirred at 60°C for 16 hr under N₂ protection and then cooled to room temperature. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (200 mL x 2). The combined organic phases were washed with saturated brine (500 mL x 5 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was slurried with PE/EA (5/1), filtered, and the solid collected to give the title compound (21 g, 59.5% yield, as a yellow solid). LC-MS(ESI)m/z:441.0[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.58(s,1H),6.83(s,1H),5.75(dd,J＝10.5,2.5H z,1H),4.44(d,J＝15.3Hz,2H),4.06–4.01(m,1H),3.77(dd,J＝10.8,2.9Hz,2H) ,3.69–3.63(m,1H),3.57(d,J＝10.9Hz,2H),2.54–2.46(m,1H),2.09–2.02(m,3 H),1.98–1.93(m,2H),1.88–1.83(m,1H),1.73–1.66(m,2H),1.54–1.50(m,1H).

步骤2：8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2保护下，将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(8.0g,18.17mmol)溶解于DMF(120mL)中，并加入(R)-3-甲基吗啉盐酸盐(2.76g,27.26mmol)、Cs2CO3(17.77g,54.51mmol)和Ruphos Pd G2(560mg,0.73mmol)。反应混合物N2保护下在130℃下搅拌16hrs，冷却至室温，向反应混合物中加入水(100mL)，用EA(100mL×2)萃取，合并有机相，用饱和食盐水(300mL×5)洗涤，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA＝1/1)得到目标化合物(5.81g,收率77.3％，淡黄色固体)。LC-MS(ESI)m/z:414.2[M+H]+。Under N 2 protection, 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8.0 g, 18.17 mmol) was dissolved in DMF (120 mL), and (R)-3-methylmorpholine hydrochloride (2.76 g, 27.26 mmol), Cs 2 CO 3 (17.77 g, 54.51 mmol) and Ruphos Pd G2 (560 mg, 0.73 mmol) were added. The reaction mixture was stirred at 130°C under N₂ protection for 16 hours, cooled to room temperature, and water (100 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL x 2). The combined organic phases were washed with saturated brine (300 mL x 5) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 1/1) to obtain the title compound (5.81 g, 77.3% yield, light yellow solid). LC-MS (ESI) m/z: 414.2 [M+H] + .

步骤3：8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(20a)的合成
Step 3: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20a)

将8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(8.0g,19.35mmol)溶于MeOH(30mL)中，加入4N盐酸/1,4-二氧六环溶液(30mL)。反应混合物在30℃搅拌16hrs。减压浓缩，残余物中加入饱和NaHCO3水溶液至弱碱性，用DCM(80mL×3)萃取，合并有机相，减压浓缩，残余物经正相柱层析分离纯化(DCM：MeOH，8％MeOH)得到目标化合物(6.0g,收率94.2％，淡黄色固体)。LC-MS(ESI)m/z:330.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8.0 g, 19.35 mmol) was dissolved in MeOH (30 mL), and a 4N hydrochloric acid/1,4-dioxane solution (30 mL) was added. The reaction mixture was stirred at 30°C for 16 hours and concentrated under reduced pressure. Saturated aqueous NaHCO₃ was added to the residue until weakly alkaline, and the mixture was extracted with DCM (80 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by normal phase column chromatography (DCM:MeOH, 8% MeOH) to obtain the title compound (6.0 g, 94.2% yield, as a pale yellow solid). LC-MS (ESI) m/z: 330.2 [M+H] ⁺ .

步骤4：8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(7.26g,22.04mmol)、氢氧化钾(3.09g,55.10mmol)加入到DMF(500mL)中，反应混合物30℃下搅拌5mins，然后缓慢加入I2(11.19g,44.08mmol)，此过程需要2.5hrs，然后在30℃下搅拌1hr。向反应混合物中加入过量饱和Na2SO3水溶液，用DCM(500mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％MeOH)，得到目标化合物(5.4g,收率53.8％，淡黄色固体)。LC-MS(ESI)m/z:456.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (7.26 g, 22.04 mmol) and potassium hydroxide (3.09 g, 55.10 mmol) were added to DMF (500 mL). The reaction mixture was stirred at 30°C for 5 mins, and then I2 (11.19 g, 44.08 mmol) was slowly added over 2.5 hrs, and then stirred at 30°C for 1 hr. An excess of saturated aqueous Na₂SO₃ was added to the reaction mixture, and the mixture was extracted with DCM (500 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to obtain the title compound (5.4 g, 53.8% yield, light yellow solid). LC-MS (ESI) m/z: 456.2 [M+H] ⁺ .

步骤5：8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(20b)的合成
Step 5: Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20b)

在N2气氛下，向8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(5.4g,11.86mmol)的NMP(150mL)中的溶液中加入(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(6.97g,35.58mmol)、无水吡啶(3.27g,47.44mmol)和Cu(CH3COO)2(4.74g,23.72mmol)，反应混合物在O2氛围下50℃下搅拌16hrs。用EA(200mL)和水(200mL)稀释反应物，用EA(500mL×5)萃取，合并有机相，减压浓缩，残余物经正相柱层析分离纯化(PE/EA＝1/1)，得到目标化合物(4.6g,收率64.1％，白色固体)。LC-MS(ESI)m/z:606.2[M+H]+。To a solution of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (5.4 g, 11.86 mmol) in NMP (150 mL) were added (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (6.97 g, 35.58 mmol), anhydrous pyridine (3.27 g, 47.44 mmol) and Cu(CH 3 COO) 2 (4.74 g, 23.72 mmol) under N 2 atmosphere, and the reaction mixture was stirred at 50° C. under O 2 atmosphere for 16 hrs. The reaction was diluted with EA (200 mL) and water (200 mL), extracted with EA (500 mL x 5), and the combined organic phases were concentrated under reduced pressure. The residue was purified by normal phase column chromatography (PE/EA = 1/1) to obtain the title compound (4.6 g, 64.1% yield, white solid). LC-MS (ESI) m/z: 606.2 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.13mmol)、Zn(CN)2(46.5mg,0.39mmol)、锌粉(25.9mg,0.39mmol)、Pd2(dba)3(12mg,0.013mmol)和Pd(dppf)Cl2(19mg,0.026mmol)依次加入到有DMA(2mL)的微波管中。在N2氛围下鼓气2mins，然后反应混合物在微波仪器中150℃搅拌1hrs，冷却至室温。向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相，用饱和食盐水(150mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)，得到目标化合物(61.3mg,收率91.9％，黄色固体)。LC-MS(ESI)m/z:505.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.13 mmol), Zn(CN) 2 (46.5 mg, 0.39 mmol), zinc powder (25.9 mg, 0.39 mmol), Pd 2 (dba) 3 (12 mg, 0.013 mmol) and Pd(dppf)Cl 2 (19 mg, 0.026 mmol) were added sequentially to a microwave tube containing DMA (2 mL). After bubbling under N 2 atmosphere for 2 mins, the reaction mixture was stirred at 150° C. in a microwave instrument for 1 hrs and cooled to room temperature. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (60 mL x 2). The combined organic phases were washed with saturated brine (150 mL x 2 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (61.3 mg, 91.9% yield, as a yellow solid). LC-MS (ESI) m/z: 505.2 [M+H] ⁺ .

步骤8：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 8: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(58.8mg,0.12mmol)溶于THF(10mL)中，加入4N盐酸/1,4二氧六环溶液(2mL)。反应混合物在50℃下搅拌3hr。减压浓缩，残余物先经硅胶柱层析分离纯化(PE：EA，74％EA)得到粗品，然后粗品悬浮于PE/EA混合溶液中(PE/EA＝1/1),过滤，收集固体再经过冻干得到目标化合物(20mg,收率40.8％，白色固体)。LC-MS(ESI)m/z:421.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),7.90(s,1H),6.83(d,J＝2.0Hz,1H),6.23(s,1H),4.61(s,2H),4.05–3.98(m,1H),3.96–3.89(m,2H),3.72–3.62(m,4H),3.57(d,J＝10.2Hz,2H),3.53–3.46(m,1H),3.00(d,J＝12.4Hz,1H),2.03–1.89(m,4H),1.07(d,J＝6.5Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (58.8 mg, 0.12 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 50°C for 3 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (PE:EA, 74% EA) to afford the crude product, which was then suspended in a PE/EA mixture (PE/EA = 1/1) and filtered. The collected solid was then lyophilized to afford the title compound (20 mg, 40.8% yield, as a white solid). LC-MS (ESI) m/z: 421.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.08(s,1H),7.90(s,1H),6.83(d,J＝2.0Hz,1H),6.23(s,1H),4.61(s,2H),4.05–3.98(m,1H),3.96–3.89(m,2H),3.72 –3.62(m,4H),3.57(d,J＝10.2Hz,2H),3.53–3.46(m,1H),3.00(d,J＝12.4Hz,1H),2.03–1.89(m,4H),1.07(d,J＝6.5Hz,3H).

实施例21和实施例22:(S)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3- 基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈和(R)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈
Example 21 and Example 22: (S)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile and (R)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl )-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile

步骤1：8-(3-碘-4-((R)-3-甲基吗啉基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将NaH(0.33g,8.24mmol)加入THF(40mL)中，在0℃条件下搅拌10mins，然后加入8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(2.50g,5.49mmol)(20a)的THF(5mL)溶液，在0℃继续搅拌30mins，再缓慢滴加SEMCl(1.37g,8.24mmol)的THF(5mL)溶液，反应混合物在0℃下搅拌2hrs。将反应混合物倒入足量水中淬灭，用EA(50mL×2)萃取，合并有机相，用水洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，4％ MeOH)得到目标化合物(2.8g,收率87.0％，黄色固体)。LC-MS(ESI)m/z:586.2[M+H]+。NaH (0.33 g, 8.24 mmol) was added to THF (40 mL) and stirred at 0°C for 10 mins. Then, a solution of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.50 g, 5.49 mmol) (20a) in THF (5 mL) was added. Stirring was continued at 0°C for 30 mins. Then, a solution of SEMCl (1.37 g, 8.24 mmol) in THF (5 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 2 hrs. The reaction mixture was poured into a sufficient amount of water to quench the reaction mixture, followed by extraction with EA (50 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na2SO4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( DCM:MeOH, 4% MeOH) to afford the title compound (2.8 g, 87.0% yield, yellow solid). LC-MS (ESI) m/z: 586.2 [M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.50g,2.56mmol)和三丁基(1-乙氧基乙烯基)锡(1.85g,5.12mmol)溶于DMF(30mL)中，然后加入Pd(PPh3)2Cl2(1.85g,5.12mmol)。反应混合物在N2保护下在100℃下搅拌16hrs，冷却至室温。向反应混合物中加入过量水和EA稀释，用EA(50mL×2)萃取。合并有机相用水洗涤，无水Na2SO4干燥，过滤，减压浓缩，然后用THF(20mL)溶解，再加入2N盐酸水溶液(20mL)，在25℃下搅拌2hrs，减压浓缩浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，5％ MeOH)，得到目标化合物(765mg,收率80.4％，棕色固体)。LC-MS(ESI)m/z:372.4[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.50 g, 2.56 mmol) and tributyl(1-ethoxyvinyl)tin (1.85 g, 5.12 mmol) were dissolved in DMF (30 mL), followed by the addition of Pd(PPh 3 ) 2 Cl 2 (1.85 g, 5.12 mmol). The reaction mixture was stirred at 100° C. for 16 hours under N 2 protection and then cooled to room temperature. Excess water and EA were added to the reaction mixture, which was then diluted and extracted with EA (50 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The mixture was then dissolved in THF (20 mL) and 2N aqueous hydrochloric acid (20 mL) was added. The mixture was stirred at 25°C for 2 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 5% MeOH) to obtain the title compound (765 mg, 80.4% yield, brown solid). LC-MS (ESI) m/z: 372.4 [M+H] + .

步骤3：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮的合成
Step 3: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮(765mg,2.06mmol)和3-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(859mg,3.09mmol)溶于NMP(10mL)中，再依次加入Cs2CO3(2014mg,6.18mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(293mg,2.06mmol)、CuI(392mg,2.06mmol)，反应混合物在N2保护下，在120℃下搅拌16hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(20mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，5％ MeOH)，得到得到粗产品(550mg,收率51.2％，黄色固体)。LC-MS(ESI)m/z:522.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one (765 mg, 2.06 mmol) and 3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (859 mg, 3.09 mmol) were dissolved in NMP (10 mL), and Cs 2 CO 3 (2014 mg, 6.18 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (293 mg, 2.06 mmol) and CuI (392 mg, 2.06 mmol) were added in sequence. The reaction mixture was stirred at 120° C. for 16 hrs under N 2 protection and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 5% MeOH) to obtain the crude product (550 mg, 51.2% yield, yellow solid). LC-MS (ESI) m/z: 522.2 [M+H] + .

步骤4：2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈的合成
Step 4: Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile

将对甲苯磺酰甲基异氰(75mg,0.38mmol)和t-BuOK(65mg,0.57mmol)溶于DME(5mL)中，在0℃下搅拌20mins，然后加入1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮(100mg,0.19mmol)，继续搅拌30mins。再加入MeOH(1mL)后，反应混合物在25℃下搅拌16hrs。向反应混合物中加入过量饱和NH4Cl溶液和EA稀释，有机相再用水洗涤三次，减压浓缩，得到混合物(80mg,78.3％，黄色固体)。LC-MS(ESI)m/z:533.2[M+H]+。Tosylmethyl isocyanate (75 mg, 0.38 mmol) and t-BuOK (65 mg, 0.57 mmol) were dissolved in DME (5 mL) and stirred at 0°C for 20 min. Then, 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one (100 mg, 0.19 mmol) was added, and stirring was continued for 30 min. MeOH (1 mL) was added, and the reaction mixture was stirred at 25°C for 16 hr. The reaction mixture was diluted with excess saturated NH 4 Cl solution and EA. The organic phase was washed three times with water and concentrated under reduced pressure to give the mixture (80 mg, 78.3%, as a yellow solid). LC-MS(ESI)m/z:533.2[M+H] + .

步骤5：(S)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈和(R)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈的合成
Step 5: Synthesis of (S)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile and (R)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile

将2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈(35mg,0.07mmol)溶于THF(2mL)中，再加入4N盐酸/二氧六环溶液(2mL)，反应混合物在N2保护下25℃搅拌过夜。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:30-60,流速:20mL/min,20min)分离纯化，得到目标化合物P1：第一个峰，(5mg,收率16.9％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),7.83(s,1H),6.74(s,1H),6.52(s,1H),4.66–4.54(m,3H),3.94–3.88(m,1H),3.86–3.76(m,2H),3.73–3.63(m,2H),3.60–3.53(m,2H),3.51–3.42(m,2H),3.28–3.20(m,1H),2.85–2.77(m,1H),2.02–1.88(m,4H),1.76(d,J＝7.1Hz,3H),0.91(d,J＝5.8Hz,3H)。2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile (35 mg, 0.07 mmol) was dissolved in THF (2 mL), and 4N hydrochloric acid/dioxane solution (2 mL) was added. The reaction mixture was stirred at 25°C overnight under N₂ protection. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate C₁₈, 21.2*250 mm, 5 μm: 0.1% FA; B%: 30-60, flow rate: 20 mL/min, 20 min) to obtain the target compound P1: the first peak (5 mg, yield 16.9%), as a white solid. LC-MS(ESI)m/z:449.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.84(s,1H),7.83(s,1H),6.74(s,1H),6.52(s,1H),4.66–4.54(m,3H),3.94–3.88(m,1H),3.86–3.76(m,2H),3.73–3.63(m,2H),3.6 0–3.53(m,2H),3.51–3.42(m,2H),3.28–3.20(m,1H),2.85–2.77(m,1H),2.02–1.88(m,4H),1.76(d,J＝7.1Hz,3H),0.91(d,J＝5.8Hz,3H).

和P2：第二个峰，(4mg,收率13.5％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),7.82(s,1H),6.73(d,J＝2.0Hz,1H),6.43(s,1H),4.65–4.54(m,3H),3.93–3.81(m,2H),3.80–3.73(m,1H),3.72–3.61(m,2H),3.59–3.48(m,3H),3.46–3.39(m,1H),3.31–3.26(m,1H),2.82–2.74(m,1H),2.01–1.86(m,4H),1.73(d,J＝7.2Hz,3H),0.90(d,J＝6.1Hz,3H)。and P2: the second peak (4 mg, yield 13.5%, white solid). LC-MS (ESI) m/z: 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.84(s,1H),7.82(s,1H),6.73(d,J＝2.0Hz,1H),6.43(s,1H),4.65 –4.54(m,3H),3.93–3.81(m,2H),3.80–3.73(m,1H),3.72–3.61(m,2H) ,3.59–3.48(m,3H),3.46–3.39(m,1H),3.31–3.26(m,1H),2.82–2.74( m,1H),2.01–1.86(m,4H),1.73(d,J＝7.2Hz,3H),0.90(d,J＝6.1Hz,3H).

实施例23:(8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂双环[3.2.1]辛烷
Example 23: (8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

步骤1：8-(4-(((R)-3-甲基吗啉基)-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(((R)-3-methylmorpholinyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(400mg,0.68mmol)溶于DMF(50mL)，加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(2.62g,13.66mmol)、六甲基磷酸三胺(5mL)和CuI(130mg,0.68mmol)。反应混合物在N2保护下在100℃下搅拌16hrs。向反应混合物中加入水(50mL)，用EA(50mL×2)萃取。合并有机相用饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，25％ EA)，得到目标化合物(237mg,收率41.4％，无色油状物)。LC-MS(ESI)m/z:528.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400 mg, 0.68 mmol) was dissolved in DMF (50 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.62 g, 13.66 mmol), hexamethylphosphoric acid triamine (5 mL), and CuI (130 mg, 0.68 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours under N protection. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 25% EA) to obtain the title compound (237 mg, 41.4% yield, colorless oil). LC-MS (ESI) m/z: 528.2 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(((R)-3-甲基吗啉基)-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(209mg,0.40mmol)溶于DCM(9mL)中，加入TFA(3mL)。反应混合物在N2保护下25℃下搅拌16小时。减压浓缩，残余物溶于MeOH(9mL)，加入TFA(3mL)，反应混合物在N2保护下在25℃下搅拌3hrs。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％ EA)，得到目标化合物(140mg,收率88.9％，白色固体)。LC-MS(ESI)m/z:398.4[M+H]+。8-(4-(((R)-3-methylmorpholinyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (209 mg, 0.40 mmol) was dissolved in DCM (9 mL) and TFA (3 mL) was added. The reaction mixture was stirred at 25°C under N₂ protection for 16 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (9 mL). TFA (3 mL) was added, and the reaction mixture was stirred at 25°C under N₂ protection for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (140 mg, 88.9% yield, as a white solid). LC-MS (ESI) m/z: 398.4 [M+H] ⁺ .

步骤3：8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-3-甲基吗啉基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(60mg,0.15mmol)的NMP(10mL)溶液中依次加入3-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(84mg,0.30mmol)、甲基[(1S，2S)-2-(甲氨基)环己基]胺(43mg,0.30mmol)、Cs2CO3(148mg,0.45mmol)和CuI(58mg,0.30mmol)。反应溶液在N2下鼓气3mins后，在微波仪器下150℃搅拌3hrs，冷却至室温。向反应混合物中加入水(40mL)，用EA(50mL×2)萃取。合并有机相用饱和食盐水(80mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，47％ EA)得到目标化合物(66mg,收率79.8％，黄色固体)。LC-MS(ESI)m/z:548.2[M+H]+。To a solution of 8-(4-((R)-3-methylmorpholinyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.15 mmol) in NMP (10 mL) were added 3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (84 mg, 0.30 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (43 mg, 0.30 mmol), Cs 2 CO 3 (148 mg, 0.45 mmol), and CuI (58 mg, 0.30 mmol) in sequence. The reaction solution was bubbled with N 2 for 3 minutes, then stirred at 150° C. in a microwave for 3 hours and cooled to room temperature. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 5 ), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 47% EA) to obtain the title compound (66 mg, 79.8% yield, yellow solid). LC-MS (ESI) m/z: 548.2 [M+H] ⁺ .

步骤4：(8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of (8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(66mg,0.12mmol)的DCM(5mL)溶液中，加入TFA(1mL)，反应混合物在25℃下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um；流动相A:0.1％FA/H2O；流动相B:ACN，梯度：36-69％B,流速：20mL/min，20min)分离纯化，得到目标化合物(9.9mg,收率17.7％，白色固体)。LC-MS(ESI)m/z:464.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.88(s,1H),6.79(d,J＝2.3Hz,1H),6.58(s,1H),4.63(d,J＝10.0Hz,2H),3.85(dd,J＝11.0,2.8Hz,1H),3.78–3.71(m,4H),3.70–3.63(m,2H),3.60–3.54(m,3H),3.41–3.37(m,1H),3.26–3.20(m,1H),2.82–2.76(m,1H),2.01–1.91(m,4H),0.88(d,J＝6.2Hz,3H).To a solution of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (66 mg, 0.12 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at 25°C for 3 hr. The product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/ H2O ; mobile phase B: ACN, gradient: 36-69% B, flow rate: 20 mL/min over 20 min) to afford the title compound (9.9 mg, 17.7% yield, as a white solid). LC-MS(ESI)m/z:464.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.02(s,1H),7.88(s,1H),6.79(d,J＝2.3Hz,1H),6.58(s,1H),4.63(d,J＝10.0Hz,2H),3.85(dd,J＝11.0,2.8Hz,1H),3.78–3.71(m,4H) ,3.70–3.63(m,2H),3.60–3.54(m,3H),3.41–3.37(m,1H),3.26–3.20(m,1H),2.82–2.76(m,1H),2.01–1.91(m,4H),0.88(d,J＝6.2Hz,3H).

实施例24:8-(5-氯-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂 -8-氮杂双环[3.2.1]辛烷
Example 24: 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa- 8-azabicyclo[3.2.1]octane

向8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(79mg,0.14mmol)溶于THF(10mL)中，加入4N盐酸/1,4二氧六环溶液(4mL)。反应混合物在50℃下搅拌3hrs，减压浓缩。残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:48-78,流速：20mL/min，20min)分离纯化，得到目标化合物(1.84mg,收率2.6％，白色固体)。LC-MS(ESI)m/z:498.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.82(d,J＝2.2Hz,1H),6.93(d,J＝2.4Hz,1H),4.60–4.55(m,1H),4.45(d,J＝6.4Hz,1H),4.14–4.02(m,2H),3.93–3.79(m,4H),3.73–3.63(m,3H),3.38(t,J＝10.4Hz,1H),2.20–1.87(m,5H),0.78(d,J＝6.4Hz,3H)。8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (79 mg, 0.14 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 50°C for 3 hours and then concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 48-78, flow rate: 20 mL/min, 20 min) to obtain the title compound (1.84 mg, 2.6% yield) as a white solid. LC-MS (ESI) m/z: 498.2[M+H]+. 1 H NMR (400MHz, Methanol-d 4 )δ7.82(d,J＝2.2Hz,1H),6.93(d,J＝2.4Hz,1H),4.60–4.55(m,1H),4.45(d,J＝6.4Hz,1H),4.14–4.02(m,2H ),3.93–3.79(m,4H),3.73–3.63(m,3H),3.38(t,J＝10.4Hz,1H),2.20–1.87(m,5H),0.78(d,J＝6.4Hz,3H).

实施例25和实施例26：(S)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3- 基)-1H-吡唑并[3,4-b]吡啶-3-基)丙酸甲酯和(R)-2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙酸甲酯
Example 25 and Example 26: Methyl (S)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propanoate and Methyl (R)-2-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl )-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propanoate

将2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙腈(100mg,0.19mmol)溶于MeOH(2mL)，再加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物在N2保护下50℃搅拌过夜。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：梯度：30-60％B,流速:20mL/min,20min)分离纯化，得到先出峰的目标化合物P1(5.0mg,收率5.5％，白色固体)。LC-MS(ESI)m/z:482.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),7.80(s,1H),6.74(d,J＝2.1Hz,1H),6.41(s,1H),4.64–4.54(m,2H),4.30–4.21(m,1H),3.90–3.69(m,4H),3.68–3.54(m,6H),3.51–3.42(m,1H),3.30–3.20(m,2H),2.75–2.65(m,1H),2.02–1.85(m,4H),1.62(d,J＝7.2Hz,3H),0.84(d,J＝6.1Hz,3H)；和后出峰的目标化合物P2(4.0mg,收率4.4％，白色固体)。LC-MS(ESI)m/z:482.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),7.79(s,1H),6.73(d,J＝2.0Hz,1H),6.44(s,1H),4.64–4.54(m,2H),4.48–4.40(m,1H),3.91–3.83(m,1H),3.82–3.61(m,7H),3.60–3.47(m,3H),3.46–3.40(m,1H),3.27–3.19(m,1H),2.85–2.76(m,1H),2.03–1.86(m,4H),1.53(d,J＝7.2Hz,3H),0.89(d,J＝6.2Hz,3H)。2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propionitrile (100 mg, 0.19 mmol) was dissolved in MeOH (2 mL), and 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 50°C under N2 protection overnight. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: gradient: 30-60% B, flow rate: 20 mL/min, 20 min) to afford the first-eluting target compound P1 (5.0 mg, 5.5% yield, white solid). LC-MS (ESI) m/z: 482.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 7.80 (s, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.41 (s, 1H), 4.64–4.54 (m, 2H), 4.30–4.21 (m, 1H), 3.90–3.69 (m, 4H), 3.68–3.54 (m, 6H), 3.51–3.42 (m, 1H), 3.30–3.20 (m, 2H), 2.75–2.65 (m, 1H), 2.02–1.85 (m, 4H), 1.62 (d, J = 7.2 Hz, 3H), 0.84 (d, J = 6.1 Hz, 3H); and the target compound P2 (4.0 mg, yield 4.4%, white solid) eluted later. LC-MS(ESI)m/z:482.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.76(s,1H),7.79(s,1H),6.73(d,J＝2.0Hz,1H),6.44(s,1H),4.64 –4.54(m,2H),4.48–4.40(m,1H),3.91–3.83(m,1H),3.82–3.61(m,7H) ,3.60–3.47(m,3H),3.46–3.40(m,1H),3.27–3.19(m,1H),2.85–2.76( m,1H),2.03–1.86(m,4H),1.53(d,J＝7.2Hz,3H),0.89(d,J＝6.2Hz,3H).

实施例27：8-(4-((R)-3-甲基吗啉基)-3-(氧杂环丁烷-3-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3- 氧杂-8-氮杂双环[3.2.1]辛烷
Example 27: 8-(4-((R)-3-methylmorpholinyl)-3-(oxetan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3- oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((R)-3-甲基吗啉基)-3-(氧杂环丁烷-3-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(oxetan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-碘-4-[(3R)-3-甲基吗啉-4-基]-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]吡唑并[3,4-b]吡啶(20b)(200mg,0.33mmol)在1,4-二氧六环(10mL)和水(2mL)中的溶液中加入氧杂环丁烷-3-基硼酸(67mg,0.66mmol)，反应物混合物在125℃下在N2保护下搅拌36hrs，冷却至室温。加入水，用EA(10mL×3)萃取，合并有机相，减压浓缩，残余物通过硅胶柱层析纯化(PE：EA，40％EA)。得到目标化合物(100mg,收率56.5％，黄色固体)。LC-MS(ESI)m/z:536.3[M+H]+。To a solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-iodo-4-[(3R)-3-methylmorpholin-4-yl]-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (20b) (200 mg, 0.33 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added oxetan-3-ylboronic acid (67 mg, 0.66 mmol). The reaction mixture was stirred at 125° C. under N protection for 36 hours and then cooled to room temperature. Water was added, and the mixture was extracted with EA (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA). The target compound (100 mg, yield 56.5%) was obtained as a yellow solid. LC-MS (ESI) m/z: 536.3 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-3-(氧杂环丁烷-3-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(oxetan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-3-甲基吗啉基)-3-(氧杂环丁烷-3-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.19mmol)的THF(2mL)溶液中加入TFA(2mL)，并将反应液在50℃下搅拌18hrs，冷却至室温。向反应液中加入饱和K2CO3水溶液(5mL)中和，过滤，滤液减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％TFA；B％:20-50,流速：20mL/min，18min)分离纯化，得到目标化合物(10.0mg,收率11.8％，类白色固体)。LC-MS(ESI)m/z:452.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),7.78(s,1H),6.75(d,J＝2.2Hz,1H),6.10(s,1H),5.66(d,J＝15.9Hz,2H),4.66–4.50(m,3H),4.30(d,J＝15.1Hz,1H),3.86(d,J＝11.3Hz,1H),3.80–3.46(m,9H),2.89(d,J＝12.4Hz,1H),2.54–2.51(m,1H),2.00–1.86(m,4H),0.90(d,J＝6.5Hz,3H)。To a solution of 8-(4-((R)-3-methylmorpholinyl)-3-(oxetan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.19 mmol) in THF (2 mL) was added TFA (2 mL), and the reaction was stirred at 50°C for 18 hrs and cooled to room temperature. The reaction mixture was neutralized with saturated aqueous K₂CO₃ (5 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% TFA; B%: 20-50, flow rate: 20 mL/min, 18 min) to obtain the title compound (10.0 mg, 11.8% yield, off-white solid). LC-MS (ESI) m/z: 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.76(s,1H),7.78(s,1H),6.75(d,J＝2.2Hz,1H),6.10(s,1H),5.66(d,J＝15.9Hz,2H),4.66–4.50(m,3H),4.30(d,J＝15.1Hz,1H ),3.86(d,J＝11.3Hz,1H),3.80–3.46(m,9H),2.89(d,J＝12.4Hz,1H),2.54–2.51(m,1H),2.00–1.86(m,4H),0.90(d,J＝6.5Hz,3H).

实施例28：2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)丙-2-醇
Example 28: 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)propan-2-ol

步骤1：2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙-2-醇的合成
Step 1: Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propan-2-ol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮(200mg,0.38mmol)溶于THF(1.5mL)中，在0℃下滴加到甲基溴化镁(5mL)中。反应混合物在N2保护下25℃下反应16hrs。向反应混合物中加入水和EA稀释，用EA(10mL×2)萃取。合并有机相用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到目标化合物(205mg,收率99.4％，黄色固体)。LC-MS((ESI)m/z:538.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one (200 mg, 0.38 mmol) was dissolved in THF (1.5 mL) and added dropwise to methylmagnesium bromide (5 mL) at 0°C. The reaction mixture was reacted at 25°C under N₂ protection for 16 hr. Water and EA were added to the reaction mixture, which was then extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (205 mg, 99.4% yield, as a yellow solid). LC-MS((ESI)m/z:538.2[M+H] + .

步骤2：2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙-2-醇的合成
Step 2: Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propan-2-ol

将2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙-2-醇(30mg,0.056mmol)溶于DCM(2.5mL)中，然后加入TFA(2.5mL)。反应混合物N2保护下在25℃下搅拌2hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um；流动相A：0.1％FA/H2O；流动相B：ACN，梯度：20-50％B,流速：20mL/min,30min)分离纯化，得到目标化合物(12.0mg,收率47.4％，白色固体)。LC-MS(ESI)m/z:454.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),7.79(s,1H),7.46(s,1H),6.89(s,1H),6.72(d,J＝2.2Hz,1H),4.63(s,2H),3.96–3.88(m,2H),3.73–3.63(m,3H),3.61–3.54(m,3H),3.26–3.22(m,1H),3.12(d,J＝12.1Hz,1H),3.04-2.96(m,1H),2.02–1.90(m,4H),1.60(s,3H),1.52(s,3H),0.79(d,J＝6.3Hz,3H)。2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propan-2-ol (30 mg, 0.056 mmol) was dissolved in DCM (2.5 mL), and then TFA (2.5 mL) was added. The reaction mixture was stirred at 25° C. under N 2 protection for 2 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: ACN, gradient: 20-50% B, flow rate: 20 mL/min, 30 min) to obtain the title compound (12.0 mg, 47.4% yield, white solid). LC-MS (ESI) m/z: 454.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.77(s,1H),7.79(s,1H),7.46(s,1H),6.89(s,1H),6.72(d,J＝2.2Hz,1H),4.63(s,2H),3.96–3.88(m,2H),3.73–3.63(m,3H),3.61–3.5 4(m,3H),3.26–3.22(m,1H),3.12(d,J＝12.1Hz,1H),3.04-2.96(m,1H),2.02–1.90(m,4H),1.60(s,3H),1.52(s,3H),0.79(d,J＝6.3Hz,3H).

实施例29：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-甲酰胺
Example 29: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine-3-carboxamide

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(58mg,0.14mmol)溶于DMSO(5mL)中，将K2CO3(38mg,0.28mmol)和H2O2(14mg,0.41mmol)加入到反应液中，反应混合物在室温下搅拌12hrs后，向反应混合物中加入饱和Na2SO3溶液(10mL)淬灭反应，用EA(20mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物通过Prep-HPLC纯化(column:Xtimate C18,20*250mm,10um:流动相A:0.05％NH3.H2O/H2O；流动相B：ACN，梯度：15-45％B,流速:24mL/min,20min)分离纯化，得到目标化合物(5mg,收率8.3％，白色固体)。LC-MS(ESI)m/z:439.2[M+H]+。1HNMR(400MHz,DMSO-d6)δ12.89(s,1H),8.20(s,1H),7.84(s,1H),7.60(s,1H),6.78(s,1H),6.16(s,1H),4.61–4.51(m,2H),3.91–3.84(m,2H),3.82–3.75(m,1H),3.73–3.64(m,3H),3.60–3.43(m,4H),2.99(d,J＝12.1Hz,1H),2.00–1.87(m,4H),0.97(d,J＝6.5Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (58 mg, 0.14 mmol) was dissolved in DMSO (5 mL), and K 2 CO 3 (38 mg, 0.28 mmol) and H 2 O 2 (14 mg, 0.41 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 12 hrs, and then saturated Na 2 SO 3 solution (10 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with EA (20 mL×2), the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 20*250 mm, 10 μm: mobile phase A: 0.05% NH 3 The title compound (5 mg, 8.3% yield, white solid) was obtained by separation and purification using H 2 O/H 2 O; mobile phase B: ACN, gradient: 15-45% B, flow rate: 24 mL/min, 20 min). LC-MS (ESI) m/z: 439.2 [M+H] + . 1 HNMR (400MHz, DMSO-d 6 )δ12.89(s,1H),8.20(s,1H),7.84(s,1H),7.60(s,1H),6.78(s,1H),6.16(s,1H),4.61–4.51(m,2H),3.91–3.84(m,2H),3 .82–3.75(m,1H),3.73–3.64(m,3H),3.60–3.43(m,4H),2.99(d,J＝12.1Hz,1H),2.00–1.87(m,4H),0.97(d,J＝6.5Hz,3H).

实施例30：8-(4-(3,3-二甲基吗啉)-1-(1H-吡唑基-3-基)-1H-吡唑基[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1] 辛烷
Example 30: 8-(4-(3,3-dimethylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶的合成
Step 1: Synthesis of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

将4,6-二氯-1H-吡唑并[3,4-d]嘧啶(1.00g,5.3mmol)，3,4-二氢吡喃(889mg,10.6mmol)和对甲基苯磺酸(86mg,0.5mmol)加入DCM(10mL)中，N2保护下，反应混合物室温搅拌过夜，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:1)得到目标化合物(1.4g,收率100％,白色固体)。LC-MS(ESI)m/z:272.9[M+H]+。4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 5.3 mmol), 3,4-dihydropyran (889 mg, 10.6 mmol), and p-toluenesulfonic acid (86 mg, 0.5 mmol) were added to DCM (10 mL). Under N₂ protection, the reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound (1.4 g, 100% yield, as a white solid). LC-MS (ESI) m/z: 272.9 [M+H] + .

步骤2：4-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-3,3-二甲基吗啉的合成
Step 2: Synthesis of 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,3-dimethylmorpholine

将4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(500mg,1.8mmol)、3,3-二甲基吗啉(254mg,2.2mmol)、DIEA(475mg,3.7mmol)加入到NMP(10mL)中。所得反应混合物在N2保护下室温搅拌3hrs。向反应混合物中加入水(15mL)，用EA(20mL×3)萃取。合并有机相依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标化合物(501mg,收率77.4％,白色固体)。LC-MS(ESI)m/z:351.9[M+H]+。4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.8 mmol), 3,3-dimethylmorpholine (254 mg, 2.2 mmol), and DIEA (475 mg, 3.7 mmol) were added to NMP (10 mL). The resulting reaction mixture was stirred at room temperature for 3 hr under N₂ protection. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine ( 30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (501 mg, 77.4% yield, as a white solid). LC-MS (ESI) m/z: 351.9 [M+H] ⁺ .

步骤3：8-(4-(3,3-二甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将4-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-3,3-二甲基吗啉(250mg,1.7mmol)、3-氧代-8-氮杂双环[3.2.1]辛烷盐酸盐(128mg,0.9mmol)、DIEA(181mg,1.4mmol)依次加入到NMP(10mL)中。反应混合物在微波仪内170℃下反应5hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标化合物(248mg,收率82.7％,白色固体)。LC-MS(ESI)m/z:429.1[M+H]+。4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,3-dimethylmorpholine (250 mg, 1.7 mmol), 3-oxo-8-azabicyclo[3.2.1]octane hydrochloride (128 mg, 0.9 mmol), and DIEA (181 mg, 1.4 mmol) were added sequentially to NMP (10 mL). The reaction mixture was reacted in a microwave at 170°C for 5 hr. After cooling to room temperature, water (15 mL) was added to the reaction mixture, which was then extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to afford the title compound (248 mg, 82.7% yield, as a white solid). LC-MS(ESI)m/z:429.1[M+H] + .

步骤4：8-(4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(248mg,0.6mmol)加入到6M盐酸水溶液/THF(2mL/4mL)，室温搅拌0.5hrs。反应结束后，用饱和NaHCO3水溶液调pH>8，用EA(20mL×3)萃取，合并有机层，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝0:100)得到目标化合物(122mg,收率59.2％,白色固体)。8-(4-(3,3-Dimethylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (248 mg, 0.6 mmol) was added to a 6 M aqueous hydrochloric acid/THF solution (2 mL/4 mL) and stirred at room temperature for 0.5 hr. After completion of the reaction, the pH was adjusted to >8 with saturated aqueous NaHCO₃. The solution was extracted with EA (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 0:100) to afford the title compound (122 mg, 59.2% yield, as a white solid).

步骤5：8-(4-(3,3-二甲基吗啉)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-(3,3-dimethylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3,3-二甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(122mg,0.4mmol)、(1S,2S)-N1，N2-二甲基环己烷-1,2-二胺(99mg,0.7mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(147mg,0.5mmol)，CuI(67mg,0.4mmol)和Cs2CO3(285mg,0.9mmol)依次加入到NMP(10mL)中。反应混合物在120℃油浴下搅拌过夜，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标化合物(88mg,收率50.9％,白色固体)。LC-MS(ESI)m/z:495.0[M+H]+。8-(4-(3,3-Dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (122 mg, 0.4 mmol), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (99 mg, 0.7 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (147 mg, 0.5 mmol), CuI (67 mg, 0.4 mmol) and Cs 2 CO 3 (285 mg, 0.9 mmol) were added sequentially to NMP (10 mL). The reaction mixture was stirred overnight in an oil bath at 120°C, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (88 mg, 50.9% yield, as a white solid). LC-MS (ESI) m/z: 495.0 [M+H] + .

步骤6：8-(4-(3,3-二甲基吗啉)-1-(1H-吡唑基-3-基)-1H-吡唑基[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(3,3-dimethylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(8-(4-(3,3-二甲基吗啉)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(88mg,0.2mmol)加入到6M盐酸水溶液/THF(2mL/4mL)，50℃搅拌1hr。冷却至室温，用饱和NaHCO3水溶液调pH>8，用EA(20mL×3)萃取，合并有机层，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM/MeOH＝30/1)得到目标化合物(57mg,收率69.2％,白色固体)。LC-MS(ESI)m/z:412.07[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.17(s,1H),7.81(s,1H),6.73(d,J＝2.3Hz,1H),4.68–4.51(m,2H),3.96–3.88(m,2H),3.86–3.78(m,2H),3.70–3.57(m,4H),3.50(s,2H),2.07–1.81(m,5H),1.51(s,6H).(8-(4-(3,3-dimethylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (88 mg, 0.2 mmol) was added to 6 M aqueous hydrochloric acid solution/THF (2 mL/4 mL) and stirred at 50 °C for 1 hr. The mixture was cooled to room temperature and adjusted to pH>8 with saturated aqueous NaHCO 3 solution. The mixture was extracted with EA (20 mL×3). The organic layers were combined, washed with saturated brine (30 mL), and anhydrous Na 2 SO The product was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 30/1) to obtain the title compound (57 mg, 69.2% yield, white solid). LC-MS (ESI) m/z: 412.07 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 4.68–4.51 (m, 2H), 3.96–3.88 (m, 2H), 3.86–3.78 (m, 2H), 3.70–3.57 (m, 4H), 3.50 (s, 2H), 2.07–1.81 (m, 5H), 1.51 (s, 6H).

实施例31：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-腈
Example 31: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine-3-carbonitrile

步骤1：((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇的合成
Step 1: Synthesis of ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

将((R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(500mg,1.06mmol)加入到NMP(10mL)中，再加入(1-(四氢-2H-吡喃-2-基)-1H-吡嗪-3-基)硼酸(624mg,3.18mmol)，吡啶(252mg,3.18mmol)和醋酸铜(424mg,2.12mmol)。在N2保护下，反应混合物在50℃下搅拌18hrs，冷却至室温。向反应混合物中加入水，用EA(50mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，减压浓缩。残余物用硅胶柱层析分离纯化，(PE：EA，60％ EA)得到目标化合物(550mg,收率83.4％，白色固体)。LC-MS(ESI)m/z:622.2[M+H]+。((R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (500 mg, 1.06 mmol) was added to NMP (10 mL), followed by (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazin-3-yl)boronic acid (624 mg, 3.18 mmol), pyridine (252 mg, 3.18 mmol), and copper acetate (424 mg, 2.12 mmol). Under N₂ protection, the reaction mixture was stirred at 50°C for 18 hours and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with EA (50 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (550 mg, yield 83.4%, white solid). LC-MS (ESI) m/z: 622.2 [M+H] + .

步骤2：8-(4-((S)-3-(氟甲基)吗啉基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((S)-3-(fluoromethyl)morpholinyl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(200mg,0.32mmol)加入到DCM(5mL)中，在N2保护中，在0℃下缓慢加入DAST(0.085mL，0.64mmol)，反应混合物在室温下反应1小时。向反应混合物中加入水，用DCM(5mL×2)萃取，减压浓缩有机相，得到目标化合物(30mg,收率14.9％，灰白色固体物)。LC-MS(ESI)m/z:624.2[M+H]+。((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (200 mg, 0.32 mmol) was added to DCM (5 mL). Under nitrogen protection, DAST (0.085 mL, 0.64 mmol) was slowly added at 0°C. The reaction mixture was allowed to react at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with DCM (5 mL x 2). The organic phase was concentrated under reduced pressure to obtain the title compound (30 mg, 14.9% yield, as an off-white solid). LC-MS (ESI) m/z: 624.2 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(fluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(4-((S)-3-(氟甲基)吗啉基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷30mg,0.048mmol)溶于DMA(2mL)中，向溶液中加入Zn(0)(9mg,0.14mmol)、Zn(CN)2(17mg,0.14mmol)、Pd(dppf)Cl2(7mg,0.01mmol)和Pd2(dba)3(5mg,0.005mmol)，反应混合物在N2保护下在150℃下搅拌1hrs，冷却至室温。向反应混合物中加入水，用EA(5mL×2)萃取，合并有机相用饱和食盐水(5mL)洗涤，干燥，过滤，滤液减压浓缩得到目标化合物(20mg,收率79.5％，黄色固体)。LC-MS(ESI)m/z:523.2[M+H]+。8-(4-((S)-3-(Fluoromethyl)morpholinyl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.048 mmol) was dissolved in DMA (2 mL). Zn(0) (9 mg, 0.14 mmol), Zn(CN) 2 (17 mg, 0.14 mmol), Pd(dppf)Cl 2 (7 mg, 0.01 mmol) and Pd 2 (dba) 3 (5 mg, 0.005 mmol) were added to the solution. The reaction mixture was stirred at 150° C. for 1 hrs under N 2 protection and cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted with EA (5 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (20 mg, yield 79.5%, yellow solid). LC-MS (ESI) m/z: 523.2 [M+H] + .

步骤4：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 4: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(20mg,0.038mmol)加入到THF(1mL)中,然后加入4N盐酸/1,4-二氧六环溶液(1mL)。反应液在50℃下搅拌16hrs，冷却至室温。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:30-60,流速：20mL/min，20min)分离纯化，得到目标化合物6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(6.0mg,类白色固体)。LC-MS(ESI)m/z:439.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.77(s,1H),6.97(d,J＝2.3Hz,1H),6.22(s,1H),4.81–4.65(m,2H),4.64-4.59(m,2H),4.35–4.25(m,1H),4.16–4.08(m,1H),4.07–3.94(m,2H),3.86–3.76(m,3H),3.71–3.59(m,3H),3.15(d,J＝12.5Hz,1H),2.16–1.98(m,4H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(fluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (20 mg, 0.038 mmol) was added to THF (1 mL), followed by a 4N hydrochloric acid/1,4-dioxane solution (1 mL). The reaction mixture was stirred at 50°C for 16 hours and then cooled to room temperature. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 30-60, flow rate: 20 mL/min, 20 min) to obtain the target compound, 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(fluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (6.0 mg, off-white solid). LC-MS (ESI) m/z: 439.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.77(s,1H),6.97(d,J＝2.3Hz,1H),6.22(s,1H),4.81–4.65(m,2H),4.64-4.59(m,2H),4.35–4.25(m,1H),4.16 –4.08(m,1H),4.07–3.94(m,2H),3.86–3.76(m,3H),3.71–3.59(m,3H),3.15(d,J=12.5Hz,1H),2.16–1.98(m,4H).

实施例32：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)乙烷-1-酮
Example 32: 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)ethan-1-one

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙烷-1-酮(45mg,0.09mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物在N2保护下25℃搅拌16hrs。减压浓缩，残余物经反相硅胶柱层析分离纯化(H2O：ACN，40％ACN)，得到目标化合物(10mg,收率26.5％，白色固体)。LC-MS(ESI)m/z:438.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),7.87(s,1H),6.83(d,J＝2.3Hz,1H),6.08(s,1H),4.59–4.50(m,2H),3.99–3.86(m,2H),3.73–3.61(m,4H),3.59–3.47(m,3H),3.31(s,1H),2.99–2.90(m,1H),2.64(s,3H),2.02–1.84(m,4H),0.92(d,J＝6.6Hz,3H)。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethan-1-one (45 mg, 0.09 mmol) was dissolved in THF (2 mL). 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 25°C under nitrogen for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography ( H₂O :ACN, 40% ACN) to obtain the title compound (10 mg, 26.5% yield, as a white solid). LC-MS (ESI) m/z: 438.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.98(s,1H),7.87(s,1H),6.83(d,J＝2.3Hz,1H),6.08(s,1H),4.59–4.50(m,2H),3.99–3.86(m,2H),3.73–3.61 (m,4H),3.59–3.47(m,3H),3.31(s,1H),2.99–2.90(m,1H),2.64(s,3H),2.02–1.84(m,4H),0.92(d,J＝6.6Hz,3H).

实施例33：((3S)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(1,1,1-三氟丙烷-2-基)-1H-吡唑 并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇
Example 33: ((3S)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo [3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

参考实施列15的合成方法合成目标化合物(10mg,白色固体)。LC-MS(ESI)m/z:508.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),9.40(s,1H),9.17(s,1H),7.82(d,J＝2.2Hz,1H),6.74(d,J＝2.3Hz,1H),6.31(s,1H),4.63(s,2H),4.55–4.33(m,3H),4.20–4.06(m,1H),4.02–3.90(m,1H),3.86–3.79(m,1H),3.78–3.65(m,5H),3.63–3.56(m,4H),3.29–3.22(m,1H),2.04–1.87(m,4H),1.62–1.54(m,3H)。The target compound (10 mg, white solid) was synthesized by referring to the synthesis method of Example 15. LC-MS (ESI) m/z: 508.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.79(s,1H),9.40(s,1H),9.17(s,1H),7.82(d,J=2.2Hz,1H),6.74( d,J＝2.3Hz,1H),6.31(s,1H),4.63(s,2H),4.55–4.33(m,3H),4.20–4.0 6(m,1H),4.02–3.90(m,1H),3.86–3.79(m,1H),3.78–3.65(m,5H),3.63 –3.56(m,4H),3.29–3.22(m,1H),2.04–1.87(m,4H),1.62–1.54(m,3H).

实施例34：8-(3-(2-氟丙烷-2-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂 -8-氮杂双环[3.2.1]辛烷
Example 34: 8-(3-(2-fluoropropan-2-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa- 8-azabicyclo[3.2.1]octane

步骤1：8-(3-(2-氟丙烷-2-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-(2-fluoropropan-2-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)丙-2-醇(110mg,0.21mmol)溶于DCM(5mL)中，0℃下，加入DAST(66.0mg,0.41mmol)，反应混合物在N2保护下0℃下搅拌30mins后，在室温下反应6hrs。将反应混合物中倒入饱和NaHCO3溶液(10mL)中淬灭反应，用EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品直接进行下一步反应。(80mg,收率72.5％，淡黄色油状物)。LC-MS(ESI)m/z:540.2[M+H]+。2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)propan-2-ol (110 mg, 0.21 mmol) was dissolved in DCM (5 mL). DAST (66.0 mg, 0.41 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes under N₂ protection and then allowed to react at room temperature for 6 hours. The reaction mixture was poured into saturated NaHCO₃ solution (10 mL) to quench the reaction. The mixture was extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (80 mg, 72.5% yield, pale yellow oil), which was directly used in the next reaction. LC-MS(ESI)m/z:540.2[M+H] + .

步骤2：8-(3-(2-氟丙烷-2-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-(2-fluoropropan-2-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-(2-氟丙烷-2-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.06mmol)溶于THF(3mL)中，然后加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物中在N2保护下在室温下反应6hrs。将反应混合物中倒入饱和NaHCO3溶液(10mL)中，用EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物通过Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：ACN，梯度：35-65％B,流速:20mL/min,18min)分离纯化，得到目标化合物(5.0mg,收率20.3％，白色固体)。LC-MS(ESI)m/z:456.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),7.83(s,1H),6.73(s,1H),6.52(s,1H),4.60(d,J＝14.2Hz,2H),3.89(dd,J＝11.0,2.7Hz,1H),3.77–3.54(m,7H),3.41–3.37(m,1H),2.69–2.60(m,1H),2.54–2.52(m,1H),2.09–1.93(m,6H),1.93–1.85(m,4H),0.89(d,J＝6.1Hz,3H)。8-(3-(2-Fluoropropan-2-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.06 mmol) was dissolved in THF (3 mL), and then 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added, and the reaction mixture was reacted at room temperature under N protection for 6 hrs. The reaction mixture was poured into saturated NaHCO₃ solution (10 mL) and extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/ H₂O ; mobile phase B: ACN, gradient: 35-65% B, flow rate: 20 mL/min, 18 min) to obtain the title compound (5.0 mg, yield 20.3%), as a white solid. LC-MS (ESI) m/z: 456.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ12.83(s,1H),7.83(s,1H),6.73(s,1H),6.52(s,1H),4.60(d,J＝14.2Hz,2H),3.89(dd,J＝11.0,2.7Hz,1H),3.77–3.54(m ,7H),3.41–3.37(m,1H),2.69–2.60(m,1H),2.54–2.52(m,1H),2.09–1.93(m,6H),1.93–1.85(m,4H),0.89(d,J＝6.1Hz,3H).

实施例35：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)-2,2,2-三氟乙烷-1-醇
Example 35: 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)-2,2,2-trifluoroethane-1-ol

步骤1：6-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲醛的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(2.00g,3.30mmol)溶于无水DMF(150mL)中，然后依次加入甲酸钠(898mg,13.21mmol)、Pd(dppf)Cl2(121mg,0.17mmol)。反应混合物在高压釜中80℃，15atm CO下搅拌16hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(150mL×2)萃取，合并有机相，用饱和食盐水(500mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物用硅胶柱层析纯化(DCM:MeOH，10％MeOH)得到目标化合物(1.40g,收率83.5％，棕色固体)。LC-MS(ESI)m/z:508.3[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.00 g, 3.30 mmol) was dissolved in anhydrous DMF (150 mL). Sodium formate (898 mg, 13.21 mmol) and Pd(dppf) Cl₂ (121 mg, 0.17 mmol) were then added sequentially. The reaction mixture was stirred in an autoclave at 80°C under 15 atm CO₂ for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (150 mL x 2). The combined organic phases were washed with saturated brine (500 mL x 5), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (1.40 g, yield 83.5%, brown solid). LC-MS (ESI) m/z: 508.3 [M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol

在N2保护下，将6-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲醛(100mg,0.11mmol)溶于THF(20mL)中，缓慢滴加三甲基三氟甲基硅烷(165mg,1.16mmol)，然后在25℃下搅拌10mims，然后再缓慢滴加TBAF，并在25℃下搅拌30mins，然后向反应液中加入6N盐酸(1mL),反应混合物N2保护下25℃再搅拌5hrs。减压浓缩，残余物用硅胶柱层析纯化(100％EA)，得到目标化合物(45mg,收率39.3％，白色固体)。LC-MS(ESI)m/z:494.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),7.84(s,1H),7.58,7.27(d,J＝8.1Hz,1H),6.76(s,1H),6.66,6.61(s,1H),5.81–5.72,5.60–5.49(m,1H),4.61(s,2H),3.94–3.80(m,2H),3.77–3.64(m,3H),3.57(d,J＝10.7Hz,2H),3.37-3.35(d,J＝10.7,6.6Hz,1H),3.31–3.29(m,2H),2.93–2.83(m,1H),2.00–1.87(m,4H),0.88,0.86(dd,J＝6.3Hz,3H)。Under N₂ protection, 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (100 mg, 0.11 mmol) was dissolved in THF (20 mL). Trimethyltrifluoromethylsilane (165 mg, 1.16 mmol) was slowly added dropwise, and the mixture was stirred at 25°C for 10 min. TBAF was then slowly added dropwise and stirred at 25°C for 30 min. 6N hydrochloric acid (1 mL) was then added to the reaction solution, and the reaction mixture was stirred at 25°C for an additional 5 hrs under N₂ protection. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% EA) to obtain the title compound (45 mg, 39.3% yield, as a white solid). LC-MS(ESI)m/z:494.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.87(s,1H),7.84(s,1H),7.58,7.27(d,J＝8.1Hz,1H),6.76(s,1H),6.66,6 .61(s,1H),5.81–5.72,5.60–5.49(m,1H),4.61(s,2H),3.94–3.80(m,2H),3.77 –3.64(m,3H),3.57(d,J＝10.7Hz,2H),3.37-3.35(d,J＝10.7,6.6Hz,1H),3.31–3 .29(m,2H),2.93–2.83(m,1H),2.00–1.87(m,4H),0.88,0.86(dd,J＝6.3Hz,3H).

实施例36和实施例37：(S)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-Example 36 and Example 37: (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazole-3-yl)- 基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇和(R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-(R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3- 甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol

步骤1：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇的合成
Step 1: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol

在N2氛围下，将6-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲醛(1.40g,2.76mmol)溶于THF(100mL)中，缓慢滴加三甲基三氟甲基硅烷(7.84g,55.16mmol)，在25℃下搅拌10mins，然后缓慢滴加TBAF(4mL)，并在25℃下搅拌30mins，然后向反应液中加入饱和NH4Cl(10mL)溶液，所得反应混合物N2保护下25℃下再搅拌5hrs。反应液中加入水(200mL)，用EA(150mL×2)萃取。合并有机相用饱和食盐水(200mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物用硅胶柱层析分离纯化(DCM:MeOH，10％MeOH)得到目标化合物(1.32g,收率82.9％，棕色固体)。LC-MS(ESI)m/z:578.2[M+H]+。Under an N₂ atmosphere, 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (1.40 g, 2.76 mmol) was dissolved in THF (100 mL). Trimethyltrifluoromethylsilane (7.84 g, 55.16 mmol) was slowly added dropwise. The mixture was stirred at 25°C for 10 min, followed by the slow addition of TBAF (4 mL). The mixture was stirred at 25°C for 30 min, and then a saturated NH₄Cl solution (10 mL) was added to the reaction mixture. The resulting reaction mixture was stirred at 25°C for an additional 5 hr under N₂ protection. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (150 mL x 2). The combined organic phases were washed with saturated brine (200 mL x 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (1.32 g, 82.9% yield, brown solid). LC-MS (ESI) m/z: 578.2 [M+H] + .

步骤2：(S)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇和(R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇的合成
Step 2: Synthesis of (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol and (R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(100mg,0.17mmol)溶于THF(6mL)中，加入4N盐酸/1,4二氧六环溶液(2mL)。反应混合物在50℃下搅拌3hrs。减压浓缩，残余物加入饱和NaHCO3溶液，EA萃取，合并有机相，减压浓缩后，残余物先经硅胶柱层析(PE：EA，0％～100％EA)分离纯化，得到粗品，再经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um；流动相A:0.1％FA/H2O；流动相B：ACN，梯度：25-65％B,流速：20mL/min，16min)分离纯化，最后手经性拆分SFC(column:Daicel Chiralpak IC,40mm I.D*250mm,10um:Supercritical CO2，B％:40,溶剂：乙醇，流速：120mL/min，7.5min)，得到目标化合物P1(31.53mg,收率36.9％，白色固体)。LC-MS(ESI)m/z:494.2[M+H]+。SFC(方法C)：RT＝2.939min。1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),7.84(s,1H),7.59(d,J＝7.2Hz,1H),6.76(d,J＝1.9Hz,1H),6.61(s,1H),5.60–5.52(m,1H),4.66–4.58(m,2H),3.93–3.87(m,1H),3.86–3.73(m,2H),3.73–3.62(m,3H),3.57(d,J＝10.8Hz,2H),3.41–3.37(m,1H),3.27(d,J＝12.8Hz,1H),2.91-2.84(m,1H),2.02–1.89(m,4H),0.86(d,J＝6.2Hz,3H)和目标化合物P2(5.91mg,收率6.9％，白色固体)。LC-MS(ESI)m/z:494.2[M+H]+.SFC(方法C)：RT＝3.420min。1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),7.83(s,1H),7.28(d,J＝6.9Hz,1H),6.75(d,J＝2.2Hz,1H),6.66(s,1H),5.82–5.75(m,1H),4.61(s,2H),3.93–3.83(m,2H),3.71–3.64(m,3H),3.57(d,J＝10.9Hz,2H),3.53–3.47(m,1H),3.42–3.39(m,1H),3.11(d,J＝11.5Hz,1H),2.94–2.88(m,1H),2.00–1.90(m,4H),0.88(d,J＝6.2Hz,3H)。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (100 mg, 0.17 mmol) was dissolved in THF (6 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 50° C. for 3 hrs. The product was concentrated under reduced pressure, and the residue was added with saturated NaHCO₃ solution, extracted with EA. The organic phases were combined and concentrated under reduced pressure. The residue was first separated and purified by silica gel column chromatography (PE:EA, 0%-100% EA) to obtain a crude product, which was then separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA/ H₂O ; mobile phase B: ACN, gradient: 25-65% B, flow rate: 20 mL/min, 16 min). Finally, chiral separation by SFC (column: Daicel Chiralpak IC, 40mm ID*250mm, 10um: Supercritical CO₂ , B%: 40, solvent: ethanol, flow rate: 120 mL/min, 7.5 min) to obtain the target compound P1 (31.53 mg, yield 36.9%, white solid). LC-MS(ESI)m/z:494.2[M+H] + . SFC (Method C): RT=2.939min. 1 H NMR (400MHz, DMSO-d 6 )δ12.88(s,1H),7.84(s,1H),7.59(d,J＝7.2Hz,1H),6.76(d,J＝1.9Hz,1H),6.61(s,1H ),5.60–5.52(m,1H),4.66–4.58(m,2H),3.93–3.87(m,1H),3.86–3.73(m,2H),3.73–3 .62 (m, 3H), 3.57 (d, J = 10.8 Hz, 2H), 3.41–3.37 (m, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.91–2.84 (m, 1H), 2.02–1.89 (m, 4H), 0.86 (d, J = 6.2 Hz, 3H) and the target compound P2 (5.91 mg, yield 6.9%, white solid). LC-MS (ESI) m/z: 494.2 [M+H] + . SFC (Method C): RT = 3.420 min. 1 H NMR (400 MHz, DMSO-d 6 )δ12.87(s,1H),7.83(s,1H),7.28(d,J＝6.9Hz,1H),6.75(d,J＝2.2Hz,1H),6 .66(s,1H),5.82–5.75(m,1H),4.61(s,2H),3.93–3.83(m,2H),3.71–3.64(m ,3H),3.57(d,J＝10.9Hz,2H),3.53–3.47(m,1H),3.42–3.39(m,1H),3.11(d, J＝11.5Hz,1H),2.94–2.88(m,1H),2.00–1.90(m,4H),0.88(d,J＝6.2Hz,3H).

实施例38：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(2,2,2-三氟-1-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-6- 基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 38: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(2,2,2-三氟-1-甲氧基乙基)-1H-吡喃并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrano[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(50mg,0.09mmol)溶于无水DMF(5mL)中，0℃下，加入NaH(3.1mg,0.13mmol)加，N2保护下，搅拌0.5小时后，加入CH3I(36.8mg,0.26mmol)，反应混合物在25℃下反应3hrs。向反应混合物中缓慢加入饱和NH4Cl水溶液(10mL)淬灭反应，用EA(20mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(50mg,粗品，淡黄色油状物)，直接用于下一步反应。LC-MS(ESI)m/z:592.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (50 mg, 0.09 mmol) was dissolved in anhydrous DMF (5 mL). NaH (3.1 mg, 0.13 mmol) was added at 0°C. Under N2 protection, the mixture was stirred for 0.5 hour, and then CH3I (36.8 mg, 0.26 mmol) was added. The reaction mixture was reacted at 25°C for 3 hrs. Saturated aqueous NH 4 Cl solution (10 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was extracted with EA (20 mL × 2). The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (50 mg, crude product, light yellow oil), which was used directly in the next reaction. LC-MS (ESI) m/z: 592.2 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(2,2,2-三氟-1-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(2,2,2-三氟-1-甲氧基乙基)-1H-吡喃并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.08mmol)溶于THF(3mL)中，然后加入4N盐酸/1,4-二氧六环(1mL)溶液，反应混合物在N2保护下在50℃下反应6hrs。减压浓缩，向残余物中加入饱和NaHCO3溶液至碱性后加入EA(5mL)和水(5mL)，EA萃取三次，有机相用无水Na2SO4干燥，过滤，滤液减压浓缩，残余物通过反相prep-HPLC(柱：Xtimate C18 5um OBD 21.2*250mm；流动相A：0.1％FA/水，流动相B：ACN；梯度：36-66％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(5.0mg,收率11.7％，白色固体)。LC-MS(ESI)m/z:508.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),7.83(s,1H),6.76(d,J＝2.2Hz,1H),6.60(s,1H),5.61–5.52(m,1H),4.61(d,J＝10.1Hz,2H),3.94–3.81(m,2H),3.81–3.72(m,1H),3.72–3.61(m,2H),3.56(d,J＝10.8Hz,2H),3.53–3.49(m,1H),3.47,3.41(s,3H),3.38–3.35(m,1H),3.24–3.16(m,1H),2.88–2.77(m,1H),2.02–1.86(m,4H),0.84(d,J＝6.1Hz,3H).8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrano[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.08 mmol) was dissolved in THF (3 mL), and then 4N hydrochloric acid/1,4-dioxane (1 mL) solution was added, and the reaction mixture was reacted at 50 ° C under N 2 protection for 6 hrs. The residue was concentrated under reduced pressure, and saturated NaHCO₃ solution was added to the residue until alkaline. EA (5 mL) and water (5 mL) were then added, and the mixture was extracted three times with EA. The organic phase was dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by reverse-phase prep-HPLC (column: Xtimate C18 5um OBD 21.2*250mm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 36-66% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (5.0 mg, yield: 11.7%), as a white solid. LC-MS (ESI) m/z: 508.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d⁶ ) )δ12.88(s,1H),7.83(s,1H),6.76(d,J＝2.2Hz,1H),6.60(s,1H),5.61–5.52(m,1 H),4.61(d,J＝10.1Hz,2H),3.94–3.81(m,2H),3.81–3.72(m,1H),3.72–3.61(m,2H ),3.56(d,J＝10.8Hz,2H),3.53–3.49(m,1H),3.47,3.41(s,3H),3.38–3.35(m,1H ),3.24–3.16(m,1H),2.88–2.77(m,1H),2.02–1.86(m,4H),0.84(d,J＝6.1Hz,3H).

实施例39和实施例40：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((S)-2,2,2-三氟-1-甲氧基乙基)-1H-吡唑 并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((R,2,2,2- 三氟-1-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 39 and Example 40: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((R,2,2,2- trifluoro-1-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(2,2,2-三氟-1-甲氧基乙基)-1H-吡喃并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.14mmol)溶于THF(6mL)中，加入4N盐酸/1,4-二氧六环(3mL)，反应混合物在N2保护下在50℃下反应12hrs。反应结束后，减压浓缩，向残余物中加入饱和NaHCO3溶液至碱性，用EA(5mL)和水(5mL)混合物萃取三次，合并有机相，用无水Na2SO4干燥，过滤，滤液减压浓缩，残余物通过反相硅胶柱层析分离纯化后，经SFC拆分(column:Daicel Chiralpak IC,40mm I.D*250mm,10um:Supercritical CO2；流动相B:MeOH，B％:50,流速：140mL/min，8min)，得到目标化合物P1(10mg,白色固体)。LC-MS(ESI)m/z:508.2[M+H]+。SFC(方法D)RT＝2.328min。1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.85(s,1H),6.77(s,1H),6.62(s,1H),5.59(q,J＝6.8Hz,1H),4.62(d,J＝12.9Hz,2H),3.94–3.76(m,3H),3.72–3.63(m,2H),3.60–3.51(m,3H),3.49–3.45(m,3H),3.39–3.35(m,1H),3.22(d,J＝12.3Hz,1H),2.89–2.79(m,1H),2.00–1.90(m,4H),0.85(d,J＝6.1Hz,3H).和P2(2mg,白色固体),LC-MS(ESI)m/z:508.2[M+H]+。SFC(方法D)RT＝3.456min。1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.85(s,1H),6.77(s,1H),6.64(s,1H),5.73–5.62(m,1H),4.63(s,2H),3.95–3.82(m,2H),3.78–3.63(m,3H),3.57(d,J＝10.9Hz,2H),3.53–3.47(m,1H),3.41(s,3H),3.08(d,J＝11.6Hz,1H),2.87–2.78(m,1H),2.03–1.90(m,5H),0.88(d,J＝6.0Hz,3H).8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrano[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.14 mmol) was dissolved in THF (6 mL), 4N hydrochloric acid/1,4-dioxane (3 mL) was added, and the reaction mixture was reacted at 50 ° C under N 2 protection for 12 hrs. After completion of the reaction, the product was concentrated under reduced pressure. Saturated NaHCO₃ solution was added to the residue until alkaline, and the product was extracted three times with a mixture of EA (5 mL) and water (5 mL). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography and separated by SFC (column: Daicel Chiralpak IC, 40 mm ID*250 mm, 10 μm: Supercritical CO₂; mobile phase B: MeOH, B%: 50, flow rate: 140 mL/min, 8 min) to obtain the target compound P1 (10 mg, white solid). LC-MS (ESI) m/z: 508.2 [M+H] ⁺ . SFC (Method D) RT = 2.328 min. 1H NMR (400 MHz, DMSO-d⁶ ) )δ12.90(s,1H),7.85(s,1H),6.77(s,1H),6.62(s,1H),5.59(q,J＝6.8Hz,1H),4. 62(d,J＝12.9Hz,2H),3.94–3.76(m,3H),3.72–3.63(m,2H),3.60–3.51(m,3H),3.4 9–3.45 (m, 3H), 3.39–3.35 (m, 1H), 3.22 (d, J=12.3 Hz, 1H), 2.89–2.79 (m, 1H), 2.00–1.90 (m, 4H), 0.85 (d, J=6.1 Hz, 3H). and P2 (2 mg, white solid), LC-MS (ESI) m/z: 508.2 [M+H] + . SFC (Method D) RT=3.456 min. 1 H NMR (400MHz, DMSO-d 6 )δ12.90(s,1H),7.85(s,1H),6.77(s,1H),6.64(s,1H),5.73–5.62(m,1H),4.63(s,2H),3.95–3.82(m,2H),3.78–3.63(m,3H),3.57(d ,J＝10.9Hz,2H),3.53–3.47(m,1H),3.41(s,3H),3.08(d,J＝11.6Hz,1H),2.87–2.78(m,1H),2.03–1.90(m,5H),0.88(d,J＝6.0Hz,3H).

实施例41：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(1,2,2,2-四氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3- 氧杂-8-氮杂双环[3.2.1]辛烷
Example 41: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,2,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3- oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((R)-3-甲基吗啉基)-3-(1,2,2,2-四氟乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(1,2,2,2-tetrafluoroethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在0℃下，在N2气氛中向1-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-[(3R)-3-甲基吗啉基-4-基]-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]吡唑并[3，4-b]吡啶-3-基]-2，2，2-三氟乙烷-1-醇(50mg,0.087mmol)的DCM(0.5mL)溶液中缓慢加入DAST(0.023mL，0.17mmol)，反应混合物在室温下搅拌1hrs。用水淬灭反应,用DCM(10mL×3)萃取，合并有机相，干燥，过滤，减压浓缩得到目标化合物(50mg,收率99.7％，黄色固体)。LC-MS(ESI)m/z:580.2[M+H]+。To a solution of 1-[6-(8 - aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridin-3-yl]-2,2,2-trifluoroethane-1-ol (50 mg, 0.087 mmol) in DCM (0.5 mL) was slowly added DAST (0.023 mL, 0.17 mmol) at 0°C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hr. The reaction was quenched with water and extracted with DCM (10 mL x 3). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to afford the title compound (50 mg, 99.7% yield, as a yellow solid). LC-MS(ESI)m/z:580.2[M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(1,2,2,2-四氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,2,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-3-甲基吗啉基)-3-(1,2,2,2-四氟乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.086mmol)的THF(1mL)溶液中加入TFA(1mL)。反应混合物在50℃下搅拌24hrs。将反应混合物减压浓缩。残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：CAN，梯度：B％:38-68,流速：20mL/min，20min)分离纯化，得到目标化合物(10.0mg,收率23.4％，类白色固体)。LC-MS(ESI)m/z:496.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.75(d,J＝2.4Hz,1H),6.89(d,J＝2.4Hz,1H),6.53(1,1H),6.66–6.45(m,1H),4.70–4.55(m,2H),4.00–3.91(m,1H),3.91–3.85(m,2H),3.85–3.76(m,2H),3.63(d,J＝10.8Hz,2H),3.60–3.44(m,2H),3.43–3.34(m,1H),2.93–2.79(m,1H),2.18–1.97(m,4H),0.99(d,J＝5.9Hz,3H)。To a solution of 8-(4-((R)-3-methylmorpholinyl)-3-(1,2,2,2-tetrafluoroethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.086 mmol) in THF (1 mL) was added TFA (1 mL). The reaction mixture was stirred at 50° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA/ H2O ; mobile phase B: ACN, gradient: B%: 38-68, flow rate: 20 mL/min, 20 min) to obtain the title compound (10.0 mg, yield 23.4%, off-white solid). LC-MS (ESI) m/z: 496.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.75(d,J＝2.4Hz,1H),6.89(d,J＝2.4Hz,1H),6.53(1,1H),6.66–6.45(m,1H),4.70–4.55(m,2H),4.00–3.91(m,1H),3.91–3.85(m,2H),3. 85–3.76(m,2H),3.63(d,J＝10.8Hz,2H),3.60–3.44(m,2H),3.43–3.34(m,1H),2.93–2.79(m,1H),2.18–1.97(m,4H),0.99(d,J＝5.9Hz,3H).

实施例42和实施例43：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-((S)-1,2,2-四氟乙基)-1H-吡唑并[3,4-b] 吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-(((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(R)-1,2,2-四氟乙 基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 42 and Example 43: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-((S)-1,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6 -yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-(((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(R)-1,2,2- tetrafluoroethyl )-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(1,2,2,2-四氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷消旋体(45mg,0.091mmol)经SFC(column:Daicel Chiralpak IC,40mm I.D*250mm,10um:流动相A:Supercritical CO2；流动相B:MeOH，B％:25,流速：140mL/min，16min)分离纯化，得到目标化合物P1(27mg,收率60.0％，白色固体)。LC-MS(ESI)m/z:496.2[M+H]+。SFC(方法D)：RT＝2.156min。1H NMR(400MHz,Methanol-d4)δ7.76(s,1H),6.89(d,J＝2.4Hz,1H),6.63–6.45(m,2H),4.67–4.60(m,2H),3.98–3.93(m,1H),3.90–3.78(m,4H),3.63(d,J＝10.9Hz,2H),3.60–3.47(m,2H),3.42–3.35(m,1H),2.91–2.81(m,1H),2.14–2.00(m,4H),0.99(d,J＝6.0Hz,3H)和目标化合物P2(6mg,收率13.3％，白色固体)。LC-MS(ESI)m/z:496.2[M+H]+.SFC(方法D)：RT＝2.578min。1H NMR(400MHz,Methanol-d4)δ7.77(d,J＝2.2Hz,1H),6.92(d,J＝2.3Hz,1H),6.70–6.49(m,2H),4.68–4.59(m,2H),3.96–3.77(m,5H),3.64(d,J＝10.9Hz,2H),3.51–3.42(m,2H),3.20(d,J＝12.4Hz,1H),2.94–2.85(m,1H),2.17–1.99(m,4H),0.96(d,J＝5.7Hz,3H)。The racemate of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(1,2,2,2-tetrafluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (45 mg, 0.091 mmol) was separated and purified by SFC (column: Daicel Chiralpak IC, 40 mm ID*250 mm, 10 μm; mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH, B%: 25, flow rate: 140 mL/min, 16 min) to afford the title compound P1 (27 mg, 60.0% yield, white solid). LC-MS (ESI) m/z: 496.2 [M+H] + . SFC (Method D): RT = 2.156 min. 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.76 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.63–6.45 (m, 2H), 4.67–4.60 (m, 2H), 3.98–3.93 (m, 1H), 3.90–3.78 (m, 4H), 3.63 (d, J = 10.9 Hz, 2H), 3.60–3.47 (m, 2H), 3.42–3.35 (m, 1H), 2.91–2.81 (m, 1H), 2.14–2.00 (m, 4H), 0.99 (d, J = 6.0 Hz, 3H) and the target compound P2 (6 mg, yield 13.3%), white solid. LC-MS (ESI) m/z: 496.2 [M+H] + .SFC (Method D): RT = 2.578 min. 1 H NMR (400MHz, Methanol-d 4 )δ7.77(d,J＝2.2Hz,1H),6.92(d,J＝2.3Hz,1H),6.70–6.49(m,2H),4.68–4.59(m,2H),3.96–3.77(m,5H),3.64(d,J＝ 10.9Hz,2H),3.51–3.42(m,2H),3.20(d,J＝12.4Hz,1H),2.94–2.85(m,1H),2.17–1.99(m,4H),0.96(d,J＝5.7Hz,3H).

实施例44：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧 杂-8-氮杂双环[3.2.1]辛烷
Example 44: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa- 8-azabicyclo[3.2.1]octane

步骤1：8-(3-(1-氯-2,2,2-三氟乙基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-(1-chloro-2,2,2-trifluoroethyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(200mg,0.35mmol)溶于DCM(5mL)中，在25℃下加入SOCl2(1mL)。反应混合物在50℃下搅拌16hrs，冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％ MeOH)，得到目标化合物(100mg,56.5％，黄色固体)。LC-MS(ESI)m/z:512.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (200 mg, 0.35 mmol) was dissolved in DCM (5 mL), and SOCl₂ (1 mL) was added at 25°C. The reaction mixture was stirred at 50°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to give the title compound (100 mg, 56.5%, yellow solid). LC-MS (ESI) m/z: 512.2 [M+H] ⁺ .

步骤2：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-3-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-3-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-(1-氯-2,2,2-三氟乙基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.20mmol)溶于MeOH(4mL)，再加入10％ Pd/C(21mg,0.20mmol)，用H2置换三次，在H2氛围下25℃搅拌16hrs。反应混合物用硅藻土过滤，滤液减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um；流动相A：0.1％FA/H2O；流动相B：ACN，梯度：35-65％B,流速:20mL/min,20min)分离纯化，得到目标化合物(5.0mg,收率5.4％，白色固体)。LC-MS(ESI)m/z:478.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),7.81(s,1H),6.75(d,J＝2.2Hz,1H),6.45(s,1H),4.65–4.54(m,2H),4.12–3.84(m,3H),3.78–3.64(m,5H),3.59–3.55(m,3H),3.27–3.22(m,1H),2.84–2.75(m,1H),2.02–1.86(m,4H),0.89(d,J＝6.1Hz,3H)。8-(3-(1-chloro-2,2,2-trifluoroethyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.20 mmol) was dissolved in MeOH (4 mL), and 10% Pd/C (21 mg, 0.20 mmol) was added. The mixture was replaced with H2 three times and stirred at 25°C under H2 atmosphere for 16 hrs. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: ACN, gradient: 35-65% B, flow rate: 20 mL/min, 20 min) to obtain the title compound (5.0 mg, yield 5.4%, white solid). LC-MS (ESI) m/z: 478.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.83(s,1H),7.81(s,1H),6.75(d,J＝2.2Hz,1H),6.45(s,1H),4.65–4.54(m,2H),4.12–3.84(m,3H),3.78–3 .64(m,5H),3.59–3.55(m,3H),3.27–3.22(m,1H),2.84–2.75(m,1H),2.02–1.86(m,4H),0.89(d,J＝6.1Hz,3H).

实施例45：8-(3-(二氟甲基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂双环[3.2.1]辛烷
Example 45: 8-(3-(Difluoromethyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

步骤1：8-(3-(二氟甲基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-(difluoromethyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲醛(30mg,0.059mmol)溶于DCM(2mL)中，然后在0℃下加入DAST(38mg,0.236mmol)。反应混合物在N2保护下在0℃下反应2hrs。向反应混合物中加入饱和NaHCO3水溶液(10mL)淬灭反应，用EA(10mL×2)萃取。合并有机相用饱和食盐水(10mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到目标化合物(31mg,收率99.0％，黄色油状物)。LC-MS(ESI)m/z:530.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (30 mg, 0.059 mmol) was dissolved in DCM (2 mL), and DAST (38 mg, 0.236 mmol) was added at 0°C. The reaction mixture was reacted at 0°C for 2 hr under N₂ protection. Saturated aqueous NaHCO₃ solution (10 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (31 mg, 99.0% yield, yellow oil). LC-MS(ESI)m/z:530.2[M+H] + .

步骤2：8-(3-(二氟甲基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-(difluoromethyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-(二氟甲基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(31mg,0.059mmol)溶于DCM(1.5mL)中，然后加入4N盐酸/1,4-二氧六环溶液(1.5mL)。反应混合物在N2保护下室温下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：ACN，梯度：30-60％B,流速:20mL/min,27min)分离纯化，得到目标化合物(5.5mg,收率21.1％，白色固体)。LC-MS(ESI)m/z:446.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),7.86(s,1H),7.25(t,J＝53.8Hz,1H),6.78(d,J＝2.0Hz,1H),6.41(s,1H),4.60(d,J＝7.5Hz,2H),3.89–3.78(m,2H),3.75–3.62(m,4H),3.56(d,J＝10.9Hz,2H),3.47(dd,J＝11.1,5.6Hz,1H),2.84–2.77(m,1H),2.00–1.89(m,4H),0.93(d,J＝6.3Hz,3H).8-(3-(Difluoromethyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (31 mg, 0.059 mmol) was dissolved in DCM (1.5 mL), and then a 4N hydrochloric acid/1,4-dioxane solution (1.5 mL) was added. The reaction mixture was stirred at room temperature for 3 hrs under N protection. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: ACN, gradient: 30-60% B, flow rate: 20 mL/min, 27 min) to obtain the title compound (5.5 mg, yield 21.1%), as a white solid. LC-MS (ESI) m/z: 446.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.95(s,1H),7.86(s,1H),7.25(t,J＝53.8Hz,1H),6.78(d,J＝2.0Hz,1H),6.41(s,1H),4.60(d,J＝7.5Hz,2H),3.89–3.78(m,2H),3 .75–3.62(m,4H),3.56(d,J＝10.9Hz,2H),3.47(dd,J＝11.1,5.6Hz,1H),2.84–2.77(m,1H),2.00–1.89(m,4H),0.93(d,J＝6.3Hz,3H).

实施例46：8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环 [3.2.1]辛烷
Example 46: 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo [3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.056mmol)溶于DCM(1.5mL)中，然后加入4N盐酸/1,4-二氧六环溶液(1.5mL)。反应混合物在N2保护下25℃下搅拌2hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:0.1％FA；B％:30-60,流速:20mL/min,30min)分离纯化，得到目标化合物(11.3mg,收率43.7％，白色固体)。LC-MS(ESI)m/z:522.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),7.81(s,1H),6.70(d,J＝2.2Hz,1H),6.20(s,1H),4.59–4.53(m,2H),4.04(dd,J＝10.9,2.6Hz,1H),3.99–3.92(m,1H),3.87(s,1H),3.73–3.61(m,3H),3.58–3.53(m,3H),3.45–3.41(m,1H),2.80–2.74(m,1H),1.99–1.89(m,4H),0.95(d,J＝6.4Hz,3H).8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.056 mmol) was dissolved in DCM (1.5 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (1.5 mL). The reaction mixture was stirred at 25°C under nitrogen for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm: 0.1% FA; B%: 30-60, flow rate: 20 mL/min, 30 min) to afford the title compound (11.3 mg, 43.7% yield, as a white solid). LC-MS(ESI)m/z:522.0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.85(s,1H),7.81(s,1H),6.70(d,J＝2.2Hz,1H),6.20(s,1H),4.59–4.53(m,2H),4.04(dd,J＝10.9,2.6Hz,1H),3.99–3.92(m,1H) ,3.87(s,1H),3.73–3.61(m,3H),3.58–3.53(m,3H),3.45–3.41(m,1H),2.80–2.74(m,1H),1.99–1.89(m,4H),0.95(d,J＝6.4Hz,3H).

实施例47：(2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)乙腈
Example 47: (2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)acetonitrile

步骤1：2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙腈的合成
Step 1: Synthesis of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetonitrile

向6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-碘-4-[(3R)-3-甲基吗啉-4-基]-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]吡唑并[3,4-b]吡啶(50mg,0.083mmol)的DMSO(3mL)/水(1mL)的溶液中加入4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)异恶唑(19mg,0.099mmol)、Pd(dppf)Cl2(3mg,0.004mmol)和KF(14mg,0.25mmol)，反应混合物在130℃下在N2保护下搅拌16hrs。用EA(10mL)和H2O(10mL)稀释反应物，用EA(10mL×2)萃取，合并有机相用水(30mL×5)洗涤，干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，88％EA)。得到目标化合物(26mg,收率60.7％，无色油状物)。LC-MS(ESI)m/z:519.2[M+H]+。To a solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-iodo-4-[(3R)-3-methylmorpholin-4-yl]-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (50 mg, 0.083 mmol) in DMSO (3 mL)/water (1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (19 mg, 0.099 mmol), Pd(dppf) Cl2 (3 mg, 0.004 mmol) and KF (14 mg, 0.25 mmol), and the reaction mixture was stirred at 130°C under N2 protection for 16 hrs. The reaction was diluted with EA (10 mL) and H 2 O (10 mL), extracted with EA (10 mL x 2), and the combined organic phases were washed with water (30 mL x 5), dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 88% EA) to obtain the title compound (26 mg, 60.7% yield, colorless oil). LC-MS (ESI) m/z: 519.2 [M+H] + .

步骤2：(2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙腈的合成
Step 2: Synthesis of (2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetonitrile

向2-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)乙腈(26mg,0.05mmol)的THF(2.5mL)溶液中加入4N盐酸/1,4二氧六环溶液(0.5mL)，反应混合物在25℃下搅拌16hrs，减压浓缩。残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：ACN，梯度25-55％B,流速：20mL/min，30min)分离纯化，得到目标化合物(4.83mg,收率22.2％，白色固体)。LC-MS(ESI)m/z:435.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.73(s,1H),6.91(s,1H),6.39(s,1H),4.63(s,2H),4.30–4.14(m,2H),4.01–3.79(m,5H),3.66–3.50(m,4H),3.40–3.34(m,1H),2.93–2.85(m,1H),2.15–2.00(m,4H),1.02(d,J＝6.1Hz,3H)。To a solution of 2-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetonitrile (26 mg, 0.05 mmol) in THF (2.5 mL) was added 4N hydrochloric acid/1,4-dioxane solution (0.5 mL). The reaction mixture was stirred at 25°C for 16 hrs and concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA/ H2O ; mobile phase B: ACN, gradient 25-55% B, flow rate: 20 mL/min, 30 min) to obtain the title compound (4.83 mg, yield 22.2%, white solid). LC-MS (ESI) m/z: 435.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.73(s,1H),6.91(s,1H),6.39(s,1H),4.63(s,2H),4.30–4.14(m,2H),4.01–3.79(m,5H),3. 66–3.50(m,4H),3.40–3.34(m,1H),2.93–2.85(m,1H),2.15–2.00(m,4H),1.02(d,J=6.1Hz,3H).

实施例48：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-5-氟-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 48: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：8-(5-氟-4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(5-fluoro-4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2保护下，使反应体系冷却到-70℃,将8-(4-(((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(500mg,1.21mmol)溶解在THF(15mL)中，向溶液中缓慢添加氟试剂selectfluor(514mg,1.45mmol)的CH3CN(10mL)溶液，然后将反应物在25℃下搅拌24hrs。用EA(20mL)和水(40mL)稀释反应物。分离有机相，用EA(20mL×2)萃取水相，合并有机相，用饱和食盐水(20mL)洗涤，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)得到目标化合物(380mg,收率72.8％，黄绿色固体)。LC-MS(ESI)m/z:432.2[M+H]+。Under N2 protection, the reaction system was cooled to -70 °C, 8-(4-(((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (500 mg, 1.21 mmol) was dissolved in THF (15 mL), and fluorine reagent selectfluor (514 mg, 1.45 mmol) in CH3 CN (10 mL) solution was added, and the reaction was stirred at 25°C for 24 hours. The reaction was diluted with EA (20 mL) and water (40 mL). The organic phase was separated, and the aqueous phase was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (380 mg, 72.8% yield, yellow-green solid). LC-MS (ESI) m/z: 432.2 [M+H] + .

步骤2：8-(5-氟-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(5-fluoro-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(5-氟-4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(400mg,0.65mmol)溶解在MeOH(3mL)溶液中，然后加入4N盐酸/1,4-二氧六环溶液(3mL)。反应混合物在25℃下反应16hrs。减压浓缩，向残余物中加入EA和H2O，搅拌，完全溶解后用EA萃取，合并有机相并减压浓缩得到目标化合物(150mg,收率66.5％，棕色固体)。LC-MS(ESI)m/z:348.2[M+H]+。8-(5-Fluoro-4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400 mg, 0.65 mmol) was dissolved in MeOH (3 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (3 mL). The reaction mixture was allowed to react at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and EA and H₂O were added to the residue, stirred, and extracted with EA after complete dissolution. The organic phases were combined and concentrated under reduced pressure to yield the title compound (150 mg, 66.5% yield, as a brown solid). LC-MS (ESI) m/z: 348.2 [M+H] ⁺ .

步骤3：8-(5-氟-3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(5-fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(5-氟-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(150mg,0.43mmol)溶解在DMF(10mL)中，向溶液中加入KOH(73mg,1.30mmol)，并缓慢加入I2(220mg,0.87mmol)，反应混合物在N2保护下25℃下搅拌反应1hr。用Na2SO3水溶液终止反应。向残余物中加入EA(10mL)和H2O(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和NaCl水溶液(10mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩。残余物经硅胶柱层析分离纯化(MeOH：DCM，7％MeOH)得到目标化合物(150mg,收率73.4％，淡黄色固体)。LC-MS(ESI)m/z:474.0[M+H]+。8-(5-Fluoro-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (150 mg, 0.43 mmol) was dissolved in DMF (10 mL). KOH (73 mg, 1.30 mmol) was added to the solution, and I (220 mg, 0.87 mmol) was slowly added. The reaction mixture was stirred at 25°C under N protection for 1 hr. The reaction was terminated with aqueous NaSO . EA (10 mL) and H2O (10 mL) were added to the residue, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated aqueous NaCl (10 mL), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM, 7% MeOH) to obtain the title compound (150 mg, 73.4% yield, light yellow solid). LC-MS (ESI) m/z: 474.0 [M+H] + .

步骤4：8-(5-氟-3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(5-fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(5-氟-3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(150mg,0.32mmol)的NMP(5mL)溶液中加入[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(186mg,0.95mmol)、醋酸铜(380mg,1.90mmol)和吡啶(102mg,1.27mmol)，并将反应混合物在O2气氛下50℃搅拌18hrs，冷却至室温。将反应混合物用EA(20mL)和水(20mL)稀释，用EA(20mL×2)萃取，合并有机相，用饱和NaCl水溶液(10mL)洗涤，过滤并减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)得到目标化合物(110mg,收率55.7％，黄色固体)。LC-MS(ESI)m/z:624.2[M+H]+。To a solution of 8-(5-fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (150 mg, 0.32 mmol) in NMP (5 mL) were added [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (186 mg, 0.95 mmol), copper acetate (380 mg, 1.90 mmol) and pyridine (102 mg, 1.27 mmol), and the reaction mixture was stirred at 50° C. under an O atmosphere for 18 hrs and cooled to room temperature. The reaction mixture was diluted with EA (20 mL) and water (20 mL), extracted with EA (20 mL x 2), and the combined organic phases were washed with saturated aqueous NaCl (10 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (110 mg, 55.7% yield, as a yellow solid). LC-MS (ESI) m/z: 624.2 [M+H] + .

步骤5：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-5-氟-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(5-氟-3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.080mmol)溶解在DMA(2mL)中，加入Zn(CN)2(28mg,0.24mmol)、Zn(0)(16mg,0.24mmol)、Pd(dppf)Cl2(12mg,0.016mmol)和Pd2(dba)3(7mg,0.008mmol)，反应混合物在N2保护下150℃下搅拌1hr，冷却至室温。反应混合物用EA(10mL)和水(10mL)稀释并用EA(5mL×2)萃取，合并有机相，用饱和NaCl水溶液(10mL)洗涤，过滤，滤液减压浓缩，得到目标化合物(35mg,收率83.5％，棕色固体)。LC-MS(ESI)m/z:523.2[M+H]+。8-(5-Fluoro-3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.080 mmol) was dissolved in DMA (2 mL), and Zn(CN) 2 (28 mg, 0.24 mmol), Zn(0) (16 mg, 0.24 mmol), Pd(dppf) Cl2 (12 mg, 0.016 mmol) and Pd2 (dba) 3 (7 mg, 0.008 mmol) were added. The reaction mixture was stirred at 150°C for 1 hr under N2 protection and cooled to room temperature. The reaction mixture was diluted with EA (10 mL) and water (10 mL) and extracted with EA (5 mL x 2). The combined organic phases were washed with saturated aqueous NaCl (10 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (35 mg, 83.5% yield, brown solid). LC-MS (ESI) m/z: 523.2 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-5-氟-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-5-氟-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(35mg,0.067mmol)溶于THF(4mL)中，然后加入4N盐酸/1,4-二氧六环溶液(4mL)。反应混合物在50℃下搅拌16hrs后冷却至室温，减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％FA/H2O；流动相B：ACN，梯度：35-65％B,流速:20mL/min,30min)分离纯化，得到目标化合物(11.0mg,收率37.4％，类白色固体)。LC-MS(ESI)m/z:439.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),7.93(s,1H),6.82(d,J＝1.9Hz,1H),4.60–4.48(m,2H),3.97(dd,J＝11.0,2.8Hz,1H),3.92–3.86(m,1H),3.83(d,J＝10.8Hz,1H),3.76–3.59(m,5H),3.58–3.50(m,1H),3.46–3.43(m,1H),3.18–3.10(m,1H),2.07–1.85(m,4H),1.04(d,J＝6.3Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (35 mg, 0.067 mmol) was dissolved in THF (4 mL), and 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 50°C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: ACN, gradient: 35-65% B, flow rate: 20 mL/min, 30 min) to obtain the title compound (11.0 mg, 37.4% yield, off-white solid). LC-MS (ESI) m/z: 439.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.16(s,1H),7.93(s,1H),6.82(d,J＝1.9Hz,1H),4.60–4.48(m,2H),3.97(dd,J＝11.0,2.8Hz,1H),3.92–3.86(m,1H),3.83(d,J＝ 10.8Hz,1H),3.76–3.59(m,5H),3.58–3.50(m,1H),3.46–3.43(m,1H),3.18–3.10(m,1H),2.07–1.85(m,4H),1.04(d,J＝6.3Hz,3H).

实施例49:8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1] 辛烷
Example 49: 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1] octane

步骤1：8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘代-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧代-8-氮杂双环[3.2.1]辛烷(214mg,0.5mmol)、(R)-3-甲基吗啉盐酸盐(98mg,1.0mmol)、RuphosPdG2(38mg,0.05mmol)和Cs2CO3(479mg,1.5mmol)依次加入到NMP(10mL)中。反应混合物在微波仪内120℃下反应5hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标化合物(125mg,收率60.7％,白色固体)。LC-MS(ESI)m/z:414.0[M+H]+。8-(4-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxo-8-azabicyclo[3.2.1]octane (214 mg, 0.5 mmol), (R)-3-methylmorpholine hydrochloride (98 mg, 1.0 mmol), RuphosPdG2 (38 mg, 0.05 mmol) and Cs2CO3 (479 mg, 1.5 mmol) were added sequentially to NMP (10 mL). The reaction mixture was reacted in a microwave at 120°C for 5 hr, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (125 mg, yield 60.7%), as a white solid. LC-MS (ESI) m/z: 414.0 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(125mg,0.3mmol)、加入到6M盐酸/THF(2mL/4mL)，室温搅拌0.5hr。反应混合物用饱和NaHCO3溶液调pH>8，用EA(15mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(EA＝100)得到目标产物(71mg,收率71.7％,白色固体)。LC-MS(ESI)m/z:331.1[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (125 mg, 0.3 mmol) was added to 6M hydrochloric acid/THF (2 mL/4 mL) and stirred at room temperature for 0.5 hr. The reaction mixture was adjusted to pH > 8 with saturated NaHCO₃ solution and extracted with EA (15 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA=100) to afford the desired product (71 mg, 71.7% yield, as a white solid). LC-MS (ESI) m/z: 331.1 [M+H] ⁺ .

步骤3：8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(71mg,0.2mmol)、(1S,2S)-N1，N2-二甲基环己烷-1,2-二胺(60mg,0.4mmol)、3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(88mg,0.3mmol)，CuI(40mg,0.2mmol)和Cs2CO3(171mg,0.5mmol)依次加入到NMP(5mL)中。反应混合物在120℃油浴下反应过夜，冷却至室温，向反应混合物中加入水(15mL)，用EA(20mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝1:4)得到目标产物(14mg,收率14.0％,白色固体)。8-(4-((R)-3-Methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (71 mg, 0.2 mmol), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (60 mg, 0.4 mmol), 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (88 mg, 0.3 mmol), CuI (40 mg, 0.2 mmol) and Cs 2 CO 3 (171 mg, 0.5 mmol) were added sequentially to NMP (5 mL). The reaction mixture was reacted in an oil bath at 120°C overnight and cooled to room temperature. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined, washed with water (30 mL × 5) and saturated brine (30 mL × 2) in that order, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA = 1:4) to give the desired product (14 mg, yield 14.0%), as a white solid.

步骤4：8-(4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(14mg,0.03mmol)加入到6M盐酸水溶液/THF(2mL/4mL)中，50℃搅拌过夜。冷却至室温，用饱和NaHCO3水溶液调pH>8，用EA(20mL×3)萃取，合并有机层，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM:MeOH＝0:1)得到目标产物(8.3mg,收率70.0％,白色固体)。LC-MS(ESI)m/z:395.96[M+H]+。1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.62(s,1H),6.76(s,1H),5.68(s,1H),4.54–4.42(m,2H),4.20(d,J＝5.0Hz,1H),4.08(d,J＝10.6Hz,1H),3.95–3.81(m,4H),3.79–3.62(m,4H),3.54–3.41(m,2H),2.18–2.10(m,2H),2.10–2.01(m,2H),1.31(d,J＝6.7Hz,3H).8-(4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (14 mg, 0.03 mmol) was added to a 6 M aqueous hydrochloric acid/THF solution (2 mL/4 mL) and stirred at 50°C overnight. The mixture was cooled to room temperature and adjusted to pH > 8 with saturated aqueous NaHCO₃ . The mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 0:1) to afford the desired product (8.3 mg, 70.0% yield, as a white solid). LC-MS(ESI)m/z:395.96[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.96(s,1H),7.62(s,1H),6.76(s,1H),5.68(s,1H),4.54–4.42(m,2H),4.20(d,J＝5.0Hz,1H),4.08(d,J＝10.6Hz,1H) ,3.95–3.81(m,4H),3.79–3.62(m,4H),3.54–3.41(m,2H),2.18–2.10(m,2H),2.10–2.01(m,2H),1.31(d,J＝6.7Hz,3H).

实施例50：8-(3-甲基-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二 环[3.2.1]辛烷
Example 50: 8-(3-methyl-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo [3.2.1]octane

步骤1：8-(3-甲基-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-methyl-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.17mmol)溶于1,4-二氧六环/水(8mL)中，然后依次加入K2CO3(71.8mg,0.52mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼烷(124mg,0.99mmol)、Pd(PPh3)4(71.8mg,0.52mmol)，反应混合物在N2保护下在100℃下搅拌16hrs，冷却至室温，将反应混合物倒入饱和食盐水(10mL)中，用EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，减压浓缩得到粗产品直接进行下一步反应。(70mg,收率85.8％，淡黄色油状物)。LC-MS(ESI)m/z:494.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.17 mmol) was dissolved in 1,4-dioxane/water (8 mL), and K 2 CO 3 (71.8 mg, 0.52 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (124 mg, 0.99 mmol), and Pd(PPh 3 ) 4 (71.8 mg, 0.52 mmol) were added in sequence. The reaction mixture was stirred at 4 ℃ for 10 min. 2 , stirred at 100°C for 16 hours. Cooled to room temperature, the reaction mixture was poured into saturated brine (10 mL) and extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the crude product (70 mg, 85.8% yield, light yellow oil), which was directly used in the next reaction. LC-MS (ESI) m/z: 494.2 [M+H] ⁺ .

步骤2：8-(3-甲基-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-methyl-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-甲基-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(70mg,0.14mmol)溶于THF(4mL)中，然后加入4N盐酸/二氧六环溶液(4mL)，反应混合物在室温下反应12hrs，将反应混合物中倒入饱和NaHCO3溶液(10mL)中，用EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物通过Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：水(含0.1％FA)；流动相B：ACN，梯度：22-52％B,流速:20mL/min,20min)分离纯化，得到目标化合物(30mg,收率55.1％，白色固体)。LC-MS(ESI)m/z:410.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),7.74(s,1H),6.71(s,1H),6.14(s,1H),4.56(s,2H),3.89–3.81(m,2H),3.73–3.62(m,4H),3.57–3.51(m,3H),3.42–3.33(m,1H),2.85–2.75(m,1H),2.51(s,3H),1.98–1.84(m,4H),0.97(d,J＝6.3Hz,3H).8-(3-Methyl-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (70 mg, 0.14 mmol) was dissolved in THF (4 mL), and then a 4N hydrochloric acid/dioxane solution (4 mL) was added. The reaction mixture was reacted at room temperature for 12 hrs. The reaction mixture was poured into a saturated NaHCO 3 solution (10 mL) and extracted with EA (10 mL×2). The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um: Mobile phase A: Water (containing 0.1% FA); Mobile phase B: ACN, gradient: 22-52% B, flow rate: 20 mL/min, 20 min) to separate and purify the title compound (30 mg, 55.1% yield, white solid). LC-MS (ESI) m/z: 410.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.68(s,1H),7.74(s,1H),6.71(s,1H),6.14(s,1H),4.56(s,2H),3.89–3.81(m,2H),3.73–3.62(m,4H),3. 57–3.51(m,3H),3.42–3.33(m,1H),2.85–2.75(m,1H),2.51(s,3H),1.98–1.84(m,4H),0.97(d,J=6.3Hz,3H).

实施例51：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(二氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 51: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(difluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：(3S)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-甲醛的合成
Step 1: Synthesis of (3S)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholine-3-carbaldehyde

将((3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-基)甲醇(100mg,0.16mmol)，TPAP(6mg,0.016mmol)和NMO(47mg,0.48mmol)依次加入到DCM(10mL)中。反应混合物在N2保护下在室温下搅拌30mins。向反应混合物中加入水(25mL)，用DCM萃取，合并有机相用饱和食盐水(10mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到目标化合物(99mg,收率99.3％，棕色固体)。LC-MS(ESI)m/z:620.2[M+H]+。((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (100 mg, 0.16 mmol), TPAP (6 mg, 0.016 mmol), and NMO (47 mg, 0.48 mmol) were added sequentially to DCM (10 mL). The reaction mixture was stirred at room temperature under N₂ protection for 30 min. Water (25 mL) was added to the reaction mixture, which was then extracted with DCM. The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (99 mg, 99.3% yield, as a brown solid). LC-MS(ESI)m/z:620.2[M+H] + .

步骤2：8-(4-((S)-3-(二氟甲基)吗啉基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((S)-3-(difluoromethyl)morpholinyl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(3S)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)吗啉-3-甲醛(500mg,0.81mmol)溶于DCM(20mL)中,然后在0℃下加入DAST(521mg,3.23mmol)。反应混合物在N2保护下在室温下反应2hrs。向反应混合物中加入水(10mL)淬灭反应，用EA(30mL×2)萃取。合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，30％EA)得到目标化合物(165mg,收率31.8％，棕色固体)。LC-MS(ESI)m/z:642.0[M+H]+。(3S)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholine-3-carbaldehyde (500 mg, 0.81 mmol) was dissolved in DCM (20 mL), and then DAST (521 mg, 3.23 mmol) was added at 0°C. The reaction mixture was reacted at room temperature under N protection for 2 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (165 mg, 31.8% yield, brown solid). LC-MS (ESI) m/z: 642.0 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(二氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(difluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(4-((S)-3-(二氟甲基)吗啉基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(160mg,0.25mmol)溶于DMA(3mL)中然后依次加入Zn(CN)2(88mg,0.75mmol)，Zn(0)(49mg,0.75mmol)，Pd2(dba)3(23mg,0.025mmol)和Pd(dppf)Cl2(36mg,0.050mmol)。反应混合物在N2保护下在150℃下反应1hr，冷却至室温。向反应混合物中加入水(20mL)，用EA(10mL×2)萃取。合并有机相用饱和食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(120mg,收率88.9％，棕色油状物)。LC-MS((ESI)m/z:541.2[M+H]+。8-(4-((S)-3-(difluoromethyl)morpholinyl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (160 mg, 0.25 mmol) was dissolved in DMA (3 mL) and Zn(CN) ( 88 mg, 0.75 mmol), Zn(0) (49 mg, 0.75 mmol), Pd (dba) ( 23 mg, 0.025 mmol) and Pd(dppf)Cl ( 36 mg, 0.050 mmol) were added in sequence. The reaction mixture was reacted at 150° C. under N protection for 1 hr and then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (120 mg, 88.9% yield, brown oil). LC-MS ((ESI) m/z: 541.2 [M+H] ⁺ ).

步骤4：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(二氟甲基)吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 4: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(difluoromethyl)morpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((S)-3-(二氟甲基)吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(100mg,0.19mmol)溶于DCM(5mL)中，然后加入4N盐酸/1,4-二氧六环溶液(5mL)。反应混合物在室温下搅拌2hrs。减压浓缩，加入饱和NaHCO3水溶液调pH值到8，用EA萃取，合并有机相，减压浓缩，残余物依次经硅胶柱层析(PE：EA，60％ EA)和反向柱层析(H2O：ACN，40％ACN)分离纯化，得到目标化合物(55mg,收率65.1％，白色固体)。LC-MS(ESI)m/z:457.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),7.90(s,1H),6.84(d,J＝1.8Hz,1H),6.54(td,J＝55.3,6.1Hz,1H),6.31(s,1H),4.60(s,2H),4.24–4.07(m,2H),3.98(d,J＝11.7Hz,2H),3.81–3.69(m,2H),3.69–3.61(m,3H),3.59–3.55(m,2H),2.01–1.89(m,4H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((S)-3-(difluoromethyl)morpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (100 mg, 0.19 mmol) was dissolved in DCM (5 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the pH was adjusted to 8 by adding saturated aqueous NaHCO₃ . The mixture was extracted with EA, and the organic phases were combined and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (PE:EA, 60% EA) and reverse-phase column chromatography ( H₂O :ACN, 40% ACN) to afford the title compound (55 mg, 65.1% yield) as a white solid. LC-MS(ESI)m/z:457.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.11(s,1H),7.90(s,1H),6.84(d,J＝1.8Hz,1H),6.54(td,J＝55.3,6.1Hz,1H),6.31(s,1H),4.60(s,2H),4.24 –4.07(m,2H),3.98(d,J＝11.7Hz,2H),3.81–3.69(m,2H),3.69–3.61(m,3H),3.59–3.55(m,2H),2.01–1.89(m,4H).

实施例52：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇
Example 52: 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol

步骤1：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇的合成
Step 1: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(50mg,0.09mmol)溶于DCM(8mL)中，然后加入NMO(20.3mg,0.17mmol)和TPAP(3mg,0.01mmol)，反应混合物在N2保护下在室温下反应12hrs，向反应混合物中加入水，用DCM(20mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品直接进行下一步反应(35mg,收率69.9％，黄色油状物)。LC-MS(ESI)m/z:594.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (50 mg, 0.09 mmol) was dissolved in DCM (8 mL), and then NMO (20.3 mg, 0.17 mmol) and TPAP (3 mg, 0.01 mmol) were added. The reaction mixture was reacted at room temperature under N2 protection for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL×2) . The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (35 mg, yield 69.9%, yellow oil) which was directly used for the next reaction. LC-MS(ESI)m/z:594.2[M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇(50mg,0.09mmol)溶于THF(3mL)中，然后加入4N盐酸/1,4-二氧六环溶液(3mL)，反应混合物在N2保护下在25℃下搅拌12hrs，减压浓缩，向残余物中加入饱和NaHCO3溶液(10mL)，用EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：25-55％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(3.0mg,收率7.1％，白色固体)。LC-MS(ESI)m/z:510.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.69(s,1H),6.84(s,1H),6.78(d,J＝5.5,2.4Hz,1H),4.59(s,2H),3.96–3.85(m,2H),3.82–3.70(m,3H),3.56(d,J＝10.9Hz,2H),3.50–3.34(m,2H),3.15–3.02(m,1H),2.96(d,J＝12.0Hz,1H),2.08–1.95(m,4H),0.84(d,J＝6.1,4.0Hz,3H).1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol (50 mg, 0.09 mmol) was dissolved in THF (3 mL), and then a 4N hydrochloric acid/1,4-dioxane solution (3 mL) was added. The reaction mixture was stirred at 25°C under N2 protection for 12 hrs, concentrated under reduced pressure, and a saturated NaHCO3 solution (10 mL) was added to the residue, and the mixture was extracted with EA (10 mL×2). The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 25-55% B, detection wavelength: 214nm, flow rate: 20mL/min, column temperature: 25°C) was used to separate and purify the title compound (3.0mg, 7.1% yield, white solid). LC-MS (ESI) m/z: 510.2[M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.69(s,1H),6.84(s,1H),6.78(d,J＝5.5,2.4Hz,1H),4.59(s,2H),3.96–3.85(m,2H),3.82–3.70(m,3H),3.56(d,J＝1 0.9Hz,2H),3.50–3.34(m,2H),3.15–3.02(m,1H),2.96(d,J＝12.0Hz,1H),2.08–1.95(m,4H),0.84(d,J＝6.1,4.0Hz,3H).

实施例53：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(1-甲基-1H-吡唑-5-基)-1-(1H-吡唑-3-基)-1H-吡嗪并[3,4-b] 吡啶-3-腈
Example 53: 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-(1-methyl-1H-pyrazol-5-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazino[3,4-b] pyridine-3-carbonitrile

步骤1：8-(4-(1-甲基-1H-吡唑-5-基)-1-(四氢-2H-吡唑-2-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(300mg,0.68mmol)，(1-甲基吡唑-5-基)硼二醇(103mg,0.82mmol)，Pd(dppf)Cl2(25mg,0.034mmol)和Na2CO3(180mg,1.70mmol)依次加入到1,4-二氧六环(10mL)/H2O(1mL)中。所得反应混合物N2保护下100℃下搅拌过夜，冷却至室温。向反应混合物中加入水(20mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，25％ EA)分离纯化得到目标化合物(255mg,收率94.8％，白色固体)。LC-MS(ESI)m/z:395.2[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (300 mg, 0.68 mmol), (1-methylpyrazol-5-yl)boranediol (103 mg, 0.82 mmol), Pd(dppf) Cl₂ (25 mg, 0.034 mmol), and Na₂CO₃ (180 mg, 1.70 mmol) were added sequentially to 1,4- dioxane (10 mL)/ H₂O (1 mL). The reaction mixture was stirred at 100°C overnight under N₂ protection and then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA, 25% EA) to obtain the title compound (255 mg, 94.8% yield, white solid). LC-MS (ESI) m/z: 395.2 [M+H] + .

步骤2：8-(4-(1-甲基-1H-吡唑-5-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(1-甲基-1H-吡唑-5-基)-1-(四氢-2H-吡唑-2-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(255mg,0.65mmol)和4N盐酸/1,4-二氧六环溶液(1.5mL)依次加入到DCM(1.5mL)中。所得反应混合物N2保护下室温搅拌2hrs。向反应混合物中加入饱和Na2CO3溶液调节pH至9-10，用EA(10mL×2)萃取。合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(160mg,79.7％，黄色固体)。LC-MS(ESI)m/z:311.2[M+H]+。8-(4-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (255 mg, 0.65 mmol) and a 4N hydrochloric acid/1,4-dioxane solution (1.5 mL) were added sequentially to DCM (1.5 mL). The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours. Saturated Na₂CO₃ solution was added to the reaction mixture to adjust the pH to 9-10, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (160 mg, 79.7%, as a yellow solid). LC-MS(ESI)m/z:311.2[M+H] + .

步骤3：8-(4-(1-甲基-1H-吡唑-5-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(1-甲基-1H-吡唑-5-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(125mg,0.40mmol)，KOH(112mg,2.01mmol)和I2(205mg,0.81mmol)依次加入到DMF(5mL)中。N2保护下，反应混合物室温搅拌2hrs。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，25％EA)分离纯化得到目标化合物(100mg,收率56.9％，白色固体)。LC-MS(ESI)m/z:437.0[M+H]+。8-(4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (125 mg, 0.40 mmol), KOH (112 mg, 2.01 mmol), and I₂ (205 mg, 0.81 mmol) were added sequentially to DMF (5 mL). Under N₂ protection, the reaction mixture was stirred at room temperature for 2 hrs. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 3 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA, 25% EA) to afford the title compound (100 mg, 56.9% yield) as a white solid. LC-MS(ESI)m/z:437.0[M+H] + .

步骤4：(8-(3-碘-4-(1-甲基-1H-吡唑-5-基)-1-(1-(四氢-2H-吡唑-2-基)-1H-吡嗪-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of (8-(3-iodo-4-(1-methyl-1H-pyrazol-5-yl)-1-(1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(1-甲基-1H-吡唑-5-基)-1H-吡嗪并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.22mmol)，[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(180mg,0.92mmol)，醋酸铜(250mg,1.38mmol)和吡啶(0.074mL,0.92mmol)依次加入到NMP(3mL)中。N2保护下，反应混合物50℃下搅拌过夜，冷却至室温。向反应混合物中加入水(20mL)，用EA(10mL×2)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物粗品(130mg,收率96.7％，棕色油状物)。LC-MS(ESI)m/z:587.2[M+H]+。8-(4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazino[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.22 mmol), [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (180 mg, 0.92 mmol), copper acetate (250 mg, 1.38 mmol), and pyridine (0.074 mL, 0.92 mmol) were added sequentially to NMP (3 mL). Under N₂ protection, the reaction mixture was stirred at 50°C overnight and then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (130 mg, 96.7% yield, brown oil). LC-MS (ESI) m/z: 587.2 [M+H] + .

步骤5：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(1-甲基-1H-吡唑-5-基)-1-(1-(四氢-2H-吡唑-2-基)-1H-吡嗪-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-methyl-1H-pyrazol-5-yl)-1-(1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(8-(3-碘-4-(1-甲基-1H-吡唑-5-基)-1-(1-(四氢-2H-吡唑-2-基)-1H-吡嗪-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.07mmol)，Zn(CN)2(24mg,0.20mmol)，锌粉(13mg,0.20mmol)，Pd2(dba)3(6.3mg,0.0070mmol)和Pd(dppf)Cl2(10mg,0.014mmol)依次加入到DMA(3mL)中。反应混合物在N2保护下150℃搅拌2hrs。向反应混合物中加入水(15mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(15mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(30mg,粗品，收率89.5％，棕色固体)。LC-MS(ESI)m/z:486.2[M+H]+。(8-(3-iodo-4-(1-methyl-1H-pyrazol-5-yl)-1-(1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.07 mmol), Zn(CN) 2 (24 mg, 0.20 mmol), zinc powder (13 mg, 0.20 mmol), Pd 2 (dba) 3 (6.3 mg, 0.0070 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) were added to DMA (3 mL) in sequence. The reaction mixture was stirred under N 2. Stir at 150°C for 2 hrs. Add water (15 mL) to the reaction mixture, extract with EA (10 mL x 2). Combine the organic phases, wash with saturated brine (15 mL x 2), dry over anhydrous Na₂SO₄ , filter, and concentrate the filtrate under reduced pressure to obtain the title compound (30 mg, crude product, 89.5% yield, brown solid). LC-MS (ESI) m/z: 486.2 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(1-甲基-1H-吡唑-5-基)-1-(1-(四氢-2H-吡唑-2-基)-1H-吡嗪-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-methyl-1H-pyrazol-5-yl)-1-(1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(1-甲基-1H-吡唑-5-基)-1-(1-(四氢-2H-吡唑-2-基)-1H-吡嗪-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(30mg,0.06mmol)和4N盐酸/1,4-二氧六环溶液(1.5mL)依次加入到DCM(1.5mL)中。N2保护下，反应混合物室温搅拌2hrs，减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um:流动相A：0.1％TFA/H2O；流动相B：ACN，梯度：25-55％B,流速：20mL/min，18min)分离纯化，得到目标化合物(8.0mg,收率32.2％，白色固体)。LC-MS(ESI)m/z:402.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),7.96–7.92(m,1H),7.62(d,J＝1.9Hz,1H),7.12(s,1H),6.87(t,J＝2.1Hz,1H),6.69(d,J＝1.9Hz,1H),4.73(s,2H),3.88(s,3H),3.65(dd,J＝36.2,10.8Hz,4H),2.07–1.93(m,4H).6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-methyl-1H-pyrazol-5-yl)-1-(1-(tetrahydro-2H-pyrazol-2-yl)-1H-pyrazin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (30 mg, 0.06 mmol) and 4N hydrochloric acid/1,4-dioxane solution (1.5 mL) were added sequentially to DCM (1.5 mL). Under N₂ protection, the reaction mixture was stirred at room temperature for 2 hr, then concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C₁₀, 21.2*250 mm, 5 μm; mobile phase A: 0.1% TFA/ H₂O ; mobile phase B: ACN, gradient: 25-55% B, flow rate: 20 mL/min, 18 min) to obtain the title compound (8.0 mg, 32.2% yield, white solid). LC-MS (ESI) m/z: 402.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.15(s,1H),7.96–7.92(m,1H),7.62(d,J＝1.9Hz,1H),7.12(s,1H),6.87(t,J＝2.1Hz,1H),6. 69(d,J＝1.9Hz,1H),4.73(s,2H),3.88(s,3H),3.65(dd,J＝36.2,10.8Hz,4H),2.07–1.93(m,4H).

实施例54:6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑 并[3,4-b]吡啶-3-腈
Example 54: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：(R)-1-苄基-2-甲基哌啶-4-酮的合成
Step 1: Synthesis of (R)-1-benzyl-2-methylpiperidin-4-one

将(R)-2-甲基哌啶-4-酮(2.80g,18.72mmol)溶于ACN(40mL)中，加入K2CO3(5.17g,37.43mmol)和溴苄(6.44g,37.43mmol)，反应混合物在25℃下搅拌16hrs。向反应混合物中加入水(40mL)，用EA(40mL×2)萃取。合并有机相用水(100mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，15％EA)得到目标化合物(3.42g,收率89.9％，无色油状物)。LC-MS(ESI)m/z:204.2[M+H]+。(R)-2-Methylpiperidin - 4-one (2.80 g, 18.72 mmol) was dissolved in ACN (40 mL), and K₂CO₃ (5.17 g, 37.43 mmol) and benzyl bromide (6.44 g, 37.43 mmol) were added. The reaction mixture was stirred at 25°C for 16 hr. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with EA (40 mL x 2). The combined organic phases were washed with water (100 mL x 5 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 15% EA) to yield the title compound (3.42 g, 89.9% yield, colorless oil). LC-MS (ESI) m/z: 204.2 [M+H] ⁺ .

步骤2：(2R)-1-苄基-2-甲基哌啶-4-醇的合成
Step 2: Synthesis of (2R)-1-benzyl-2-methylpiperidin-4-ol

将((R)-1-苄基-2-甲基哌啶-4-酮(3.42g,16.82mmol)溶于THF(50mL)中，降温至0℃，分批缓慢加入NaBH4(1.28g,33.65mmol)，所得反应混合物在0℃下搅拌2hrs。向反应混合物中加入水(40mL)淬灭反应，用EA(40mL×2)萃取，合并有机相，用水(200mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗品目标化合物(3.30g,收率95.5％，无色油状物)。LC-MS(ESI)m/z:206.2[M+H]+。((R)-1-Benzyl-2-methylpiperidin-4-one (3.42 g, 16.82 mmol) was dissolved in THF (50 mL), cooled to 0°C, and NaBH₄ (1.28 g, 33.65 mmol) was slowly added portionwise. The resulting reaction mixture was stirred at 0°C for 2 hrs. Water (40 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EA (40 mL × 2). The combined organic phases were washed with water (200 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound (3.30 g, 95.5% yield, colorless oil). LC-MS (ESI) m/z: 206.2 [M+H] ⁺ .

步骤3：(2R)-1-苄基-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶的合成
Step 3: Synthesis of (2R)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine

将(2R)-1-苄基-2-甲基哌啶-4-醇(3.30g,16.07mmol)和TBSCl(3.63g,24.11mmol)溶于DMF(50mL)中，在0℃下，加入咪唑(2.74g,40.19mmol)，反应混合物在25℃下搅拌16hrs。向反应混合物中加入水(50mL)，用EA(50mL×2)萃取。合并有机相用水(200mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，10％EA)，然后减压浓缩，得到目标化合物(3.30g,收率64.2％，无色油状物)。LC-MS(ESI)m/z:320.4[M+H]+。(2R)-1-Benzyl-2-methylpiperidin-4-ol (3.30 g, 16.07 mmol) and TBSCl (3.63 g, 24.11 mmol) were dissolved in DMF (50 mL). Imidazole (2.74 g, 40.19 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 16 hr. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with water (200 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 10% EA), followed by concentration under reduced pressure to yield the title compound (3.30 g, 64.2% yield, colorless oil). LC-MS (ESI) m/z: 320.4 [M+H] ⁺ .

步骤4：(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶的合成
Step 4: Synthesis of (2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine

将(2R)-1-苄基-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶(2.80g,8.76mmol)溶于MeOH(60mL)中，加入10％ Pd/C(900mg)。反应混合物在H2氛围下置换三次，然后反应液在H2氛围下25℃搅拌16hrs。反应混合物通过硅藻土过滤，滤液减压浓缩，得到目标化合物(2.00g,收率99.5％，无色液体)。LC-MS(ESI)m/z:230.4[M+H]+。(2R)-1-Benzyl-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine (2.80 g, 8.76 mmol) was dissolved in MeOH (60 mL) and 10% Pd/C (900 mg) was added. The reaction mixture was purged three times under an H₂ atmosphere, and then stirred at 25°C under an H₂ atmosphere for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.00 g, 99.5% yield, colorless liquid). LC-MS (ESI) m/z: 230.4 [M+H] ⁺ .

步骤5：8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(1.65g,3.75mmol)和(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶(1.29g,5.62mmol)溶于NMP(60mL)中，然后依次加入Cs2CO3(3.67g,11.24mmol)和Ruphos Pd G2(146mg,0.19mmol)。反应混合物在N2保护下130℃搅拌16hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(80mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，得到粗品目标化合物(2.03g,收率100％，黄色油状物)。LC-MS(ESI)m/z:542.4[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (1.65 g, 3.75 mmol) and (2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine (1.29 g, 5.62 mmol) were dissolved in NMP (60 mL). CsCO (3.67 g, 11.24 mmol) and Ruphos Pd G (146 mg, 0.19 mmol) were then added. The reaction mixture was stirred at 130°C for 16 hours under N protection and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (80 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (2.03 g, 100% yield, yellow oil). LC-MS (ESI) m/z: 542.4 [M+H] + .

步骤6：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 6: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(2.03g,3.75mmol)溶于THF(30mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)，然后反应混合物在N2保护下25℃下搅拌16hrs。减压浓缩，向残余物加入饱和NaHCO3溶液至碱性，用DCM(50mL×2)萃取，合并有机相，用饱和NaHCO3溶液(80mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析(PE：EA，0％～100％EA到DCM:MeOH,10％MeOH)分离纯化得到目标化合物(521mg,收率40.5％，淡黄色固体)。LC-MS(ESI)m/z:344.4[M+H]+。8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.03 g, 3.75 mmol) was dissolved in THF (30 mL), and a 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. The reaction mixture was then stirred at 25°C under N protection for 16 hrs. The mixture was concentrated under reduced pressure, and a saturated NaHCO3 solution was added to the residue until it became alkaline. The mixture was extracted with DCM (50 mL × 2). The organic phases were combined, washed with a saturated NaHCO3 solution (80 mL × 2), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 0%-100% EA to DCM:MeOH, 10% MeOH) to obtain the title compound (521 mg, 40.5% yield, light yellow solid). LC-MS (ESI) m/z: 344.4 [M+H] + .

步骤7：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 7: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(490mg,1.43mmol)和KOH(200mg,3.57mmol)溶解于DMF(30mL)中，再分批量缓慢加入I2(724mg,2.85mmol)，反应混合物在N2保护下在25℃下搅拌2hrs。加入饱和Na2SO3水溶液淬灭反应，用EA(30mL×2)萃取，再用水洗涤两次，无水Na2SO4干燥，过滤。减压浓缩，残余物经正相柱层析分离纯化(PE:EA，80％ EA)，得到目标化合物(203mg,收率30.3％，淡黄色油状物)。LC-MS(ESI)m/z:470.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (490 mg, 1.43 mmol) and KOH (200 mg, 3.57 mmol) were dissolved in DMF (30 mL). I₂ (724 mg, 2.85 mmol ) was slowly added portionwise. The reaction mixture was stirred at 25°C for 2 hr under N₂ protection. The reaction mixture was quenched by addition of saturated aqueous Na₂SO₃ solution, extracted with EA (30 mL x 2), washed twice with water, dried over anhydrous Na₂SO₄ , and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by normal phase column chromatography (PE:EA, 80% EA) to obtain the title compound (203 mg, 30.3% yield, as a light yellow oil). LC-MS(ESI)m/z:470.2[M+H] + .

步骤8：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 8: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(100mg,0.21mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(125mg,0.64mmol)、吡啶(67mg,0.85mmol)和醋酸铜(85mg,0.43mmol)依次加入到NMP(10mL)中。在O2氛围下置换三次，反应液在O2氛围下50℃搅拌16hrs，冷却至室温。向反应混合物中加入水(20mL)，用EA(20mL×2)萃取。合并有机相用，饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，10％EA)，得到目标化合物(100mg,收率75.8％，黄色固体)。LC-MS(ESI)m/z:620.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (100 mg, 0.21 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (125 mg, 0.64 mmol), pyridine (67 mg, 0.85 mmol), and copper acetate (85 mg, 0.43 mmol) were added sequentially to NMP (10 mL). The atmosphere was replaced with O₂ three times, and the reaction solution was stirred at 50°C under an O₂ atmosphere for 16 hrs before cooling to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 5), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 10% EA) to obtain the title compound (100 mg, 75.8% yield, yellow solid). LC-MS (ESI) m/z: 620.2 [M+H] ⁺ .

步骤9：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 9: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(50mg,0.081mmol)、Zn(CN)2(28mg,0.24mmol)、锌粉(16mg,0.24mmol)、Pd2(dba)3(3.7mg,0.004mmol)和Pd(dppf)Cl2(5.9mg,0.008mmol)依次加入到DMA(30mL)中。反应混合物在N2保护下下150℃搅拌1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取。合并有机相，用饱和食盐水(30mL×5)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到粗品目标化合物(41.8mg,粗品，黑色油状物)。LC-MS(ESI)m/z:519.4[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (50 mg, 0.081 mmol), Zn(CN) ( 28 mg, 0.24 mmol), zinc powder (16 mg, 0.24 mmol), Pd (dba) ( 3.7 mg, 0.004 mmol), and Pd(dppf) Cl (5.9 mg, 0.008 mmol) were added sequentially to DMA (30 mL). The reaction mixture was stirred at 150° C. under N protection for 1 hr and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 5), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the crude title compound (41.8 mg, crude product, black oil). LC-MS (ESI) m/z: 519.4 [M+H] ⁺ .

步骤10：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 10: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(41.8mg,粗品)溶于THF(3mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(column:Xtimate C18,21.2*250mm,5um；流动相：0.1％FA/H2O；流动相B：ACN，梯度：25-55％B,流速：20mL/min，30min)分离纯化，得到目标化合物(6.75mg,收率19.3％，白色固体)。LC-MS(ESI)m/z:435.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.89(s,1H),6.83(t,J＝2.0Hz,1H),6.34(s,1H),4.76(d,J＝3.7Hz,1H),4.62–4.60(m,2H),3.84–3.73(m,2H),3.68–3.62(m,2H),3.58–3.52(m,3H),2.89–2.84(m,1H),2.07–2.04(m,1H),1.99–1.93(m,4H),1.82–1.78(m,2H),1.5 3–1.46(m,1H),1.13(d,J＝6.2Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (41.8 mg, crude product) was dissolved in THF (3 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at 25° C. for 16 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase: 0.1% FA/H 2 O; mobile phase B: ACN, gradient: 25-55% B, flow rate: 20 mL/min, 30 min) to obtain the title compound (6.75 mg, yield 19.3%, white solid). LC-MS (ESI) m/z: 435.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.07(s,1H),7.89(s,1H),6.83(t,J＝2.0Hz,1H),6.34(s,1H),4.76(d,J＝3.7Hz,1H),4.62–4.60(m,2H),3.84–3.73(m, 2H),3.68–3.62(m,2H),3.58–3.52(m,3H),2.89–2.84(m,1H),2.07–2.04(m,1H),1.99–1.93(m,4H),1.82–1.78(m,2H),1.5 3–1.46(m,1H),1.13(d,J＝6.2Hz,3H).

实施例55:8-(3-(乙基磺酰基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂双环[3.2.1]辛烷
Example 55: 8-(3-(ethylsulfonyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

步骤1：8-(3-(乙基磺酰基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-(ethylsulfonyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.17mmol)的DMSO(10mL)溶液中加入乙烷亚磺酸钠(58mg,0.50mmol)、L-脯氨酸(1.9mg,0.017mmol)、CuI(3.2mg,0.017mmol)和K3PO4(38mg,0.18mmol)，N2气保护下，将反应混合物在100℃下在搅拌16hrs。用EA(20mL)和H2O(20mL)稀释反应物，用EA(10mL×2)萃取反应，合并有机相，用水(50mL×5)洗涤，减压浓缩，得到目标化合物(94mg,粗品，黄色油状物)。LC-MS(ESI)m/z:572.2[M+H]+。To a solution of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.17 mmol) in DMSO (10 mL) were added sodium ethanesulfinate (58 mg, 0.50 mmol), L-proline (1.9 mg, 0.017 mmol), CuI (3.2 mg, 0.017 mmol) and K 3 PO 4 (38 mg, 0.18 mmol). Under N 2 protection, the reaction mixture was stirred at 100° C. for 16 hrs. The reaction was diluted with EA (20 mL) and H 2 O (20 mL), extracted with EA (10 mL×2), and the organic phases were combined, washed with water (50 mL×5), and concentrated under reduced pressure to obtain the target compound (94 mg, crude product, yellow oil). LC-MS (ESI) m/z: 572.2 [M+H] + .

步骤2：8-(3-(乙基磺酰基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-(ethylsulfonyl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(3-(乙基磺酰基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(94mg,0.16mmol)的THF(9mL)溶液中加入4N盐酸/1,4二氧六环溶液(3mL)，反应液在25℃下搅拌16hrs，减压浓缩。残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：30-60％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(20.59mg,收率25.7％，白色固体)。LC-MS(ESI)m/z:488.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),7.89(s,1H),6.80(d,J＝2.3Hz,1H),6.55(s,1H),4.66–4.60(m,2H),3.95–3.89(m,1H),3.88–3.63(m,7H),3.63–3.55(m,3H),3.46–3.42(m,1H),2.75–2.69(m,1H),2.02–1.91(m,4H),1.23(t,J＝7.4Hz,3H),0.89(d,J＝6.2Hz,3H).To a solution of 8-(3-(ethylsulfonyl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (94 mg, 0.16 mmol) in THF (9 mL) was added 4N hydrochloric acid/1,4-dioxane solution (3 mL). The reaction solution was stirred at 25°C for 16 hrs and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Xtimate C18 column, 21.2 x 250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 30-60% B, detection wavelength at 214 nm, flow rate: 20 mL/min, column temperature at 25°C) to obtain the title compound (20.59 mg, 25.7% yield, white solid). LC-MS (ESI) m/z: 488.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.05(s,1H),7.89(s,1H),6.80(d,J＝2.3Hz,1H),6.55(s,1H),4.66–4.60(m,2H),3.95–3.89(m,1H),3.88–3.63(m,7H) ,3.63–3.55(m,3H),3.46–3.42(m,1H),2.75–2.69(m,1H),2.02–1.91(m,4H),1.23(t,J＝7.4Hz,3H),0.89(d,J＝6.2Hz,3H).

实施例56:8-(5-氯-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环 [3.2.1]辛烷
Example 56: 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo [3.2.1]octane

步骤1：8-(5-氯-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

0℃下，往三口烧瓶中加入i-PrMgCl(0.25mL)，然后滴加8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.17mmol)的THF(4mL)溶液，搅拌2hrs后，将反应温度降低至-30℃后，然后缓慢加入NCS(220mg,1.65mmol)，继续搅拌6hrs，加入饱和NH4Cl溶液，用EA(10mL×2)萃取，合并有机相，减压浓缩，得到粗产品(80mg,收率94.2％，黄色油状物)，直接进行下一步反应。LC-MS(ESI)m/z:514.4[M+H]+。To a three-necked flask at 0°C, i-PrMgCl (0.25 mL) was added, followed by dropwise addition of a solution of 8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.17 mmol) in THF (4 mL). After stirring for 2 hrs, the reaction temperature was lowered to -30°C, and NCS (220 mg, 1.65 mmol) was slowly added. Stirring was continued for 6 hrs, followed by addition of saturated NH4Cl solution, and extraction with EA (10 mL × 2). The organic phases were combined and concentrated under reduced pressure to give the crude product (80 mg, 94.2% yield, yellow oil), which was directly used for the next step. LC-MS(ESI)m/z:514.4[M+H] + .

步骤2：8-(5-氯-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(5-氯-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(70mg,0.14mmol)溶于THF(6mL)中，加入4N盐酸/1,4-二氧六环溶液(3mL)后，立即置换N2三次，反应液在N2保护下在25℃下搅拌12hrs。减压浓缩，残余物中加入饱和NaHCO3溶液(10mL)至碱性，用EA(5mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：10-40％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(5.0mg,收率8.5％，黄色固体)。LC-MS(ESI)m/z:430.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.66(s,1H),8.18(t,J＝3.5Hz,1H),6.14(d,J＝2.2Hz,1H),4.59(d,J＝4.1Hz,1H),4.45(d,J＝6.5Hz,1H),4.18–4.05(m,1H),3.98–3.83(m,3H),3.76–3.60(m,5H),3.33(s,1H),3.02(d,J＝11.5Hz,1H),1.97–1.74(m,4H),0.84(d,J＝6.5Hz,3H)。8-(5-chloro-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (70 mg, 0.14 mmol) was dissolved in THF (6 mL). After adding 4N hydrochloric acid/1,4-dioxane solution (3 mL), the N2 atmosphere was immediately replaced three times. The reaction solution was stirred at 25°C under N2 protection for 12 hrs. The mixture was concentrated under reduced pressure, and saturated NaHCO₃ solution (10 mL) was added to the residue until alkaline. The mixture was extracted with EA (5 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2 x 250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 10-40% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (5.0 mg, yield: 8.5%), as a yellow solid. LC-MS (ESI) m/z: 430.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ10.07(s,1H),8.66(s,1H),8.18(t,J＝3.5Hz,1H),6.14(d,J＝2.2Hz,1H),4.59(d,J＝4.1Hz,1H),4.45(d,J＝6.5Hz,1H),4.18–4 .05(m,1H),3.98–3.83(m,3H),3.76–3.60(m,5H),3.33(s,1H),3.02(d,J＝11.5Hz,1H),1.97–1.74(m,4H),0.84(d,J＝6.5Hz,3H).

实施例57:6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 57: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：8-(1-(四氢-2H-吡喃-2-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(1-(tetrahydro-2H-pyran-2-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(600mg,1.36mmol)，[2-(三氟甲基)吡啶-3-基]硼二醇(312mg,1.63mmol)，Pd(dppf)Cl2(49.86mg,0.068mmol)和Na2CO3(361mg,3.40mmol)依次加入到1,4-二氧六环(10mL)/H2O(2mL)混合溶液中。反应混合物N2保护下100℃下搅拌过夜。冷却至室温。向反应混合物中加入水(20mL)，用EA(10mL×2)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，30％EA)，得到目标化合物(400mg,收率63.8％，白色固体)。LC-MS(ESI)m/z:460.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (600 mg, 1.36 mmol), [2-(trifluoromethyl)pyridin-3-yl]boranediol (312 mg, 1.63 mmol), Pd(dppf) Cl₂ (49.86 mg, 0.068 mmol), and Na₂CO₃ (361 mg, 3.40 mmol) were added sequentially to a mixture of 1,4-dioxane (10 mL) and H₂O (2 mL). The reaction mixture was stirred at 100°C overnight under N₂ protection and cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (400 mg, yield 63.8%, white solid). LC-MS (ESI) m/z: 460.2 [M+H] + .

步骤2：8-(4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(1-(四氢-2H-吡喃-2-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(400mg,0.87mmol)和4N盐酸/1,4-二氧六环溶液(10mL)依次加入到MeOH(10mL)中。反应混合物N2保护下50℃下搅拌16hrs，冷却至室温。向反应混合物中加入饱和Na2CO3水溶液(10mL)，用EA(10mL×2)萃取。合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(300mg,0.80mmol，收率91.8％，白色固体)。LC-MS(ESI)m/z:376.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),8.90–8.84(m,1H),8.10–8.06(m,1H),7.88–7.83(m,1H),7.50(s,1H),6.69(s,1H),4.56(s,2H),3.70(d,J＝10.8Hz,2H),3.54(d,J＝10.7Hz,2H),2.03–1.90(m,5H).8-(1-(tetrahydro-2H-pyran-2-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400 mg, 0.87 mmol) and a 4N hydrochloric acid/1,4-dioxane solution (10 mL) were added sequentially to MeOH (10 mL). The reaction mixture was stirred at 50°C under N₂ protection for 16 hours and then cooled to room temperature. Saturated aqueous Na₂CO₃ solution (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (300 mg, 0.80 mmol, 91.8% yield) as a white solid. LC-MS(ESI)m/z:376.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.05(s,1H),8.90–8.84(m,1H),8.10–8.06(m,1H),7.88–7.83(m,1H),7.50(s,1H),6. 69(s,1H),4.56(s,2H),3.70(d,J＝10.8Hz,2H),3.54(d,J＝10.7Hz,2H),2.03–1.90(m,5H).

步骤3：8-(3-碘-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(3-iodo-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(300mg,0.80mmol)，KOH(134mg,2.40mmol)依次加入到DMF(20mL)中，分批次缓慢加入I2(406mg,1.60mmol)，反应混合物N2保护下室温搅拌2hrs。向反应混合物中加入水(20mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(400mg,收率99.8％，黄色固体)。LC-MS(ESI)m/z:502.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),8.87(d,J＝4.6Hz,1H),8.05–7.98(m,1H),7.89–7.83(m,1H),6.72(s,1H),4.57(s,2H),3.73–3.61(m,2H),3.59–3.49(m,2H),1.99–1.90(m,4H).8-(4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (300 mg, 0.80 mmol) and KOH (134 mg, 2.40 mmol) were added sequentially to DMF (20 mL). I₂ (406 mg, 1.60 mmol) was added slowly in batches. The reaction mixture was stirred at room temperature under nitrogen for 2 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 3 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (400 mg, 99.8% yield, as a yellow solid). LC-MS (ESI) m/z: 502.0 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.44(s,1H),8.87(d,J＝4.6Hz,1H),8.05–7.98(m,1H),7.89–7.83(m,1H),6. 72(s,1H),4.57(s,2H),3.73–3.61(m,2H),3.59–3.49(m,2H),1.99–1.90(m,4H).

步骤4：8-(3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(300mg,0.60mmol)，醋酸铜(435mg,2.40mmol)，吡啶(189mg,2.39mmol)和[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(352mg,1.80mmol)依次加入到NMP(6mL)中。反应混合物在N2保护下50℃搅拌24hrs。向反应混合物中加入水(30mL)，用EA(30mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)，得到目标化合物(300mg,收率76.9％，淡黄色固体)。LC-MS(ESI)m/z:652.2[M+H]+。8-(3-iodo-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (300 mg, 0.60 mmol), copper acetate (435 mg, 2.40 mmol), pyridine (189 mg, 2.39 mmol), and [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (352 mg, 1.80 mmol) were added sequentially to NMP (6 mL). The reaction mixture was stirred at 50° C. under N protection for 24 hrs. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (300 mg, 76.9% yield, light yellow solid). LC-MS (ESI) m/z: 652.2 [M+H] + .

步骤5：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.15mmol)，ZnCN(54mg,0.46mmol)，锌粉(30mg,0.46mmol)，Pd(dppf)Cl2(22mg,0.031mmol)和Pd2(dba)3(14mg,0.015mmol)依次加入到DMA(5mL)中。N2保护下，反应混合物在150℃下搅拌1.5hrs，冷却至室温。向反应混合物中加入水(5mL)，用EA(10mL×3)萃取，合并有机相依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，70％EA)，得到目标化合物(80mg,收率94.6％，类白色固体)。LC-MS(ESI)m/z:551.2[M+H]+。8-(3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.15 mmol), ZnCN (54 mg, 0.46 mmol), zinc powder (30 mg, 0.46 mmol), Pd(dppf) Cl₂ (22 mg, 0.031 mmol), and Pd₂ (dba) ₃ (14 mg, 0.015 mmol) were added sequentially to DMA (5 mL). Under N₂ protection, the reaction mixture was stirred at 150°C for 1.5 hrs and then cooled to room temperature. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 70% EA) to obtain the title compound (80 mg, 94.6% yield, off-white solid). LC-MS (ESI) m/z: 551.2 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(2-(三氟甲基)吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(80mg,0.15mmol)溶于THF(3mL)中，加入4N盐酸/1,4-二氧六环溶液(3mL)。反应混合物在50℃下搅拌3hrs，冷却至室温。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：32-62％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(15.0mg,收率22.3％，白色固体)。LC-MS(ESI)m/z:467.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.94(d,J＝4.7Hz,1H),8.21(d,J＝7.8Hz,1H),7.96–7.90(m,2H),7.11(s,1H),6.89(d,J＝1.7Hz,1H),4.68(s,2H),3.72–3.60(m,4H),2.08–1.93(m,4H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (80 mg, 0.15 mmol) was dissolved in THF (3 mL), and a 4N hydrochloric acid/1,4-dioxane solution (3 mL) was added. The reaction mixture was stirred at 50°C for 3 hours and then cooled to room temperature. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 32-62% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (15.0 mg, 22.3% yield, white solid). LC-MS (ESI) m/z: 467.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.18(s,1H),8.94(d,J＝4.7Hz,1H),8.21(d,J＝7.8Hz,1H),7.96–7.90(m,2H),7. 11(s,1H),6.89(d,J＝1.7Hz,1H),4.68(s,2H),3.72–3.60(m,4H),2.08–1.93(m,4H).

实施例58和实施例59:(S)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3- 基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺和(R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3- 甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺
Example 58 and Example 59: (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine and (R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3- methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine

步骤1：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙基甲磺酰酯的合成
Step 1: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethyl methanesulfonyl ester

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(100mg,0.17mmol)溶于DCM(2mL)溶液中，加入Et3N(23mg,0.23mmol)和甲磺酰氯(30mg,0.17mmol)，反应混合物在室温下搅拌16hrs后，减压浓缩，得到目标化合物(50mg,收率66.9％，黄色油状物)。LC-MS(ESI)m/z:656.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (100 mg, 0.17 mmol) was dissolved in DCM (2 mL). Et₃N (23 mg, 0.23 mmol) and methanesulfonyl chloride (30 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to obtain the title compound (50 mg, 66.9% yield, yellow oil). LC-MS (ESI) m/z: 656.2 [M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙基甲磺酰酯(100mg,0.15mmol)加入到高压反应釜中，然后向釜中加入7.0N氨甲醇溶液，密封反应釜在80℃下搅拌3hrs，减压浓缩，残余物用反向柱分离纯化(MeCN：H2O，50％MeCN)得到目标化合物(50mg,收率56.8％，白色固体)。LC-MS(ESI)m/z:577.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethyl methanesulfonyl ester (100 mg, 0.15 mmol) was added to an autoclave. 7.0 N ammonia methanol solution was then added. The autoclave was sealed and stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified using a reverse phase column chromatography (MeCN: H2O , 50% MeCN) to afford the title compound (50 mg, 56.8% yield, as a white solid). LC-MS (ESI) m/z: 577.2 [M+H] + .

步骤3：(R))-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺和(S))-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺的合成
Step 3: Synthesis of (R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine and (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-胺(40mg,0.069mmol)溶于THF(1mL)中，加入4N盐酸/1,4二氧六环溶液(1mL)。反应混合物在室温下搅拌3hrs。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.05％NH3.H2O/水，流动相B：ACN；梯度：25-55％B，检测波长214nm，流速：20mL/min，柱温25℃)纯化。最后经手性拆分SFC(column：Daicel ChiralCel OD，40mm I.D.*250mm，10um：Supercritical CO2；B％：40，溶剂：0.1％ NH3H2O Methanol，流速：120mL/min，6.55/8.5min)分离纯化得到目标化合物P1(31.53mg,收率36.9％，白色固体)。LC-MS(ESI)m/z:493.2[M+H]+。SFC(方法D)：RT＝1.656min。1H NMR(400MHz,Methanol-d4)δ7.64(s,1H),6.83(s,1H),6.50(s,1H),5.37–5.27(m,1H),4.54(s,2H),3.85–3.78(m,2H),3.77–3.66(m,3H),3.54(d,J＝10.8Hz,2H),3.42–3.29(m,2H),3.10–3.03(m,1H),2.91–2.83(m,1H),2.06–1.91(m,4H),0.84(d,J＝6.0Hz,3H)。和P2(5.91mg,收率6.9％，白色固体)。LC-MS(ESI)m/z:493.2[M+H]+。SFC(方法A)：RT＝2.299min。1H NMR(400MHz,Methanol-d4)δ7.64(s,1H),6.85(s,1H),6.35(s,1H),4.95(s,1H),4.56–4.51(m,2H),3.88–3.82(m,1H),3.82–3.75(m,3H),3.72(d,J＝10.8Hz,1H),3.54(d,J＝11.0Hz,2H),3.49–3.42(m,1H),3.41–3.34(m,1H),3.31–3.24(m,1H),2.78–2.70(m,1H),2.06–1.90(m,4H),0.88(d,J＝6.1Hz,3H).1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-amine (40 mg, 0.069 mmol) was dissolved in THF (1 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.05% NH₃.H₂O /water, mobile phase B: ACN; gradient: 25-55% B, detection wavelength: 214 nm, flow rate: 20 mL/ min , column temperature: 25°C). Finally, chiral separation and purification by SFC (column: Daicel ChiralCel OD, 40 mm ID*250 mm, 10 μm: Supercritical CO₂ ; B%: 40, solvent: 0.1% NH₃H₂O / Methanol, flow rate: 120 mL/min, 6.55/8.5 min) afforded the title compound P1 (31.53 mg, 36.9% yield, white solid). LC-MS (ESI) m/z: 493.2 [M+H] ⁺ . SFC (Method D): RT = 1.656 min. 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.64 (s, 1H), 6.83 (s, 1H), 6.50 (s, 1H), 5.37–5.27 (m, 1H), 4.54 (s, 2H), 3.85–3.78 (m, 2H), 3.77–3.66 (m, 3H), 3.54 (d, J = 10.8 Hz, 2H), 3.42–3.29 (m, 2H), 3.10–3.03 (m, 1H), 2.91–2.83 (m, 1H), 2.06–1.91 (m, 4H), 0.84 (d, J = 6.0 Hz, 3H). And P2 (5.91 mg, 6.9% yield, white solid). LC-MS (ESI) m/z: 493.2 [M+H] + . SFC (Method A): RT = 2.299 min. 1 H NMR (400MHz, Methanol-d 4 )δ7.64(s,1H),6.85(s,1H),6.35(s,1H),4.95(s,1H),4.56–4.51(m,2H),3.88–3.82(m,1H),3.82–3.75(m,3H),3.72(d,J＝10.8Hz,1H),3. 54(d,J＝11.0Hz,2H),3.49–3.42(m,1H),3.41–3.34(m,1H),3.31–3.24(m,1H),2.78–2.70(m,1H),2.06–1.90(m,4H),0.88(d,J＝6.1Hz,3H).

实施例60：8-(4-((R)-3-甲基吗啉基)-3-(全氟乙基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂双环[3.2.1]辛烷
Example 60: 8-(4-((R)-3-methylmorpholinyl)-3-(perfluoroethyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

步骤1：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇的合成
Step 1: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1-醇(100mg,0.17mmol)溶于DCM(8mL)中，然后加入NMO(40.6mg,0.35mmol)和TPAP(6.0mg,0.02mmol)，反应混合物在N2保护下在室温下搅拌12hrs，向反应混合物中加入水，用DCM(20mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品直接进行下一步反应(80mg,收率77.9％，黄色油状物)。LC-MS((ESI)m/z:594.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1-ol (100 mg, 0.17 mmol) was dissolved in DCM (8 mL), and then NMO (40.6 mg, 0.35 mmol) and TPAP (6.0 mg, 0.02 mmol) were added. The reaction mixture was stirred at room temperature under N2 protection for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL×2) . The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (80 mg, yield 77.9%, yellow oil) which was directly used for the next reaction. LC-MS((ESI)m/z:594.2[M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-3-(全氟乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(perfluoroethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,2,2-三氟乙烷-1,1-二醇(80mg,0.13mmol)溶于DCM(6mL)中，然后在0℃下缓慢滴加DAST(130mg,0.81mmol)，反应混合物在N2保护下在室温下反应12hrs，反应结束后，向反应混合物中加入饱和NaHCO3溶液，用DCM(20mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品直接进行下一步反应(80mg,收率99.3％，黄色油状物)。LC-MS(ESI)m/z:598.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol (80 mg, 0.13 mmol) was dissolved in DCM (6 mL), and then DAST (130 mg, 0.81 mmol) was slowly added dropwise at 0°C. The reaction mixture was reacted at room temperature under N2 protection for 12 hrs. After the reaction, saturated NaHCO3 solution was added to the reaction mixture, and the mixture was extracted with DCM (20 mL×2). The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product which was directly used for the next reaction (80 mg, yield 99.3%, yellow oil). LC-MS(ESI)m/z:598.2[M+H] + .

步骤3：8-(4-((R)-3-甲基吗啉基)-3-(全氟乙基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-(perfluoroethyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-3-(全氟乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.13mmol)溶于DCM(5mL)中，然后加入TFA(2.5mL)，反应混合物在N2保护下在室温下搅拌12hrs。向反应混合物中加入饱和NaHCO3溶液(10mL)，用EA(10mL×2)萃取，合并有机相用水(10mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/H2O，流动相B：ACN；梯度：45-75％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化后得到目标化合物(10.0mg,收率14.6％，白色固体)。LC-MS(ESI)m/z:514.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.88(s,1H),6.77(s,1H),6.63(s,1H),4.61(d,J＝15.6Hz,2H),3.83(dd,J＝11.0,2.8Hz,1H),3.80–3.72(m,1H),3.72–3.59(m,3H),3.59–3.51(m,3H),3.38–3.33(m,1H),3.22(d,J＝12.6Hz,1H),2.80–2.70(m,1H),2.01–1.82(m,4H),0.85(d,J＝6.2Hz,3H).8-(4-((R)-3-methylmorpholinyl)-3-(perfluoroethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.13 mmol) was dissolved in DCM (5 mL), and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature under N protection for 12 hrs. Saturated NaHCO₃ solution (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with water (10 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/ H₂O , mobile phase B: ACN; gradient: 45-75% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (10.0 mg, yield: 14.6%, white solid). LC-MS (ESI) m/z: 514.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.88(s,1H),6.77(s,1H),6.63(s,1H),4.61(d,J＝15.6Hz,2H),3.83(dd,J＝11.0,2.8Hz,1H),3.80–3.72(m,1H),3.72– 3.59(m,3H),3.59–3.51(m,3H),3.38–3.33(m,1H),3.22(d,J＝12.6Hz,1H),2.80–2.70(m,1H),2.01–1.82(m,4H),0.85(d,J＝6.2Hz,3H).

实施例61：8-(7-((R)-3-甲基吗啉基)-3-(1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-5-基)-3-氧 杂-8-氮杂双环[3.2.1]辛烷
Example 61: 8-(7-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-oxa- 8-azabicyclo[3.2.1]octane

步骤1：7-溴-5-氯-3-碘-1H-吡唑并[4,3-b]吡啶的合成
Step 1: Synthesis of 7-bromo-5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

将7-溴-5-氯-1H-吡唑并[4,3-b]吡啶(785mg,3.38mmol)和NIS(1026mg,4.56mmol)依次加入到DMF(39mL)中。N2保护下，反应混合物在35℃下搅拌过夜。向反应混合物中加入水(50mL)，用EA(20mL×2)萃取。合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，15％EA)得到目标化合物(1.2g,收率99.2％，黄色固体)。LC-MS(ESI)m/z:357.8[M+H]+。7-Bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (785 mg, 3.38 mmol) and NIS (1026 mg, 4.56 mmol) were added sequentially to DMF (39 mL). Under N₂ protection, the reaction mixture was stirred at 35°C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 15% EA) to obtain the title compound (1.2 g, 99.2% yield, as a yellow solid). LC-MS (ESI) m/z: 357.8 [M+H] ⁺ .

步骤2：7-溴-5-氯-3-碘-1-(2,2,2-三氟乙基)吡唑并[4,3-b]吡啶的合成
Step 2: Synthesis of 7-bromo-5-chloro-3-iodo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine

将7-溴-5-氯-3-碘-1H-吡唑并[4，3-b]吡啶(1g,2.79mmol)溶于DMF(30mL)，然后依次加入Cs2CO3(2.73g,8.37mmol)和2，2，2-三氟乙基三氟甲磺酸酯(0.71g,3.07mmol)。反应混合物在N2保护下25℃下搅拌16hrs。向反应混合物中加入饱和NH4Cl溶液和EA稀释，用EA(80mL×2)萃取。合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，10％EA)得到目标化合物(750mg,收率61.0％，白色固体)。LC-MS(ESI)m/z:439.8[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),5.65(q,J＝8.6Hz,2H)。7-Bromo-5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (1 g, 2.79 mmol) was dissolved in DMF (30 mL), followed by the addition of Cs2CO3 (2.73 g, 8.37 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.71 g, 3.07 mmol). The reaction mixture was stirred at 25°C for 16 hr under N2 protection. Saturated NH4Cl solution and EA were added to the reaction mixture, which was then extracted with EA (80 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 10% EA) to afford the title compound (750 mg, 61.0% yield, as a white solid). LC-MS (ESI) m/z: 439.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 5.65 (q, J = 8.6Hz, 2H).

步骤3：(R)-4-(5-氯-3-碘-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-7-基)-3-甲基吗啉的合成
Step 3: Synthesis of (R)-4-(5-chloro-3-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-3-methylmorpholine

将7-溴-5-氯-3-碘-1-(2，2，2-三氟乙基)吡唑并[4，3-b]吡啶(600mg,1.36mmol)溶于NMP(10mL)中，加入(R)-3-甲基吗啉(1378mg,13.62mmol)，反应混合物在微波条件下160℃搅拌2hrs，冷却至室温。向反应混合物中加入水(50mL)，用EA(50mL×2)萃取，合并有机相,用食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，经硅胶柱层析分离纯化(PE：EA，30％EA)得到目标化合物(200mg,收率31.8％，黄色固体)。LC-MS(ESI)m/z:461.0[M+H]+。7-Bromo-5-chloro-3-iodo-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine (600 mg, 1.36 mmol) was dissolved in NMP (10 mL), and (R)-3-methylmorpholine (1378 mg, 13.62 mmol) was added. The reaction mixture was stirred at 160°C under microwave conditions for 2 hours and then cooled to room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The title compound was isolated and purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (200 mg, 31.8% yield, as a yellow solid). LC-MS (ESI) m/z: 461.0 [M+H] ⁺ .

步骤4：(3R)-4-(5-氯-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡喃并[4,3-b]吡啶-7-基)-3-甲基吗啉的合成
Step 4: Synthesis of (3R)-4-(5-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrano[4,3-b]pyridin-7-yl)-3-methylmorpholine

将(R)-4-(5-氯-3-碘-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-7-基)-3-甲基吗啉(200mg,0.43mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(127mg,0.65mmol)、K3PO4(276mg,1.30mmol)和Pd(dppf)Cl2(31.8mg,0.043mmol)依次加入到1,4-二氧六环(5mL)和水(1mL)混合溶液中。反应混合物在N2保护下80℃搅拌16hrs，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取。合并有机相用饱和食盐水(10mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(60mg,收率28.5％，黄色固体)。LC-MS(ESI)m/z:485.2[M+H]+。(R)-4-(5-chloro-3-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-3-methylmorpholine (200 mg, 0.43 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (127 mg, 0.65 mmol), K₃PO₄ ( 276 mg, 1.30 mmol), and Pd(dppf) Cl₂ (31.8 mg, 0.043 mmol) were added sequentially to a mixture of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 80°C under N₂ protection for 16 hours and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 50% EA) to afford the title compound (60 mg, 28.5% yield, yellow solid). LC-MS (ESI) m/z: 485.2 [M+H] ⁺ .

步骤5：8-(7-((R)-3-甲基吗啉基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(7-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(3R)-4-(5-氯-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡喃并[4,3-b]吡啶-7-基)-3-甲基吗啉(45mg,0.09mmol)和3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐(32mg,0.28mmol)溶于1,4-二氧六环(2mL)中，然后依次加入Cs2CO3(182mg,0.56mmol)，RuPhos(8.7mg,0.019mmol)和Ruphos Pd G2(7.8mg,0.009mmol)。反应混合物在N2保护下100℃搅拌16hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(10mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，68％EA)得到目标化合物(40mg,收率76.7％，黄色油状物)。LC-MS(ESI)m/z:562.2[M+H]+。(3R)-4-(5-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrano[4,3-b]pyridin-7-yl)-3-methylmorpholine (45 mg, 0.09 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (32 mg, 0.28 mmol) were dissolved in 1,4-dioxane (2 mL), and then Cs 2 CO 3 (182 mg, 0.56 mmol), RuPhos (8.7 mg, 0.019 mmol), and Ruphos Pd G2 (7.8 mg, 0.009 mmol) were added in sequence. The reaction mixture was stirred at 100° C. under N 2 protection for 16 hrs and then cooled to room temperature. The reaction mixture was diluted with water and EA, extracted with EA (10 mL x 2), and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 68% EA) to obtain the title compound (40 mg, 76.7% yield, yellow oil). LC-MS (ESI) m/z: 562.2 [M+H] + .

步骤6：8-(7-((R)-3-甲基吗啉基)-3-(1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(7-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(7-((R)-3-甲基吗啉基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-b]吡啶-5-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.053mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)。反应混合物在50℃下搅拌16hrs，冷却至室温。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：30-60％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(12.0mg,收率47.0％，白色固体)。LC-MS(ESI)m/z:478.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),7.64(s,1H),7.03(s,1H),6.91(s,1H),5.55–5.47(m,1H),5.37–5.26(m,1H),4.60(d,J＝15.8Hz,2H),4.03(t,J＝6.4Hz,1H),3.93–3.81(m,2H),3.79–3.69(m,3H),3.57(d,J＝10.8Hz,2H),3.51–3.42(m,1H),3.40–3.31(m,1H),3.09(s,1H),2.91–2.83(m,1H),2.01–1.86(m,4H),0.84(d,J＝6.1Hz,3H)。8-(7-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.053 mmol) was dissolved in THF (2 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 50°C for 16 hours and then cooled to room temperature. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 30-60% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (12.0 mg, yield: 47.0%, white solid). LC-MS (ESI) m/z: 478.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.03(s,1H),7.64(s,1H),7.03(s,1H),6.91(s,1H),5.55–5.47(m,1H),5.3 7–5.26(m,1H),4.60(d,J＝15.8Hz,2H),4.03(t,J＝6.4Hz,1H),3.93–3.81(m,2H ),3.79–3.69(m,3H),3.57(d,J＝10.8Hz,2H),3.51–3.42(m,1H),3.40–3.31(m, 1H), 3.09 (s, 1H), 2.91–2.83 (m, 1H), 2.01–1.86 (m, 4H), 0.84 (d, J = 6.1Hz, 3H).

实施例62：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-d] 嘧啶-3-碳腈
Example 62: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d] pyrimidine-3-carbonitrile

步骤1：(3R)-4-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基吗啉的合成
Step 1: Synthesis of (3R)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine

将4,6-二氯-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-d]嘧啶(3.40g,12.45mmol)和(R)-3-甲基吗啉(1.89g,18.67mmol)溶于THF(70mL)中，加入DIPEA(4.83g,37.35mmol)，反应混合物在50℃下搅拌16hrs冷却至室温。向反应混合物中加入水和EA稀释，用EA萃取，合并有机相用水(50mL×2)洗涤，干燥，过滤，滤液减压浓缩，得到粗产品(4.00g,收率95.1％，黄色固体)。LC-MS(ESI)m/z:338.2[M+H]+。4,6-Dichloro-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine (3.40 g, 12.45 mmol) and (R)-3-methylmorpholine (1.89 g, 18.67 mmol) were dissolved in THF (70 mL). DIPEA (4.83 g, 37.35 mmol) was added, and the reaction mixture was stirred at 50°C for 16 hours and cooled to room temperature. The reaction mixture was diluted with water and EA, extracted with EA, and the combined organic phases were washed with water (50 mL x 2), dried, filtered, and the filtrate concentrated under reduced pressure to give the crude product (4.00 g, 95.1% yield, as a yellow solid). LC-MS (ESI) m/z: 338.2 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(3R)-4-(6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基吗啉(4.00g,11.84mmol)和8-氮杂-3-氧杂双环[3.2.1]辛烷(2.01g,17.76mmol)溶于NMP(80mL)中，加入DIPEA(4.59g,35.52mmol)，反应混合物在130℃下搅拌16hrs，冷却至室温，向反应混合物中加入水(100mL)，用EA(100mL×2)萃取，合并有机相用水(100mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，35％EA)得到目标化合物(3.26g,收率66.4％，黄色固体)。LC-MS(ESI)m/z:415.4[M+H]+。(3R)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (4.00 g, 11.84 mmol) and 8-aza-3-oxabicyclo[3.2.1]octane (2.01 g, 17.76 mmol) were dissolved in NMP (80 mL), and DIPEA (4.59 g, 35.52 mmol) was added. The reaction mixture was stirred at 130°C for 16 hrs, cooled to room temperature, and water (100 mL) was added to the reaction mixture. The mixture was extracted with EA (100 mL×2), and the combined organic phases were washed with water (100 mL×2), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 35% EA) to obtain the title compound (3.26 g, yield 66.4%, yellow solid). LC-MS (ESI) m/z: 415.4 [M+H] + .

步骤3：8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(3.26g,7.86mmol)溶于THF(30mL)中，加入4N盐酸/1,4-二氧六环溶液(30mL)。反应混合物在25℃下搅拌16hrs。向反应混合物中加入足量饱和Na2CO3水溶液调pH至碱性，用EA(30mL×2)萃取，合并有机相用水(50mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％MeOH)，得到目标化合物(2.30g,收率88.5％，白色固体)。LC-MS(ESI)m/z:331.2[M+H]+。8-(4-((R)-3-methylmorpholinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (3.26 g, 7.86 mmol) was dissolved in THF (30 mL), and a 4N hydrochloric acid/1,4-dioxane solution (30 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. Sufficient saturated aqueous Na₂CO₃ solution was added to the reaction mixture to adjust the pH to basic. The mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with water (50 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to obtain the title compound (2.30 g, 88.5% yield, as a white solid). LC-MS(ESI)m/z:331.2[M+H] + .

步骤4：8-(3-溴-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(3-bromo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(700mg,2.12mmol)溶于DMF(40mL)中，在0℃条件下加入NBS(566mg,3.18mmol)。反应混合物在25℃下搅拌2hrs。向反应混合物中加入足量饱和Na2SO3水溶液，用EA(50mL×2)萃取，合并有机相用水(50mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)，得到目标化合物(230mg,收率26.5％，黄色固体)。LC-MS(ESI)m/z:409.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),4.61–4.44(m,3H),4.00–3.85(m,2H),3.74–3.53(m,7H),3.50–3.41(m,1H),1.99–1.84(m,4H),1.31(d,J＝6.7Hz,3H)。8-(4-((R)-3-Methylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (700 mg, 2.12 mmol) was dissolved in DMF (40 mL), and NBS (566 mg, 3.18 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hr. A saturated aqueous Na₂SO₃ solution was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 2). The combined organic phases were washed with water (50 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (230 mg, 26.5% yield, as a yellow solid). LC-MS (ESI) m/z: 409.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.21(s,1H),4.61–4.44(m,3H),4.00–3.85(m,2H),3.74–3.53(m,7H),3.50–3.41(m,1H),1.99–1.84(m,4H),1.31(d,J＝6.7Hz,3H).

步骤5：8-(3-溴-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(3-bromo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-溴-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(150mg,0.37mmol)和[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(359mg,1.83mmol)溶于NMP(10mL)中，再加入吡啶(145mg,1.83mmol)、醋酸铜(220mg,1.10mmol)。O2氛围下置换三次，反应混合物在O2氛围下在50℃下搅拌16hrs，冷却至室温，向反应混合物中加入水和EA稀释，用EA(50mL×2)萃取，合并有机相用水(50mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)，得到目标化合物(100mg,收率48.8％，黄色固体)。LC-MS(ESI)m/z:559.2[M+H]+。8-(3-Bromo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (150 mg, 0.37 mmol) and [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (359 mg, 1.83 mmol) were dissolved in NMP (10 mL), followed by the addition of pyridine (145 mg, 1.83 mmol) and copper acetate (220 mg, 1.10 mmol). The reaction mixture was stirred at 50°C for 16 hr under an O2 atmosphere, cooled to room temperature, diluted with water and EA, and extracted with EA (50 mL × 2). The combined organic phases were washed with water (50 mL × 3), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (100 mg, 48.8% yield, yellow solid). LC-MS (ESI) m/z: 559.2 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-3-碳腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

将8-(3-溴-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.18mmol)和Zn(CN)2(63mg,0.54mmol)溶于二氧六环(4mL)和水(1mL)中，加入tBuBrettPhos Pd G3(31mg,0.04mmol)。反应混合物在N2保护下在120℃条件下搅拌16hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(20mL×2)萃取，合并有机相，用水洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶板层析分离纯化(PE：EA，50％EA)，得到目标化合物(50mg,收率55.3％，黄色固体)。LC-MS(ESI)m/z:506.4[M+H]+。8-(3-Bromo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.18 mmol) and Zn(CN) ₂ (63 mg, 0.54 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and tBuBrettPhos PdG₃ (31 mg, 0.04 mmol) was added. The reaction mixture was stirred at 120°C under N₂ protection for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (20 mL x 2). The organic phases were combined, washed with water, dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA, 50% EA) to obtain the title compound (50 mg, 55.3% yield, yellow solid). LC-MS (ESI) m/z: 506.4 [M+H] + .

步骤7：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-3-碳腈的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-3-碳腈(50mg,0.10mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物在N2保护下，25℃下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％TFA/水，流动相B：ACN；梯度：23-36％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(5.0mg,收率12.0％，白色固体)。LC-MS(ESI)m/z:422.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.17(s,1H),7.95(d,J＝2.3Hz,1H),6.88(d,J＝2.4Hz,1H),4.78–4.57(m,3H),4.42–4.33(m,1H),4.06–4.01(m,1H),3.84–3.79(m,1H),3.78–3.73(m,1H),3.71–3.65(m,4H),3.64–3.60(m,2H),2.06–1.90(m,4H),1.45(d,J＝6.8Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (50 mg, 0.10 mmol) was dissolved in THF (2 mL), and 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 25° C. under N 2 protection for 16 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% TFA/water, mobile phase B: ACN; gradient: 23-36% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (5.0 mg, 12.0% yield, white solid). LC-MS (ESI) m/z: 422.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.17(s,1H),7.95(d,J＝2.3Hz,1H),6.88(d,J＝2.4Hz,1H),4.78–4.57(m,3H),4.42–4.33(m,1H),4.06–4.01(m,1H) ,3.84–3.79(m,1H),3.78–3.73(m,1H),3.71–3.65(m,4H),3.64–3.60(m,2H),2.06–1.90(m,4H),1.45(d,J＝6.8Hz,3H).

实施例63：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-基)二甲基氧化膦
Example 63: (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridin-3-yl)dimethylphosphine oxide

步骤1：(6-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)二甲基氧化膦的合成
Step 1: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)dimethylphosphine oxide

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-碘-4-[(3R)-3-甲基-吗啉基-4-基]-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]吡唑并[3,4-b]吡啶(200mg,0.33mmol)和二甲基氧化膦(129mg,1.65mmol)溶于1,4-二氧六环(2mL)中，然后依次加入Cs2CO3(323mg,0.99mmol)，Xantphos(38mg,0.07mmol)，Pd2(dba)3(30mg,0.03mmol)。反应混合物在N2保护下微波120℃搅拌1hr。向反应混合物中加入水和EA稀释，用EA(10mL×2)萃取。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，8％MeOH)得到目标化合物(30mg,收率16.4％，白色固体)。LC-MS(ESI)m/z:556.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-iodo-4-[(3R)-3-methylmorpholinyl-4-yl]-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (200 mg, 0.33 mmol) and dimethylphosphine oxide (129 mg, 1.65 mmol) were dissolved in 1,4-dioxane (2 mL), followed by the addition of Cs 2 CO 3 (323 mg, 0.99 mmol), Xantphos (38 mg, 0.07 mmol), and Pd 2 (dba) 3 (30 mg, 0.03 mmol). The reaction mixture was stirred in a microwave at 120°C for 1 hr under N 2 protection. The reaction mixture was diluted with water and EA, and extracted with EA (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 8% MeOH) to obtain the title compound (30 mg, 16.4% yield, white solid). LC-MS (ESI) m/z: 556.2 [M+H] + .

步骤2：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)二甲基氧化膦的合成
Step 2: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)dimethylphosphine oxide

将(6-(3-氧杂-8-氮杂二环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)二甲基氧化膦(100mg,0.20mmol)溶于THF(3mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(column：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/H2O；流动相B：CAN；梯度:15-45％B，检测波长：214nm，流速:20mL/min，柱温25℃)分离纯化得到目标化合物(5.0mg,收率5.4％，白色固体)。LC-MS(ESI)m/z:472.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),7.86(s,1H),6.76(d,J＝2.2Hz,1H),6.43(s,1H),4.68–4.53(m,2H),4.05–3.87(m,3H),3.75–3.53(m,6H),3.47–3.41(m,1H),2.72–2.63(m,1H),2.02–1.82(m,10H),0.91(d,J＝6.2Hz,3H)。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)dimethylphosphine oxide (100 mg, 0.20 mmol) was dissolved in THF (3 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at 25°C for 16 hours and concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/H 2 O; mobile phase B: ACN; gradient: 15-45% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature 25°C) to obtain the title compound (5.0 mg, 5.4% yield, white solid). LC-MS (ESI) m/z: 472.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.93(s,1H),7.86(s,1H),6.76(d,J＝2.2Hz,1H),6.43(s,1H),4.68–4.53(m,2H),4.05–3.87(m,3H ),3.75–3.53(m,6H),3.47–3.41(m,1H),2.72–2.63(m,1H),2.02–1.82(m,10H),0.91(d,J=6.2Hz,3H).

实施例64：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-吗啉-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 64: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-morpholin-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

参考实施例20的方法合成实施例64(10.0mg,收率15.1％，白色固体)。LC-MS(ESI)m/z:407.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),7.89(s,1H),6.83(d,J＝1.8Hz,1H),6.23(s,1H),4.63-4.60(m,2H),3.86–3.82(m,4H),3.66(d,J＝10.8Hz,2H),3.57(d,J＝10.7Hz,2H),3.31–3.27(m,4H),2.01–1.90(m,4H)。Example 64 (10.0 mg, 15.1% yield, white solid) was synthesized using the method of Example 20. LC-MS (ESI) m/z: 407.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.09 (s, 1H), 7.89 (s, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.23 (s, 1H), 4.63-4.60 (m, 2H), 3.86-3.82 (m, 4H), 3.66 (d, J = 10.8 Hz, 2H), 3.57 (d, J = 10.7 Hz, 2H), 3.31-3.27 (m, 4H), 2.01-1.90 (m, 4H).

实施例65：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(3-(三氟甲基) 吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 65: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(3-(trifluoromethyl) morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

实施例66和实施例67：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-((S)-3-(三氟甲基)吗啉 基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-((R)-3-(三氟甲基) 吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 66 and Example 67: 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-((S)-3-(trifluoromethyl)morpholinyl )-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-((R)-3-(trifluoromethyl) morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：3-(苄氨基)-1,1,1-三氟丙-2-醇的合成
Step 1: Synthesis of 3-(benzylamino)-1,1,1-trifluoropropan-2-ol

将2-(三氟甲基)环氧乙烷(24.00g,214mmol)缓慢滴加到苯基甲胺(23.00g,215mmol)中，并产生轻微回流，冷却至40℃后，反应物用正己烷(30mL)稀释，并40℃继续搅拌16hrs。过滤，收集固体，用正己烷/EA(10：1，50mL)洗涤，得到目标产品(32.0g,收率68.0％，白色固体)。LC-MS(ESI)m/z:220.0[M+H]+。2-(Trifluoromethyl)oxirane (24.00 g, 214 mmol) was slowly added dropwise to phenylmethylamine (23.00 g, 215 mmol) with a slight reflux. After cooling to 40°C, the reaction was diluted with n-hexane (30 mL) and stirred at 40°C for 16 hours. The solid was collected by filtration and washed with n-hexane/EA (10:1, 50 mL) to obtain the desired product (32.0 g, 68.0% yield, as a white solid). LC-MS (ESI) m/z: 220.0 [M+H] + .

步骤2：1-苄基-2-(三氟甲基)氮丙啶的合成
Step 2: Synthesis of 1-benzyl-2-(trifluoromethyl)aziridine

将三苯基膦(105g,401.44mmol)溶于ACN(200mL)中，加入CCl4(150mL)后反应混合物搅拌1hr，然后加入将3-(苄氨基)-1,1,1-三氟丙-2-醇(22g,100mmol)的ACN(300mL)溶液，再加入Et3N(71g,703mmol)，反应混合物在25℃下搅拌16hrs。过滤，滤饼用正己烷(200mL)洗涤，合并滤液，减压浓缩，残余物经正相柱层析分离纯化(PE：DCM，15％DCM)得到目标化合物(13.6g,收率67.4％，黄色油状物)。LC-MS(ESI)m/z:202.0[M+H]+。Triphenylphosphine (105 g, 401.44 mmol) was dissolved in ACN (200 mL). CCl₄ (150 mL) was added, and the reaction mixture was stirred for 1 hour. A solution of 3-(benzylamino)-1,1,1-trifluoropropan-2-ol (22 g, 100 mmol) in ACN (300 mL) was then added, followed by Et₃N (71 g, 703 mmol). The reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filter cake was washed with n-hexane (200 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by normal phase column chromatography (PE:DCM, 15% DCM) to obtain the title compound (13.6 g, 67.4% yield, as a yellow oil). LC-MS (ESI) m/z: 202.0 [M+H] ⁺ .

步骤3：2-(苄氨基)-3,3-3-三氟丙-1-醇的合成
Step 3: Synthesis of 2-(benzylamino)-3,3-trifluoropropan-1-ol

将1-苄基-2-(三氟甲基)氮丙啶(13.60g,68mmol)溶于水(150mL)中，加入浓H2SO4(3.80mL，71mmol，w/w：98％)，所得反应混合物N2保护下25℃搅拌16hrs。减压浓缩得到粗产品(10.30g,收率69.6％，白色固体)。LC-MS(ESI)m/z:200.2[M+H]+。1-Benzyl-2-(trifluoromethyl)aziridine (13.60 g, 68 mmol) was dissolved in water (150 mL), and concentrated H₂SO₄ (3.80 mL, 71 mmol, w/w: 98%) was added. The resulting reaction mixture was stirred at 25°C under nitrogen for 16 hours. The mixture was concentrated under reduced pressure to afford the crude product (10.30 g, 69.6% yield, white solid). LC-MS (ESI) m/z: 200.2 [M+H] ⁺ .

步骤4：2-[苄基(2-氯乙酰基)氨基]-3,3,3-三氟丙基氯乙酸的合成
Step 4: Synthesis of 2-[Benzyl(2-chloroacetyl)amino]-3,3,3-trifluoropropyl chloroacetic acid

将1-苄基-2-(三氟甲基)氮丙啶(10.30g,47mmol)溶于DCM(200mL)中，在0℃条件下缓慢加入氯乙酰氯(26.53g,235mmol)和Et3N(19.02g,188mmol)。反应液在25℃下搅拌16hrs。加水稀释，分离，有机相用饱和NaHCO3(200mL×2)溶液洗涤，再用饱和食盐水(200mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩，得到粗产品(16.0g,收率91.5％，褐色油状物)。LC-MS(ESI)m/z:372.0[M+H]+。1-Benzyl-2-(trifluoromethyl)aziridine (10.30 g, 47 mmol) was dissolved in DCM (200 mL). Chloroacetyl chloride (26.53 g, 235 mmol) and Et₃N (19.02 g, 188 mmol) were slowly added at 0°C. The reaction mixture was stirred at 25°C for 16 hr. The mixture was diluted with water and separated. The organic phase was washed with saturated NaHCO₃ (200 mL x 2) and then with saturated brine (200 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude product (16.0 g, 91.5% yield, brown oil). LC-MS (ESI) m/z: 372.0 [M+H] ⁺ .

步骤5：4-苄基-5-(三氟甲基)吗啉-3-酮的合成
Step 5: Synthesis of 4-benzyl-5-(trifluoromethyl)morpholin-3-one

将K2CO3(726mg,2.23mmol)和水(20mL)加到2-[苄基(2-氯乙酰基)氨基]-3,3,3-三氟丙基氯乙酸(16.0g,0.74mmol)的MeOH(200mL)溶液中，反应混合物在80℃下搅拌16hrs，冷却至室温。减压除去有机溶剂，残余物中加入DCM(100mL)，分离有机相，有机相用水(200mL×2)洗涤，再依次用用2N HCl溶液和饱和食盐水洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：DCM，15％ DCM)得到目标化合物(11.06g,收率99.2％，黄色油状物)。LC-MS(ESI)m/z:260.0[M+H]+。 K₂CO₃ (726 mg , 2.23 mmol) and water (20 mL) were added to a solution of 2-[benzyl(2-chloroacetyl)amino]-3,3,3-trifluoropropylchloroacetic acid (16.0 g, 0.74 mmol) in MeOH (200 mL). The reaction mixture was stirred at 80°C for 16 hours and then cooled to room temperature. The organic solvent was removed under reduced pressure, and DCM (100 mL) was added to the residue. The organic phase was separated and washed with water (200 mL x 2), then with 2N HCl solution and saturated brine, dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:DCM, 15% DCM) to obtain the title compound (11.06 g, 99.2% yield, yellow oil). LC-MS (ESI) m/z: 260.0 [M+H] ⁺ .

步骤6：4-苄基-3-(三氟甲基)吗啉的合成
Step 6: Synthesis of 4-benzyl-3-(trifluoromethyl)morpholine

将4-苄基-5-(三氟甲基)吗啉-3-酮(11.06g,42.67mmol)溶于THF(110mL)中，在0℃条件下，缓慢加入1.0M硼烷-四氢呋喃络合物(128mL)。反应混合物在H2氛围下加热到80℃搅拌16hrs，冷却至室温，在冰水浴条件下，小心地将MeOH(50mL)逐滴加入到混合物中淬灭反应。减压浓缩，用DCM和水稀释，然后用DCM(100mL×2)萃取，合并有机相用Na2SO4干燥，过滤，滤液减压浓缩，得到目标化合物(9.00g,收率86.0％，无色油状物)。LC-MS(ESI)m/z:246.0[M+H]+。4-Benzyl-5-(trifluoromethyl)morpholin-3-one (11.06 g, 42.67 mmol) was dissolved in THF (110 mL) and 1.0 M borane-tetrahydrofuran complex (128 mL) was slowly added at 0°C. The reaction mixture was heated to 80°C under an H₂ atmosphere and stirred for 16 hours. The mixture was cooled to room temperature and quenched by the careful addition of MeOH (50 mL) dropwise in an ice-water bath. The mixture was concentrated under reduced pressure, diluted with DCM and water, and then extracted with DCM (100 mL x 2). The combined organic phases were dried over Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (9.00 g, 86.0% yield, colorless oil). LC-MS (ESI) m/z: 246.0 [M+H] ⁺ .

步骤7：3-(三氟甲基)吗啉的合成
Step 7: Synthesis of 3-(trifluoromethyl)morpholine

将10％ Pd/C(1.74g)加到4-苄基-3-(三氟甲基)吗啉(4.00g,16.31mmol)的MeOH(40mL)溶液中，反应混合物在H2氛围下置换三次，然后在H2氛围下25℃下搅拌16hrs。反应混合物用硅藻土过滤，滤液中加入4N盐酸/1,4-二氧六环溶液(8mL)，在25℃条件下继续搅拌30mins，减压浓缩，得到粗产品(2.90g,收率93.0％，黄色固体)。LC-MS(ESI)m/z:156.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),4.60–4.46(m,1H),4.20–4.08(m,1H),4.01–3.92(m,1H),3.88–3.74(m,3H),3.30–3.21(m,1H),3.19–3.09(m,1H)。10% Pd/C (1.74 g) was added to a solution of 4-benzyl-3-(trifluoromethyl)morpholine (4.00 g, 16.31 mmol) in MeOH (40 mL). The reaction mixture was replaced three times under a H₂ atmosphere and then stirred at 25°C under a H₂ atmosphere for 16 hours. The reaction mixture was filtered through Celite, and a 4N hydrochloric acid/1,4-dioxane solution (8 mL) was added to the filtrate. Stirring was continued at 25°C for 30 minutes and the mixture was concentrated under reduced pressure to obtain the crude product (2.90 g, 93.0% yield, yellow solid). LC-MS (ESI) m/z: 156.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ10.80(s,1H),4.60–4.46(m,1H),4.20–4.08(m,1H),4.01–3.92(m,1H),3.88–3.74(m,3H),3.30–3.21(m,1H),3.19–3.09(m,1H).

步骤8：8-(1-(四氢-2H-吡喃-2-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(1-(tetrahydro-2H-pyran-2-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

依次将Cs2CO3(7.10g,21.80mmol)、rac-BINAP(0.91g,1.45mmol)、醋酸钯(0.16g,0.73mmol)加到6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(3.20g,7.27mmol)和3-(三氟甲基)吗啉(1.69g,10.90mmol)的甲苯(60mL)溶液中，。反应混合物在N2保护下130℃下搅拌16hrs，冷却至室温，向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取。合并有机相用水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相柱层析分离纯化(PE：EA，35％EA)，得到目标化合物(1.90g,收率55.9％，褐色固体)。LC-MS(ESI)m/z:468.2[M+H]+。Cs 2 CO 3 (7.10 g, 21.80 mmol), rac-BINAP (0.91 g, 1.45 mmol), and palladium acetate (0.16 g, 0.73 mmol) were added sequentially to a toluene (60 mL) solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (3.20 g, 7.27 mmol) and 3-(trifluoromethyl)morpholine (1.69 g, 10.90 mmol). The reaction mixture was stirred at 130° C. for 16 hrs under N 2 protection, cooled to room temperature, diluted with water and EA, and extracted with EA (100 mL×2). The combined organic phases were washed with water, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (PE:EA, 35% EA) to obtain the title compound (1.90 g, 55.9% yield, brown solid). LC-MS (ESI) m/z: 468.2 [M+H] + .

步骤9：8-(4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 9: Synthesis of 8-(4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(1-(四氢-2H-吡喃-2-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.70g,3.63mmol)溶于THF(20mL)中，加入4N盐酸/1,4-二氧六环溶液(20mL)，N2保护下，反应混合物在25℃下搅拌16hrs。减压浓缩，残余物中加入EA和饱和Na2CO3溶液稀释，有机相用水洗涤，减压浓缩，得到粗产品(1.30g,收率93.5％，黄色油状物)。LC-MS(ESI)m/z:384.2[M+H]+。8-(1-(tetrahydro-2H-pyran-2-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.70 g, 3.63 mmol) was dissolved in THF (20 mL). 4N hydrochloric acid/1,4-dioxane solution (20 mL) was added. Under nitrogen protection, the reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with EA and saturated Na₂CO₃ solution . The organic phase was washed with water and concentrated under reduced pressure to give the crude product (1.30 g, 93.5% yield, yellow oil). LC-MS (ESI) m/z: 384.2 [M+H] + .

步骤10：8-(3-碘-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 10: Synthesis of 8-(3-iodo-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.30g,3.39mmol)和KOH(0.48g,8.48mmol)溶解于DMF(80mL)中，再分批加入I2(1.72g,6.78mmol)。反应混合物在N2保护下在25℃下搅拌2hrs。加入饱和Na2SO3水溶液淬灭反应，用EA(100mL×3)萃取，合并有机相用水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相层析柱分离纯化(PE：EA，30％ EA)得到目标化合物(825mg,收率47.8％，黄色固体)。LC-MS(ESI)m/z:509.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),6.24(s,1H),4.60–4.50(m,3H),4.22–4.15(m,2H),3.98–3.92(m,1H),3.84–3.74(m,1H),3.71–3.59(m,3H),3.56–3.50(m,2H),3.10(d,J＝12.3Hz,1H),1.99–1.86(m,4H).8-(4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.30 g, 3.39 mmol) and KOH (0.48 g, 8.48 mmol) were dissolved in DMF (80 mL), and I₂ (1.72 g, 6.78 mmol) was added portionwise. The reaction mixture was stirred at 25°C for 2 hr under N₂ protection. The reaction was quenched by addition of saturated aqueous Na₂SO₃ solution and extracted with EA (100 mL x 3). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (PE:EA, 30% EA) to afford the title compound (825 mg, 47.8% yield) as a yellow solid. LC-MS(ESI)m/z:509.9[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.26(s,1H),6.24(s,1H),4.60–4.50(m,3H),4.22–4.15(m,2H),3.98–3.92(m,1H),3.84– 3.74(m,1H),3.71–3.59(m,3H),3.56–3.50(m,2H),3.10(d,J＝12.3Hz,1H),1.99–1.86(m,4H).

步骤11：8-(3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 11: Synthesis of 8-(3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(300mg,0.59mmol)和1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(346mg,1.77mmol)溶解在NMP(10mL)中，再依次加入吡啶(140mg,1.77mmol)和醋酸铜(235mg,1.18mmol)。在O2氛围下置换三次，反应液在O2氛围下50℃搅拌16hrs，冷却至室温。向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用水(50mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)得到目标化合物(264mg,收率68.0％，黄色油状物)。LC-MS(ESI)m/z:660.0[M+H]+。8-(3-iodo-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (300 mg, 0.59 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (346 mg, 1.77 mmol) were dissolved in NMP (10 mL). Pyridine (140 mg, 1.77 mmol) and copper acetate (235 mg, 1.18 mmol) were added sequentially. The atmosphere was replaced with O₂ three times, and the reaction solution was stirred at 50°C under O₂ for 16 hrs before cooling to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with water (50 mL x 3 ), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (264 mg, 68.0% yield, yellow oil). LC-MS (ESI) m/z: 660.0 [M+H] + .

步骤12：8-(1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 12: Synthesis of 8-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(200mg,0.30mmol)、Zn(CN)2(106mg,0.90mmol)、锌粉(59mg,0.90mmol)、Pd2(dba)3(28mg,0.03mmol)和Pd(dppf)Cl2(44mg,0.06mmol)依次加入到DMA(5mL)中。N2保护下，反应混合物在150℃下搅拌1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用水(30mL×3)洗涤，无水Na2SO4干燥，过滤。残余物经硅胶柱层析分离纯化(PE：EA，40％ EA)，得到目标化合物(150mg,收率88.5％，黄色固体)。LC-MS(ESI)m/z:559.2[M+H]+。8-(3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (200 mg, 0.30 mmol), Zn(CN) (106 mg , 0.90 mmol), zinc powder (59 mg, 0.90 mmol), Pd (dba) (28 mg, 0.03 mmol ), and Pd(dppf) Cl (44 mg, 0.06 mmol) were added sequentially to DMA (5 mL). Under N protection, the reaction mixture was stirred at 150°C for 1 hr and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with water (30 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (150 mg, 88.5% yield, as a yellow solid). LC-MS (ESI) m/z: 559.2 [M+H] ⁺ .

步骤13：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 13: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.18mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％MeOH)得到目标化合物(70mg,收率82.4％，白色固体)。LC-MS(ESI)m/z:475.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.93–7.87(m,1H),6.83(t,J＝2.1Hz,1H),6.46(s,1H),4.74–4.60(m,3H),4.27–4.20(m,1H),4.08–3.94(m,2H),3.92–3.81(m,1H),3.70–3.54(m,5H),3.37(d,J＝12.5Hz,1H),2.03–1.87(m,4H)。8-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.18 mmol) was dissolved in THF (2 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 25°C for 16 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to afford the title compound (70 mg, 82.4% yield, as a white solid). LC-MS (ESI) m/z: 475.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.10(s,1H),7.93–7.87(m,1H),6.83(t,J＝2.1Hz,1H),6.46(s,1H),4.74–4.60(m,3H),4.27–4.20(m, 1H), 4.08–3.94 (m, 2H), 3.92–3.81 (m, 1H), 3.70–3.54 (m, 5H), 3.37 (d, J = 12.5Hz, 1H), 2.03–1.87 (m, 4H).

步骤14：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-((S)-3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-((R)-3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈合成
Step 14: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-((S)-3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-((R)-3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈经Chiral Pre-SFC(柱：Regis WhelkO1(R,R)，40mm I.D*250mm，10um；流动相A：Supercritical CO2，流动相B：MeOH；梯度：50％ B，检测波长210/254nm，流速：140mL/min，柱温40℃)手性拆分得到目标化合物P1(35.87mg,收率51.2％，白色固体)。LC-MS(ESI)m/z:475.2[M+H]+。SFC(方法E)：RT＝2.756min。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.90(s,1H),6.83(d,J＝2.3Hz,1H),6.46(s,1H),4.74–4.60(m,3H),4.24(d,J＝12.7Hz,1H),4.10–4.00(m,1H),4.00–3.94(m,1H),3.91–3.82(m,1H),3.68–3.54(m,5H),3.37(d,J＝12.5Hz,1H),2.03–1.90(m,4H)和目标化合物P2(25.18mg,收率36.0％，白色固体)。LC-MS(ESI)m/z:475.2[M+H]+.SFC(方法E)：RT＝3.784min。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.90(s,1H),6.83(d,J＝2.3Hz,1H),6.46(s,1H),4.72–4.61(m,3H),4.24(d,J＝12.9Hz,1H),4.09–4.01(m,1H),3.99–3.93(m,1H),3.87(t,J＝11.4Hz,1H),3.68–3.55(m,5H),3.37(d,J＝11.8Hz,1H),2.02–1.90(m,4H)。Chiral separation of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was performed by Chiral Pre-SFC (column: Regis Whelk O1(R,R), 40 mm ID*250 mm, 10 μm; mobile phase A: Supercritical CO 2 , mobile phase B: MeOH; gradient: 50% B, detection wavelength 210/254 nm, flow rate: 140 mL/min, column temperature 40°C) to afford the title compound P1 (35.87 mg, 51.2% yield, white solid). LC-MS (ESI) m/z: 475.2 [M+H] + . SFC (Method E): RT = 2.756 min. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 7.90 (s, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.46 (s, 1H), 4.74–4.60 (m, 3H), 4.24 (d, J = 12.7 Hz, 1H), 4.10–4.00 (m, 1H), 4.00–3.94 (m, 1H), 3.91–3.82 (m, 1H), 3.68–3.54 (m, 5H), 3.37 (d, J = 12.5 Hz, 1H), 2.03–1.90 (m, 4H) and the target compound P2 (25.18 mg, yield 36.0%, white solid). LC-MS (ESI) m/z: 475.2[M+H] + .SFC (Method E): RT=3.784min. 1 H NMR (400MHz, DMSO-d 6 )δ13.10(s,1H),7.90(s,1H),6.83(d,J＝2.3Hz,1H),6.46(s,1H),4.72–4.61(m,3H),4.24(d,J＝12.9Hz,1H),4.09–4 .01(m,1H),3.99–3.93(m,1H),3.87(t,J＝11.4Hz,1H),3.68–3.55(m,5H),3.37(d,J＝11.8Hz,1H),2.02–1.90(m,4H).

实施例68:6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(4-氰基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 68: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(4-cyanotetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈的合成
Step 1: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

在N2保护下,将四氢-2H-吡喃-4-碳腈(744mg,6.81mmol，tetrahydro-2H-pyran-4-carbonitrile,CAS:4295-99-2)溶于THF(40mL)中，冷却至-78℃，在此温度下缓慢逐滴滴加LDA(3.75mL，7.50mmol)，然后继续在-78℃下搅拌1hr，然后在此温度下缓慢逐滴滴加6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(20b)(1.50g,3.41mmol)的THF(40mL)溶液，混合物在-78℃下搅拌1hr。向反应混合物中加入饱和NH4Cl(10mL)溶液淬灭反应，用EA(50mL×2)萃取。合并有机相，用水(200mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物用硅胶柱层析分离纯化(DCM：MeOH，10％MeOH)得到目标化合物(1.43g,收率99.6％，黄色固体)。LC-MS(ESI)m/z:424.2[M+H]+。Under N2 protection, tetrahydro-2H-pyran-4-carbonitrile (744 mg, 6.81 mmol, tetrahydro-2H-pyran-4-carbonitrile, CAS: 4295-99-2) was dissolved in THF (40 mL) and cooled to -78 °C. LDA (3.75 mL, 7.50 mmol) was slowly added dropwise at this temperature, and then stirring was continued at -78 °C for 1 hr. Then, a solution of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (20b) (1.50 g, 3.41 mmol) in THF (40 mL) was slowly added dropwise at this temperature, and the mixture was stirred at -78 °C for 1 hr. The reaction mixture was quenched by adding saturated NH₄Cl solution (10 mL) and extracted with EA (50 mL x 2). The combined organic phases were washed with water (200 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (1.43 g, 99.6% yield, yellow solid). LC-MS (ESI) m/z: 424.2 [M+H] ⁺ .

步骤2：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H-吡喃-4-碳腈的合成
Step 2: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

将4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈(1.43g,3.38mmol)溶于THF(12mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在25℃下搅拌16hrs。减压除去有机溶剂，向残余物中加入饱和NaHCO3(50mL)溶液至碱性，用DCM(50mL×2)萃取，合并有机相，用饱和NaHCO3(80mL×2)水溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，得到目标化合物粗品(1.15g,收率100％，淡黄色固体)。LC-MS(ESI)m/z:340.2[M+H]+。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (1.43 g, 3.38 mmol) was dissolved in THF (12 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 25°C for 16 hrs. The organic solvent was removed under reduced pressure, and saturated NaHCO₃ solution (50 mL) was added to the residue until basic. The residue was extracted with DCM (50 mL × 2). The combined organic phases were washed with saturated NaHCO₃ aqueous solution (80 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude title compound (1.15 g, 100% yield, light yellow solid). LC-MS(ESI)m/z:340.2[M+H] + .

步骤3：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H-吡喃-4-碳腈的合成
Step 3: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

将4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H-吡喃-4-碳腈(950mg,2.80mmol)溶于DMF(30mL)中，加入NIS(3.14g,14.00mmol)，反应混合物在80℃下搅拌16hrs，冷却至室温，向反应混合物中加入饱和NaHCO3溶液(30mL)，用EA(30mL×2)萃取，合并有机相，用水(100mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物用硅胶柱层析分离纯化(PE：EA，10％EA)得到目标化合物(388mg,粗品，收率29.8％，类白色固体)。LC-MS(ESI)m/z:466.0[M+H]+。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (950 mg, 2.80 mmol) was dissolved in DMF (30 mL), and NIS (3.14 g, 14.00 mmol) was added. The reaction mixture was stirred at 80°C for 16 hrs, cooled to room temperature, and saturated NaHCO3 solution (30 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL×2). The combined organic phases were washed with water (100 mL× 2 ), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 10% EA) to give the title compound (388 mg, crude product, yield 29.8%, off-white solid). LC-MS(ESI)m/z:466.0[M+H] + .

步骤4：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈的合成
Step 4: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

向4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H-吡喃-4-碳腈(350mg,0.75mmol)的NMP(15mL)溶液中加入(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(442mg,2.26mmol)、无水吡啶(238mg,3.01mmol)和醋酸铜(300mg,1.50mmol)，在O2氛围下，反应混合物在50℃下搅拌16hrs，冷却至室温。用EA(20mL)和H2O(20mL)稀释反应液，用EA(20mL×2)萃取反应，合并有机相，用饱和食盐水(50mL×5)洗涤，减压浓缩，残余物用硅胶柱层析分离纯化(PE：EA，64％EA)得到目标化合物(320mg,收率69.1％，白色固体)。LC-MS(ESI)m/z:616.2[M+H]+。To a solution of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (350 mg, 0.75 mmol) in NMP (15 mL) were added (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (442 mg, 2.26 mmol), anhydrous pyridine (238 mg, 3.01 mmol) and copper acetate (300 mg, 1.50 mmol). Under an O atmosphere, the reaction mixture was stirred at 50 ° C for 16 hrs and cooled to room temperature. The reaction solution was diluted with EA (20 mL) and H 2 O (20 mL), extracted with EA (20 mL x 2), and the organic phases were combined, washed with saturated brine (50 mL x 5), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 64% EA) to obtain the title compound (320 mg, yield 69.1%, white solid). LC-MS (ESI) m/z: 616.2 [M+H]+.

步骤5：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(4-氰基四氢-2H-吡喃-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(4-cyanotetrahydro-2H-pyran-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈(50mg,0.081mmol)溶于DMF(3mL)中，加入Zn(CN)2(28mg,0.24mmol)，锌粉(16mg,0.24mmol)，Pd(dppf)Cl2(11.89mg,0.016mmol)和Pd2(dba)3(7.44mg,0.008mmol)。反应混合物在N2保护下150℃下搅拌1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用水(10mL×2)洗涤，无水Na2SO4干燥，减压浓缩，得到目标化合物(40mg,收率95.6％，棕色固体)。LC-MS(ESI)m/z:515.2[M+H]+。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (50 mg, 0.081 mmol) was dissolved in DMF (3 mL), and Zn(CN) ( 28 mg, 0.24 mmol), zinc powder (16 mg, 0.24 mmol), Pd(dppf) Cl (11.89 mg, 0.016 mmol), and Pd (dba) (7.44 mg, 0.008 mmol) were added . The reaction mixture was stirred at 150° C. for 1 hr under N protection and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with water (10 mL × 2), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain the title compound (40 mg, yield 95.6%, brown solid). LC-MS (ESI) m/z: 515.2 [M+H] + .

步骤6：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(4-氰基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(4-cyanotetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(4-氰基四氢-2H-吡喃-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(30mg,0.015mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，混合物在25℃下搅拌4hrs。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：25-55％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(15mg,收率59.7％，白色固体)。LC-MS(ESI)m/z:431.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.17(s,1H),7.96–7.91(m,1H),6.90(s,1H),6.84(t,J＝2.2Hz,1H),4.71(s,2H),4.16–4.07(m,2H),3.79(t,J＝11.5Hz,2H),3.64(dd,J＝25.3,10.7Hz,4H),2.43(d,J＝13.0Hz,2H),2.27(td,J＝13.5,4.0Hz,2H),2.06–1.91(m,4H)。6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(4-cyanotetrahydro-2H-pyran-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (30 mg, 0.015 mmol) was dissolved in THF (2 mL), 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added, and the mixture was stirred at 25 ° C for 4 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 25-55% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (15 mg, 59.7% yield, white solid). LC-MS (ESI) m/z: 431.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.17(s,1H),7.96–7.91(m,1H),6.90(s,1H),6.84(t,J＝2.2Hz,1H),4.71(s,2H),4.16–4.07(m,2H),3.79(t,J＝1 1.5Hz, 2H), 3.64 (dd, J＝25.3, 10.7Hz, 4H), 2.43 (d, J＝13.0Hz, 2H), 2.27 (td, J＝13.5, 4.0Hz, 2H), 2.06–1.91 (m, 4H).

实施例69:4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4- 基)四氢-2H-吡喃-4-碳腈
Example 69: 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4- yl)tetrahydro-2H-pyran-4-carbonitrile

步骤1：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡喃并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈的合成
Step 1: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

将4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈(60mg,0.097mmol)溶于DMF(5mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(152mg,0.49mmol)，微波管中鼓N2 3mins，反应混合物在微波仪器中130℃下搅拌2hrs，冷却至室温，向反应混合物中加入水(5mL)，用EA(10mL×2)萃取，合并有机相，用水(30mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经Pre-TLC纯化(PE/EA＝2/1)得到目标化合物(30mg,收率27.6％，无色油状物)。LC-MS(ESI)m/z:558.2[M+H]+。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (60 mg, 0.097 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (152 mg, 0.49 mmol) was added. N2 was bubbled in a microwave tube for 3 mins. The reaction mixture was stirred at 130°C in a microwave apparatus for 2 hrs, cooled to room temperature, and water (5 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL×2). The organic phases were combined, washed with water (30 mL×5), and anhydrous Na2SO4 4 , dried, concentrated under reduced pressure, and the residue was purified by Pre-TLC (PE/EA=2/1) to give the title compound (30 mg, yield 27.6%, colorless oil). LC-MS (ESI) m/z: 558.2 [M+H] + .

步骤2：4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)四氢-2H-吡喃-4-碳腈的合成
Step 2: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile

将4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡喃并[3,4-b]吡啶-4-基)四氢-2H吡喃-4-碳腈(30mg,0.054mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：32-62％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(1.57mg,收率6.2％，白色固体)。LC-MS(ESI)m/z:474.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.80(s,1H),6.92(d,J＝2.4Hz,1H),6.89(s,1H),4.71–4.69(s,2H),4.14–4.11(m,2H),3.95(t,J＝11.4Hz,2H),3.82(d,J＝10.9Hz,2H),3.66(d,J＝10.8Hz,2H),2.42(d,J＝13.1Hz,2H),2.26–2.18(m,2H),2.17–2.06(m,4H)。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (30 mg, 0.054 mmol) was dissolved in THF (2 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 32-62% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (1.57 mg, 6.2% yield, white solid). LC-MS (ESI) m/z: 474.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.80(s,1H),6.92(d,J＝2.4Hz,1H),6.89(s,1H),4.71–4.69(s,2H),4.14–4.11(m,2H),3.95(t,J＝11.4Hz,2H ),3.82(d,J＝10.9Hz,2H),3.66(d,J＝10.8Hz,2H),2.42(d,J＝13.1Hz,2H),2.26–2.18(m,2H),2.17–2.06(m,4H).

实施例70:8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲酯)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂双环[3.2.1]辛烷
Example 70: 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

实施例71和实施例72：8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-((S)-3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡 啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-((R)-3-(三氟甲基)吗啉基)-1H- 吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 71 and Example 72: 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-((S)-3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b] pyridin- 6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-((R)-3-(trifluoromethyl)morpholinyl)-1H -pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.15mmol)和(1,10-菲咯啉)(三氟甲基)铜(I)(143mg，0.46mmol)依次加入到DMF(3mL)中。反应混合物微波下130℃反应3hrs，冷却至室温后，向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用水(30mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)得到目标化合物(50mg,收率54.8％，黄色固体)。LC-MS(ESI)m/z:602.2[M+H]+。8-(3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.15 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (143 mg, 0.46 mmol) were added sequentially to DMF (3 mL). The reaction mixture was reacted at 130°C under microwave conditions for 3 hr. After cooling to room temperature, water (10 mL) was added to the reaction mixture and extracted with EA (10 mL x 2) . The combined organic phases were washed with water (30 mL x 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (50 mg, 54.8% yield, as a yellow solid). LC-MS (ESI) m/z: 602.2 [M+H] + .

步骤2：8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.08mmol)溶于THF(1mL)中，然后加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％MeOH)得到目标化合物(38mg,收率88.4％，白色固体)。LC-MS(ESI)m/z:518.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),7.92–7.84(m,1H),6.79(t,J＝2.2Hz,1H),6.58(s,1H),4.64(s,2H),4.49–4.39(m,1H),4.15–4.08(m,1H),4.05–3.97(m,1H),3.86–3.78(m,1H),3.75–3.54(m,6H),3.20–3.13(m,1H),2.03–1.86(m,4H)。8-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.08 mmol) was dissolved in THF (1 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (1 mL). The reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to afford the title compound (38 mg, 88.4% yield, as a white solid). LC-MS (ESI) m/z: 518.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.04(s,1H),7.92–7.84(m,1H),6.79(t,J＝2.2Hz,1H),6.58(s,1H),4.64(s,2H),4.49–4.39(m,1H),4.15 –4.08(m,1H),4.05–3.97(m,1H),3.86–3.78(m,1H),3.75–3.54(m,6H),3.20–3.13(m,1H),2.03–1.86(m,4H).

步骤3：8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-((S)-3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-((R)-3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-((S)-3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-((R)-3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(1-(1H-吡唑-3-基)-3-(三氟甲基)-4-(3-(三氟甲基)吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷消旋体(36mg)经Chiral Pre-SFC(柱：Daicel Chiralpak IK，40mm I.D*250mm，10um；流动相A：Supercritical CO2，流动相B：异丙醇；梯度：30％B，检测波长210/254nm，流速：120mL/min，柱温40℃)手性拆分得到目标化合物P1(7.96mg,收率20.9％，白色固体)。LC-MS(ESI)m/z:518.2[M+H]+。SFC(方法C)：RT＝3.926min。1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),7.89(s,1H),6.80(d,J＝1.8Hz,1H),6.58(s,1H),4.65(s,2H),4.51–4.39(m,1H),4.16–4.08(m,1H),4.06–3.98(m,1H),3.87–3.79(m,1H),3.76–3.52(m,6H),3.22–3.11(m,1H),2.04–1.87(m,4H)。和目标化合物P2(8.64mg,收率22.7％，白色固体)。LC-MS(ESI)m/z:518.2[M+H]+.SFC(方法C)：RT＝4.613min。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.95(s,1H),6.85(d,J＝2.1Hz,1H),6.64(s,1H),4.70(s,2H),4.55–4.45(m,1H),4.20–4.13(m,1H),4.11–4.03(m,1H),3.92–3.83(m,1H),3.82–3.59(m,6H),3.27–3.18(m,1H),2.10–1.92(m,4H)。Chiral separation of the racemate of 8-(1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-4-(3-(trifluoromethyl)morpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36 mg) was performed by Chiral Pre-SFC (column: Daicel Chiralpak IK, 40 mm ID*250 mm, 10 μm; mobile phase A: Supercritical CO 2 , mobile phase B: isopropanol; gradient: 30% B, detection wavelength 210/254 nm, flow rate: 120 mL/min, column temperature 40°C) to afford the target compound P1 (7.96 mg, 20.9% yield, white solid). LC-MS (ESI) m/z: 518.2 [M+H] + . SFC (Method C): RT = 3.926 min. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 7.89 (s, 1H), 6.80 (d, J=1.8 Hz, 1H), 6.58 (s, 1H), 4.65 (s, 2H), 4.51–4.39 (m, 1H), 4.16–4.08 (m, 1H), 4.06–3.98 (m, 1H), 3.87–3.79 (m, 1H), 3.76–3.52 (m, 6H), 3.22–3.11 (m, 1H), 2.04–1.87 (m, 4H). The target compound P2 (8.64 mg, yield 22.7%) was obtained as a white solid. LC-MS (ESI) m/z: 518.2 [M+H] + .SFC (Method C): RT = 4.613 min. 1 H NMR (400MHz, DMSO-d 6 )δ13.10(s,1H),7.95(s,1H),6.85(d,J＝2.1Hz,1H),6.64(s,1H),4.70(s,2H),4.55–4.45(m,1H),4.20–4. 13(m,1H),4.11–4.03(m,1H),3.92–3.83(m,1H),3.82–3.59(m,6H),3.27–3.18(m,1H),2.10–1.92(m,4H).

实施例73：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H- 吡唑并[3,4-b]吡啶-3-腈
Example 73: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H -pyrazolo[3,4-b]pyridine-3-carbonitrile

实施例74和实施例75：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H- 吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-甲氧基-2-甲基哌 啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 74 and Example 75: 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H -pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-4-methoxy-2-methylpiperidin -1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：8-(3-碘-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-iodo-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(200mg,0.32mmol)溶于DMF(15mL)中，在0℃下，N2保护下加入NaH(39mg,0.96mmol)，反应混合物在25℃下搅拌10mins，然后再缓慢滴加CH3I(137mg,0.96mmol)，得到的反应混合物在25℃搅拌2hrs。向反应混合物中加入水(15mL)，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(50mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)得到目标化合物(125mg,收率61.1％，淡黄色油状物)。LC-MS(ESI)m/z:634.2[M+H]+。1H NMR(400MHz,Chloroform-d)δ7.57(dd,J＝2.5,0.8Hz,1H),6.85(dd,J＝2.5,1.0Hz,1H),5.97(s,1H),5.41(dd,J＝9.4,2.8Hz,1H),4.40(s,2H),4.04–3.96(m,1H),3.85–3.74(m,2H),3.68–3.59(m,1H),3.55(d,J＝10.2Hz,2H),3.49–3.36(m,3H),3.35–3.33(m,1H),2.62–2.53(m,2H),2.21–2.13(m,1H),2.13–1.89(m,11H),1.67–1.57(m,3H),1.57–1.52(m,2H),1.04(d,J＝6.2Hz,3H).(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (200 mg, 0.32 mmol) was dissolved in DMF (15 mL). NaH (39 mg, 0.96 mmol) was added at 0°C under N2 protection. The reaction mixture was stirred at 25°C for 10 mins, and then CH3I (137 mg, 0.96 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at 25°C for 2 hrs. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (125 mg, 61.1% yield, light yellow oil). LC-MS (ESI) m/z: 634.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.57(dd,J＝2.5,0.8Hz,1H),6.85(dd,J＝2.5,1.0Hz,1H),5.97(s ,1H),5.41(dd,J＝9.4,2.8Hz,1H),4.40(s,2H),4.04–3.96(m,1H),3.85–3.74(m,2H),3.68–3.5 9(m,1H),3.55(d,J＝10.2Hz,2H),3.49–3.36(m,3H),3.35–3.33(m,1H),2.62–2.53(m,2H),2.21 –2.13(m,1H),2.13–1.89(m,11H),1.67–1.57(m,3H),1.57–1.52(m,2H),1.04(d,J=6.2Hz,3H).

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(60mg,0.095mmol)、Zn(CN)2(33mg,0.28mmol)、Zn(0)(19mg,0.28mmol)、Pd2(dba)3(4.3mg,0.005mmol)和Pd(dppf)Cl2(6.9mg,0.009mmol)依次加入到DMA(15mL)中，反应混合物在N2保护下150℃搅拌1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(30mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，82％EA)得到目标化合物(42mg,收率83.3％，淡棕色固体)。LC-MS(ESI)m/z:533.2[M+H]+。8-(3-iodo-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.095 mmol), Zn(CN) 2 (33 mg, 0.28 mmol), Zn(0) (19 mg, 0.28 mmol), Pd2 (dba) 3 (4.3 mg, 0.005 mmol) and Pd(dppf) Cl2 (6.9 mg, 0.009 mmol) were added sequentially to DMA (15 mL), and the reaction mixture was stirred at 150°C for 1 hr under N2 protection and cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 5 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 82% EA) to obtain the title compound (42 mg, 83.3% yield, light brown solid). LC-MS (ESI) m/z: 533.2 [M+H] ⁺ .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(42mg,0.079mmol)溶于DCM(4mL)中，加入TFA(2mL)，混合物在25℃下搅拌16hrs。减压浓缩，残余物经Prep-TLC(PE/EA＝1/1)分离纯化得到目标化合物(20.8mg,收率58.8％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (42 mg, 0.079 mmol) was dissolved in DCM (4 mL). TFA (2 mL) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was isolated and purified by Prep-TLC (PE/EA = 1/1) to obtain the title compound (20.8 mg, 58.8% yield, as a white solid). LC-MS (ESI) m/z: 449.2 [M+H] + .

步骤4：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的制备
Step 4: Preparation of 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(20.8mg,0.046mmol)经过手性SFC拆分(column：Daicel ChiralCel OD，40mm I.D.*250mm，10um：Supercritical CO2；B％：30％，溶剂：正己烷、乙醇，流速：80mL/min，17.0/21.3min)得到目标化合物P1(9.58mg,收率46.1％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。SFC(方法B)：RT＝6.399min。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.89(s,1H),6.83(d,J＝2.3Hz,1H),6.30(s,1H),4.60(d,J＝11.3Hz,2H),3.94–3.82(m,1H),3.65(t,J＝10.5Hz,2H),3.61–3.44(m,4H),3.30(s,3H),2.99–2.89(m,1H),2.17–2.07(m,1H),2.03–1.81(m,7H),1.73–1.63(m,1H),1.12(d,J＝6.4Hz,3H).和目标化合物P2(1.19mg,收率5.7％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。SFC(方法B)：RT＝7.678min。Chiral SFC (column: Daicel ChiralCel OD, 40 mm ID x 250 mm, 10 μm: Supercritical CO 2 ; B%: 30%, solvent: n-hexane, ethanol, flow rate: 80 mL/min, 17.0/21.3 min) of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-methoxy - 2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (20.8 mg, 0.046 mmol) afforded the title compound P1 (9.58 mg, 46.1% yield, white solid) using LC-MS (ESI) m/z: 449.2 [M+H] + . SFC (Method B): RT = 6.399 min. 1H NMR (400 MHz, DMSO- d6 ) δ 13.07 (s, 1H), 7.89 (s, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.30 (s, 1H), 4.60 (d, J = 11.3 Hz, 2H), 3.94–3.82 (m, 1H), 3.65 (t, J = 10.5 Hz, 2H), 3.61–3.44 (m, 4H), 3.30 (s, 3H), 2.99–2.89 (m, 1H), 2.17–2.07 (m, 1H), 2.03–1.81 (m, 7H), 1.73–1.63 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H). And the target compound P2 (1.19 mg, yield 5.7%), white solid. LC-MS (ESI) m/z: 449.2 [M+H] + . SFC (Method B): RT = 7.678 min.

实施例76：8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6- 基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 76: 8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)-3-oxa-8-azabicyclo[3.2.1]octane

实施例77和实施例78：8-(4-((2R,4R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑 并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑 -3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 77 and Example 78: 8-(4-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol -3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(60mg,0.095mmol)溶于DMF(8mL)中，然后加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(89mg,0.28mmol)，反应混合物在微波仪器中130℃下搅拌3hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(15mL×2)萃取，合并有机相，用水(40mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)得到目标化合物(42mg,收率77.0％，白色固体)。LC-MS(ESI)m/z:576.2[M+H]+。8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.095 mmol) was dissolved in DMF (8 mL), and then (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (89 mg, 0.28 mmol) was added. The reaction mixture was stirred at 130° C. for 3 hrs in a microwave apparatus, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (15 mL×2). The organic phases were combined, washed with water (40 mL×5), and anhydrous Na 2 SO 4 was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to give the title compound (42 mg, yield 77.0%, white solid). LC-MS (ESI) m/z: 576.2 [M+H] + .

步骤2：8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(42mg,0.073mmol)溶于DCM(4mL)中，加入TFA(2mL)，反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经Prep-TLC(PE/EA＝1/1)纯化得到目标化合物(23.0mg,收率64.1％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (42 mg, 0.073 mmol) was dissolved in DCM (4 mL). TFA (2 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC (PE/EA = 1/1) to afford the title compound (23.0 mg, 64.1% yield, as a white solid). LC-MS (ESI) m/z: 492.2 [M+H] + .

步骤3：8-(4-((2R,4R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的制备
Step 3: Preparation of 8-(4-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-((2R)-4-甲氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(23mg,0.04mmol)经过手性拆分SFC(column：Daicel ChiralCel OD，40mm I.D.*250mm，10um：Supercritical CO2；B％：15％，溶剂：正己烷、乙醇，流速：80mL/min)得到目标化合物P2(10.25mg,收率52.2％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。SFC(方法B)：RT＝6.459min。1HNMR(400MHz,DMSO-d6)δ13.02(s,1H),7.88(s,1H),6.79(d,J＝2.3Hz,1H),6.68(s,1H),4.61(d,J＝7.7Hz,2H),3.71–3.56(m,4H),3.40–3.33(m,2H),3.22(d,J＝12.3Hz,1H),2.62(t,J＝10.6Hz,1H),2.12(d,J＝12.6Hz,1H),2.03–1.92(m,5H),1.56–1.47(m,1H),1.30–1.23(m,1H),0.94(d,J＝6.0Hz,3H)。和目标化合物P1(1.78mg,收率9.1％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。SFC(方法B)：RT＝5.531min。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.88(t,J＝2.0Hz,1H),6.79(t,J＝2.1Hz,1H),6.44(s,1H),4.66–4.55(m,2H),3.84–3.73(m,1H),3.71–3.62(m,2H),3.61–3.52(m,3H),3.29(s,3H),3.18–3.10(m,1H),3.04–2.94(m,1H),2.01–1.90(m,5H),1.87–1.79(m,1H),1.76–1.68(m,1H),1.65–1.55(m,1H),0.93(d,J＝6.4Hz,3H).Chiral separation of 8-(4-((2R)-4-methoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (23 mg, 0.04 mmol) by SFC (column: Daicel ChiralCel OD, 40 mm ID*250 mm, 10 μm: Supercritical CO 2 ; B%: 15%, solvent: n-hexane, ethanol, flow rate: 80 mL/min) afforded the title compound P2 (10.25 mg, 52.2% yield, white solid). LC-MS (ESI) m/z: 492.2 [M+H] + . SFC (Method B): RT = 6.459 min. 1 HNMR (400MHz, DMSO-d 6 )δ13.02(s,1H),7.88(s,1H),6.79(d,J＝2.3Hz,1H),6.68(s,1H),4.61(d,J＝7.7Hz,2H),3.71–3.56(m,4H),3.40–3.33(m,2H),3.22(d,J＝1 2.3Hz,1H),2.62(t,J＝10.6Hz,1H),2.12(d,J＝12.6Hz,1H),2.03–1.92(m,5H),1.56–1.47(m,1H),1.30–1.23(m,1H),0.94(d,J＝6.0Hz,3H). and the target compound P1 (1.78 mg, yield 9.1%, white solid). LC-MS (ESI) m/z: 492.2 [M+H] + . SFC (Method B): RT = 5.531 min. 1 H NMR (400 MHz, DMSO-d 6 )δ13.01(s,1H),7.88(t,J＝2.0Hz,1H),6.79(t,J＝2.1Hz,1H),6.44(s,1H), 4.66–4.55(m,2H),3.84–3.73(m,1H),3.71–3.62(m,2H),3.61–3.52(m,3H) ,3.29(s,3H),3.18–3.10(m,1H),3.04–2.94(m,1H),2.01–1.90(m,5H),1.8 7–1.79(m,1H),1.76–1.68(m,1H),1.65–1.55(m,1H),0.93(d,J＝6.4Hz,3H).

实施例79：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡 啶-4-基)-2-甲基哌啶-4-醇
Example 79: (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin -4-yl)-2-methylpiperidin-4-ol

实施例80和实施例81：(2R,4R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H- 吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇和(2R,4S)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3- 基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇
Example 80 and Example 81: (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H -pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol and (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3- yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

步骤1：8-(3-碘-4-((2R)-2-甲基-4-((四氢-2H-吡喃-2-基)氧基)哌啶-1-基)-1-(1-(四氢-1H-吡喃2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-iodo-4-((2R)-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-1-yl)-1-(1-(tetrahydro-1H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(200mg,0.32mmol)溶于DCM(15mL)中，加入吡啶甲磺酸盐(163mg,0.65mmol)和3.4-二氢-2H-吡喃(136mg,1.62mmol)。在N2保护下，反应混合物在25℃下搅拌1hr。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，85％EA)，得到目标化合物(210mg,收率92.5％，白色固体)。LC-MS(ESI)m/z:704.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (200 mg, 0.32 mmol) was dissolved in DCM (15 mL), and pyridine methanesulfonate (163 mg, 0.65 mmol) and 3,4-dihydro-2H-pyran (136 mg, 1.62 mmol) were added. Under N₂ protection, the reaction mixture was stirred at 25°C for 1 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 85% EA) to obtain the title compound (210 mg, 92.5% yield) as a white solid. LC-MS(ESI)m/z:704.2[M+H] + .

步骤2：8-(4-((2R)-2-甲基-4-((四氢-2H-吡喃-2-基)氧基)哌啶-1-基)-1-(1-(四氢-1H-吡喃2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-1-yl)-1-(1-(tetrahydro-1H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((2R)-2-甲基-4-((四氢-2H-吡喃-2-基)氧基)哌啶-1-基)-1-(1-(四氢-1H-吡喃2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(200mg,0.28mmol)溶于DMF(24mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(266mg,0.85mmol)，反应液在微波仪器中130℃下搅拌3hrs，冷却至室温，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相用水(80mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，58％EA)，得到目标化合物(153mg,粗品，白色固体)。LC-MS(ESI)m/z:646.3[M+H]+。8-(3-iodo-4-((2R)-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-1-yl)-1-(1-(tetrahydro-1H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (200 mg, 0.28 mmol) was dissolved in DMF (24 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (266 mg, 0.85 mmol) was added. The reaction mixture was stirred at 130°C for 3 hrs in a microwave apparatus, cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL×2). The combined organic phases were washed with water (80 mL×5) and anhydrous Na 2 SO 4. The residue was dried and concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA, 58% EA) to obtain the title compound (153 mg, crude product, white solid). LC-MS (ESI) m/z: 646.3 [M+H] + .

步骤3：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(153mg)溶于THF(4mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经Prep-TLC(PE/EA＝1/2)分离纯化得到目标化合物(42mg,收率37.1％，白色固体)。LC-MS(ESI)m/z:478.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (153 mg) was dissolved in THF (4 mL). 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was isolated and purified by Prep-TLC (PE/EA = 1/2) to obtain the title compound (42 mg, 37.1% yield, as a white solid). LC-MS (ESI) m/z: 478.2 [M+H] + .

步骤4：2R,4R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇和(2R,4S)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的制备
Step 4: Preparation of (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol and (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(32mg,0.057mmol)经过手性拆分SFC(column：Daicel ChiralCel OD，40mm I.D.*250mm，10um：Supercritical CO2；B％：15％，溶剂：正己烷、乙醇，流速：80mL/min)得到目标化合物P2(14.03mg,收率51.6％，白色固体)。LC-MS(ESI)m/z:478.2[M+H]+。SFC(方法F)：RT＝7.926min。1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),7.87(d,J＝2.2Hz,1H),6.79(d,J＝2.3Hz,1H),6.69(s,1H),4.75(d,J＝3.6Hz,2H),4.65–4.57(m,2H),3.73–3.56(m,5H),3.19–3.13(m,1H),2.58(t,J＝10.9Hz,1H),2.01–1.89(m,6H),1.83(d,J＝11.1Hz,1H),1.59–1.50(m,1H),1.33–1.26(m,1H),0.92(d,J＝5.9Hz,3H).和目标化合物P1(3.83mg,收率14.1％，白色固体)。LC-MS(ESI)m/z:478.2[M+H]+。SFC(方法F)：RT＝5.531min。Chiral separation of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (32 mg, 0.057 mmol) by SFC (column: Daicel ChiralCel OD, 40 mm ID*250 mm, 10 μm: Supercritical CO 2 ; B%: 15%, solvent: n-hexane, ethanol, flow rate: 80 mL/min) afforded the title compound P2 (14.03 mg, 51.6% yield, white solid). LC-MS (ESI) m/z: 478.2 [M+H] + . SFC (Method F): RT = 7.926 min. 1 H NMR (400 MHz, DMSO-d 6 )δ13.03(s,1H),7.87(d,J＝2.2Hz,1H),6.79(d,J＝2.3Hz,1H),6.69(s,1H),4.75(d,J＝3.6Hz,2H),4.65–4.57(m,2H),3.73–3.56(m,5H),3.19–3.13(m,1H),2.58(t,J＝10.9Hz,1H),2.01–1.89(m,6H),1.83(d,J＝11.1Hz,1H),1.59–1.50(m,1H),1.33–1.26(m,1H),0.92(d,J＝5.9Hz,3H).And target compound P1 (3.83 mg, yield 14.1%, white solid). LC-MS (ESI) m/z: 478.2 [M+H] + . SFC (Method F): RT = 5.531 min.

实施例82：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2,4-二甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H- 吡唑并[3,4-b]吡啶-3-腈
Example 82: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H -pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：苄基(2R)-4-羟基-2,4-二甲基哌啶-1-羧酸酯的合成
Step 1: Synthesis of benzyl (2R)-4-hydroxy-2,4-dimethylpiperidine-1-carboxylate

将苄基(R)-2-甲基-4-氧代哌啶-1-甲酸酯(6.0g,24.26mmol)溶于THF(120mL)中，置换N2后，将反应体系温度降到-70℃，缓慢的滴加1N甲基溴化镁(97mL)，N2保护下，反应液在-70℃搅拌2hrs。然后反应液升温至室温搅拌2hrs，向反应混合物中加入水(150mL)，用EA(100mL×3)萃取，合并有机相，用水(100mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，22％EA)得到目标化合物(3.2g,收率50.1％，白色油状物)。LC-MS(ESI)m/z:286.2[M+Na]+。Benzyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (6.0 g, 24.26 mmol) was dissolved in THF (120 mL). After replacing the nitrogen atmosphere, the reaction system was cooled to -70°C and 1N methylmagnesium bromide (97 mL) was slowly added dropwise. Under nitrogen , the reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was then warmed to room temperature and stirred for 2 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with water ( 100 mL × 5), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 22% EA) to obtain the title compound (3.2 g, 50.1% yield, white oil). LC-MS (ESI) m/z: 286.2 [M+Na] + .

步骤2：苄基(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶-1-甲酸酯的合成
Step 2: Synthesis of benzyl (2R)-4-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpiperidine-1-carboxylate

将苄基(2R)-4-羟基-2,4-二甲基哌啶-1-羧酸酯(3.0g,11.39mmol)和2,6-二甲基吡啶(2.76g,22.78mmol)溶于DCM(60mL)中，降温至0℃，N2保护下加入TBSOTf(4.52g,17.09mmol)，搅拌5mins后，反应液升温到35℃搅拌16hrs。向反应混合物中加入水(50mL)淬灭反应，用EA(50mL×2)萃取。合并有机相，用水(200mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，10％EA)得到目标化合物(3.20g,收率74.4％，黄色油状物)。LC-MS(ESI)m/z:400.2[M+Na]+。Benzyl (2R)-4-hydroxy-2,4-dimethylpiperidine-1-carboxylate (3.0 g, 11.39 mmol) and 2,6-lutidine (2.76 g, 22.78 mmol) were dissolved in DCM (60 mL). The temperature was cooled to 0°C. Under N₂ protection, TBSOTf (4.52 g, 17.09 mmol) was added. After stirring for 5 minutes, the reaction mixture was warmed to 35°C and stirred for 16 hours. Water (50 mL) was added to the reaction mixture to quench the reaction, which was then extracted with EA (50 mL x 2). The combined organic phases were washed with water (200 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 10% EA) to afford the title compound (3.20 g, 74.4% yield, as a yellow oil). LC-MS(ESI)m/z:400.2[M+Na] + .

步骤3：(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶的合成
Step 3: Synthesis of (2R)-4-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpiperidine

将苄基(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶-1-甲酸酯(3.0g,7.95mmol)溶于MeOH(30mL)，加入10％ Pd/C(500mg)。反应混合物在H2氛围下25℃搅拌3hrs。反应混合物通过硅藻土过滤，滤液减压浓缩得到目标化合物(1.96g,收率98.2％，无色油状物)。LC-MS(ESI)m/z:244.2[M+H]+。Benzyl (2R)-4-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpiperidine-1-carboxylate (3.0 g, 7.95 mmol) was dissolved in MeOH (30 mL) and 10% Pd/C (500 mg) was added. The reaction mixture was stirred at 25°C under an H₂ atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to provide the title compound (1.96 g, 98.2% yield, colorless oil). LC-MS (ESI) m/z: 244.2 [M+H] ⁺ .

步骤4：8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(20a)(3.0g,6.81mmol)和(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶(1.90g,7.80mmol)溶于NMP(120mL)，然后依次加入Cs2CO3(6.66g,20.44mmol)和Ruphos Pd G2(0.26g,0.34mmol)。反应混合物在N2保护下130℃搅拌3hrs，冷却至室温，向反应混合物中加入水和EA稀释，用EA(80mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(600mg,收率15.8％，棕色油状物)。LC-MS(ESI)m/z:556.4[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (20a) (3.0 g, 6.81 mmol) and (2R)-4-((tert-butyldimethylsilyl)oxy)-2,4-dimethylpiperidine (1.90 g, 7.80 mmol) were dissolved in NMP (120 mL), and then Cs 2 CO 3 (6.66 g, 20.44 mmol) and Ruphos Pd G2 (0.26 g, 0.34 mmol) were added in sequence. The reaction mixture was stirred at 130°C for 3 hours under N₂ protection, cooled to room temperature, diluted with water and EA, and extracted with EA (80 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (600 mg, 15.8% yield, brown oil). LC-MS (ESI) m/z: 556.4 [M+H] ⁺ .

步骤5：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 5: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2,4-二甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(600mg,1.08mmol)溶于MeOH(10mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)，然后反应混合物在N2保护下40℃搅拌16hrs。减压浓缩，残余物中加入饱和Na2CO3溶液至碱性，用EA(10mL×2)萃取，合并有机相，用饱和Na2CO3溶液(10mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(300mg,收率77.7％，黄色固体)。LC-MS(ESI)m/z:358.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.81(s,1H),5.76(s,1H),5.75(s,1H),4.46(s,2H),4.43–4.35(m,1H),3.70–3.60(m,3H),3.52–3.39(m,3H),1.96–1.83(m,4H),1.74–1.55(m,4H),1.30(d,J＝6.9Hz,3H),1.15(s,3H).8-(4-((2R)-4-((tert-Butyldimethylsilyl)oxy)-2,4-dimethylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (600 mg, 1.08 mmol) was dissolved in MeOH (10 mL), 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added, and the reaction mixture was stirred at 40° C. under N 2 protection for 16 hrs. The mixture was concentrated under reduced pressure, and saturated Na₂CO₃ solution was added to the residue until alkaline. The mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated Na₂CO₃ solution (10 mL × 2), dried over anhydrous Na₂SO₄ , filtered , and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, yield 77.7%, yellow solid). LC-MS (ESI) m/z: 358.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ12.56(s,1H),7.81(s,1H),5.76(s,1H),5.75(s,1H),4.46(s,2H),4.43–4.35(m,1H),3.70–3.60( m,3H),3.52–3.39(m,3H),1.96–1.83(m,4H),1.74–1.55(m,4H),1.30(d,J＝6.9Hz,3H),1.15(s,3H).

步骤6：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 6: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(300mg,0.84mmol)和KOH(141mg,2.51mmol)溶解于DMF(20mL)中，再分批缓慢加入I2(426mg,1.68mmol)。在N2保护下，反应液在室温下搅拌1hr。加入饱和Na2SO3水溶液淬灭反应，用EA(30mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相柱层析分离纯化(PE：EA，90％EA)得到目标化合物(170mg,收率49.9％，黄色固体)。LC-MS(ESI)m/z:484.0[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (300 mg, 0.84 mmol) and KOH (141 mg, 2.51 mmol) were dissolved in DMF (20 mL), and I (426 mg, 1.68 mmol) was slowly added portionwise. Under nitrogen , the reaction mixture was stirred at room temperature for 1 hr. The reaction was quenched by the addition of saturated aqueous NaSO solution and extracted with EA (30 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous NaSO , filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (PE:EA, 90% EA) to afford the title compound (170 mg, 49.9% yield) as a yellow solid. LC-MS(ESI)m/z:484.0[M+H] + .

步骤7：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 7: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(170mg,0.35mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(800mg,4.08mmol)、吡啶(167mg,2.11mmol)和醋酸铜(250mg,1.25mmol)依次加入到NMP(4.5mL)中。反应混合物在O2氛围下50℃搅拌16hrs，冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×2)萃取，合并有机相用饱和食盐水(30mL×5)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)得到目标化合物(165mg,收率74.1％，淡黄色固体)。LC-MS(ESI)m/z:634.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (170 mg, 0.35 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (800 mg, 4.08 mmol), pyridine (167 mg, 2.11 mmol), and copper acetate (250 mg, 1.25 mmol) were added sequentially to NMP (4.5 mL). The reaction mixture was stirred at 50°C under an O atmosphere for 16 hr, cooled to room temperature, and water (30 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 5 ), dried over anhydrous Na₂SO₄ , and filtered. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA, 60% EA) to afford the title compound (165 mg, 74.1% yield, light yellow solid). LC-MS (ESI) m/z: 634.2 [M+H] + .

步骤8：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2,4-二甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 8: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(80mg,0.13mmol)、Zn(CN)2(44mg,0.38mmol)、锌粉(25mg,0.38mmol)、Pd2(dba)3(11.5mg,0.013mmol)和Pd(dppf)Cl2(18.5mg,0.025mmol)依次加入到DMA(0.5mL)中。反应混合物在N2保护下150℃搅拌1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相用饱和食盐水(10mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)得到目标化合物(55mg,收率81.7％，黄色固体)。LC-MS(ESI)m/z:533.4[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (80 mg, 0.13 mmol), Zn(CN) ( 44 mg, 0.38 mmol), zinc powder (25 mg, 0.38 mmol), Pd (dba) ( 11.5 mg, 0.013 mmol), and Pd(dppf) Cl (18.5 mg, 0.025 mmol) were added sequentially to DMA (0.5 mL). The reaction mixture was stirred at 150° C. under N protection for 1 hr and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 5), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (55 mg, 81.7% yield, yellow solid). LC-MS (ESI) m/z: 533.4 [M+H] + .

步骤9：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2,4-二甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 9: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-羟基-2,4-二甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.094mmol)溶于THF(1mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在室温下搅拌18hrs。减压浓缩，残余物经反向柱层析分离纯化(H2O：CH3CN，55％CH3CN)得到目标化合物(20.0mg,收率47.5％，白色固体)。LC-MS(ESI)m/z:449.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.88(s,1H),6.83(d,J＝2.2Hz,1H),6.22(s,1H),4.59(s,2H),4.39(s,1H),4.13(s,1H),3.66(t,J＝10.6Hz,2H),3.59–3.47(m,3H),3.13–3.04(m,1H),2.07–1.82(m,5H),1.78–1.58(m,3H),1.21(s,3H),1.18(d,J＝6.7Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.094 mmol) was dissolved in THF (1 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O : CH₃CN , 55% CH₃CN ) to afford the title compound (20.0 mg, 47.5% yield, as a white solid). LC-MS (ESI) m/z: 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.07(s,1H),7.88(s,1H),6.83(d,J＝2.2Hz,1H),6.22(s,1H),4.59(s,2H),4.39(s,1H),4.13(s,1H),3.66(t,J＝10.6 Hz,2H),3.59–3.47(m,3H),3.13–3.04(m,1H),2.07–1.82(m,5H),1.78–1.58(m,3H),1.21(s,3H),1.18(d,J＝6.7Hz,3H).

实施例83：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡 啶-4-基)-2,4-二甲基哌啶-4-醇
Example 83: (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin -4-yl)-2,4-dimethylpiperidin-4-ol

步骤1：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡喃并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 1: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(70mg,0.11mmol)溶于DMF(4mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(138mg,0.44mmol)，反应混合物在微波仪器中130℃下搅拌2hrs，冷却至室温，向反应混合物中加入水(5mL)，用EA(10mL×2)萃取，合并有机相，用水(10mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，63％EA)得到目标化合物(50mg,收率78.6％，黄色固体)。LC-MS(ESI)m/z:576.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (70 mg, 0.11 mmol) was dissolved in DMF (4 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (138 mg, 0.44 mmol) was added. The reaction mixture was stirred at 130°C for 2 hrs in a microwave apparatus, cooled to room temperature, and water (5 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL×2). The organic phases were combined, washed with water (10 mL×5), and dried over anhydrous Na 2 SO 4 was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 63% EA) to give the title compound (50 mg, yield 78.6%, yellow solid). LC-MS (ESI) m/z: 576.2 [M+H] + .

步骤2：(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 2: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡喃并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(30mg,0.054mmol)溶于THF(1mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)，反应混合物在室温下搅拌18hrs。减压浓缩，残余物经反向柱层析分离纯化(H2O：MeCN，55％MeCN)得到目标化合物(17.0mg,收率44.2％，白色固体)。LC-MS(ESI)m/z:492.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.88(s,1H),6.80(s,1H),6.65(s,1H),4.66–4.58(m,2H),4.47(s,1H),3.71–3.61(m,2H),3.60–3.55(m,2H),3.54–3.47(m,1H),3.25–3.17(m,1H),2.74–2.66(m,1H),2.01–1.89(m,4H),1.79–1.70(m,2H),1.58–1.46(m,2H),1.25(s,3H),0.94(d,J＝6.1Hz,3H)。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (30 mg, 0.054 mmol) was dissolved in THF (1 mL). 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O :MeCN, 55% MeCN) to afford the title compound (17.0 mg, 44.2% yield, as a white solid). LC-MS (ESI) m/z: 492.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.88(s,1H),6.80(s,1H),6.65(s,1H),4.66–4.58(m,2H),4.47(s,1H),3.71–3.61(m,2H),3.60–3.55(m,2H),3.54–3.47( m,1H),3.25–3.17(m,1H),2.74–2.66(m,1H),2.01–1.89(m,4H),1.79–1.70(m,2H),1.58–1.46(m,2H),1.25(s,3H),0.94(d,J＝6.1Hz,3H).

实施例84：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-甲基-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡嗪并 [3,4-b]吡啶-3-腈
Example 84: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazino [3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(参考20a,步骤4合成)(1.10g,2.42mmol)溶于DMA(15mL)中，然后依次加入Zn(CN)2(0.85g,7.25mmol)，锌粉(0.47g,7.25mmol)，Pd2(dba)3(0.22g,0.24mmol)和Pd(dppf)Cl2(0.35g,0.48mmol)，反应混合物在150℃下反应1hr，冷却至室温，向反应混合物中加入EA(10mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝5:1)得到目标产物(600mg,收率70.1％，黄色固体)。LC-MS(ESI)m/z:355.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Reference 20a, step 4) (1.10 g, 2.42 mmol) was dissolved in DMA (15 mL), and then Zn(CN) 2 (0.85 g, 7.25 mmol), zinc powder (0.47 g, 7.25 mmol), Pd 2 (dba) 3 (0.22 g, 0.24 mmol) and Pd(dppf)Cl 2 (0.35 g, 0.48 mmol) were added in sequence. The reaction mixture was reacted at 150° C. for 1 hr and cooled to room temperature. EA (10 mL×2) was added to the reaction mixture for extraction. The organic phases were combined and anhydrous Na 2 SO 4. Dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA=5:1) to obtain the desired product (600 mg, yield 70.1%, yellow solid). LC-MS (ESI) m/z: 355.2 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1-甲基-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

向((6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.14mmol)的NMP(1mL)溶液中加入甲基[(1S，2S)-2-(甲氨基)环己基]胺(40mg,0.28mmol)、3-碘-1-甲基吡唑(44mg,0.21mmol)、CuI(27mg,0.14mmol)和Cs2CO3(138mg,0.42mmol)，N2保护下，反应混合物在120℃下在搅拌3hrs，冷却至室温，加入H2O(10mL)，用EA(10mL×2)萃取，合并有机相，用水(10mL×5)洗涤，干燥，减压浓缩，残余物经反向柱层析分离纯化(H2O：MeCN，60％MeCN)得到目标化合物(20.0mg,收率32.6％，白色固体)。LC-MS(ESI)m/z:435.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝2.2Hz,1H),6.82(d,J＝2.3Hz,1H),6.23(s,1H),4.61(s,2H),4.05–3.97(m,1H),3.95–3.90(m,2H),3.90(s,3H),3.72–3.61(m,4H),3.59–3.54(m,2H),3.53–3.45(m,1H),3.00(d,J＝12.6Hz,1H),2.02–1.89(m,4H),1.07(d,J＝6.5Hz,3H)。To a solution of ((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.14 mmol) in NMP (1 mL) were added methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (40 mg, 0.28 mmol), 3-iodo-1-methylpyrazole (44 mg, 0.21 mmol), CuI (27 mg, 0.14 mmol) and Cs 2 CO 3 (138 mg, 0.42 mmol). Under N 2 protection, the reaction mixture was stirred at 120° C. for 3 hrs, cooled to room temperature, and H 2 O (10 mL), extracted with EA (10 mL × 2), the organic phases were combined, washed with water (10 mL × 5), dried, and concentrated under reduced pressure. The residue was separated and purified by reverse column chromatography (H 2 O:MeCN, 60% MeCN) to obtain the target compound (20.0 mg, yield 32.6%, white solid). LC-MS (ESI) m/z: 435.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.84(d,J＝2.2Hz,1H),6.82(d,J＝2.3Hz,1H),6.23(s,1H),4.61(s,2H),4.05–3.97(m,1H),3.95–3.90(m,2H),3.90(s,3H) ,3.72–3.61(m,4H),3.59–3.54(m,2H),3.53–3.45(m,1H),3.00(d,J＝12.6Hz,1H),2.02–1.89(m,4H),1.07(d,J＝6.5Hz,3H).

实施例85：8-(3-溴-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环 [3.2.1]辛烷
Example 85: 8-(3-Bromo-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo [3.2.1]octane

将8-(3-溴-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(参考实施例62，步骤5合成)(50mg,0.09mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，在N2保护下，反应混合物在25℃下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.01％TFA/水，流动相B：ACN；梯度：23-36％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(6.0mg,收率14.1％，白色固体)。LC-MS(ESI)m/z:477.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),7.82(d,J＝2.3Hz,1H),6.70(d,J＝2.3Hz,1H),4.63–4.48(m,3H),3.99(d,J＝13.3Hz,1H),3.91(dd,J＝8.0,3.3Hz,1H),3.71–3.68(m,2H),3.65–3.64(m,1H),3.63–3.61(m,2H),3.57–3.56(m,1H),3.55–3.53(m,1H),3.52–3.50(m,1H),1.99–1.84(m,4H),1.34(d,J＝6.7Hz,3H)。8-(3-Bromo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Reference Example 62, synthesized in Step 5) (50 mg, 0.09 mmol) was dissolved in THF (2 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. Under N protection, the reaction mixture was stirred at 25° C. for 16 hrs, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate C18 column, 21.2 x 250 mm, 5 μm; mobile phase A: 0.01% TFA/water, mobile phase B: ACN; gradient: 23-36% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) was used to separate and purify the title compound (6.0 mg, 14.1% yield, white solid). LC-MS (ESI) m/z: 477.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.87(s,1H),7.82(d,J＝2.3Hz,1H),6.70(d,J＝2.3Hz,1H),4.63–4.48(m,3H),3.99(d,J＝13.3Hz,1H),3.91(dd,J＝8.0,3.3Hz,1H),3.71–3.68 (m,2H),3.65–3.64(m,1H),3.63–3.61(m,2H),3.57–3.56(m,1H),3.55–3 .53(m,1H),3.52–3.50(m,1H),1.99–1.84(m,4H),1.34(d,J＝6.7Hz,3H).

实施例86：3-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-氰基-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-1- 基)-N-甲基苯甲酰胺
Example 86: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-cyano-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridin-1- yl)-N-methylbenzamide

参考实施例84的合成方法合成实施例86(10mg,白色固体)。LC-MS(ESI)m/z:488.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.65–8.51(m,1H),8.31(d,J＝8.0Hz,1H),7.82(d,J＝7.8Hz,1H),7.63(t,J＝7.9Hz,1H),6.26(s,1H),4.64(s,2H),4.04–3.97(m,1H),3.92(d,J＝11.1Hz,2H),3.73–3.62(m,4H),3.57–3.41(m,3H),2.99(d,J＝12.8Hz,1H),2.79(d,J＝4.4Hz,3H),2.03–1.90(m,4H),1.07(d,J＝6.4Hz,3H).Example 86 (10 mg, white solid) was synthesized by referring to the synthesis method of Example 84. LC-MS (ESI) m/z: 488.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.73(s,1H),8.65–8.51(m,1H),8.31(d,J＝8.0Hz,1H),7.82(d,J＝7.8Hz ,1H),7.63(t,J＝7.9Hz,1H),6.26(s,1H),4.64(s,2H),4.04–3.97(m,1H),3 .92(d,J＝11.1Hz,2H),3.73–3.62(m,4H),3.57–3.41(m,3H),2.99(d,J＝12 .8Hz,1H),2.79(d,J＝4.4Hz,3H),2.03–1.90(m,4H),1.07(d,J＝6.4Hz,3H).

实施例87：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(3-(羟甲基)苯基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b] 吡啶-3-腈
Example 87: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(3-(hydroxymethyl)phenyl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b] pyridine-3-carbonitrile

步骤1：叔丁基((3-碘苄基)氧基)二甲基硅烷的合成
Step 1: Synthesis of tert-butyl((3-iodobenzyl)oxy)dimethylsilane

将(3-碘苯基)甲醇(500mg,2.14mmol)和TBSCl(386mg,2.56mmol)溶于DCM(100mL)中，在0℃下，加入咪唑(174mg,2.56mmol)，反应混合物在25℃下搅拌16hrs。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，6％EA)得到目标化合物(666mg,收率89.5％，无色油状物)。1HNMR(400MHz,CDCl3)δ7.57(s,1H),7.47(d,J＝7.8Hz,1H),7.18(d,J＝7.7Hz,1H),6.96(t,J＝7.8Hz,1H),4.58(s,2H),0.84(s,9H),0.01(s,6H)。(3-Iodophenyl)methanol (500 mg, 2.14 mmol) and TBSCl (386 mg, 2.56 mmol) were dissolved in DCM (100 mL). Imidazole (174 mg, 2.56 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 16 hrs. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with water (30 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 6% EA) to obtain the title compound (666 mg, 89.5% yield, as a colorless oil). 1 HNMR (400MHz, CDCl 3 ) δ7.57 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 4.58 (s, 2H), 0.84 (s, 9H), 0.01 (s, 6H).

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(3-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)-4-(((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.14mmol)、叔丁基((3-碘苄基)氧基)二甲基硅烷(59mg,0.17mmol)、甲基[(1S，2S)-2-(甲氨基)环己基]胺(20mg,0.14mmol)、Cs2CO3(115mg,0.35mmol)和CuI(27mg,0.14mmol)依次加入到DMSO(5mL)中。反应混合物在N2保护下120℃搅拌16hrs，反应混合物冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，46％ EA)得到目标化合物(49mg,收率60.5％，黄色固体)。LC-MS(ESI)m/z:575.3[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.14 mmol), tert-butyl((3-iodobenzyl)oxy)dimethylsilane (59 mg, 0.17 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (20 mg, 0.14 mmol), Cs 2 CO 3 (115 mg, 0.35 mmol), and CuI (27 mg, 0.14 mmol) were added sequentially to DMSO (5 mL). The reaction mixture was stirred at 120° C. under N 2 protection for 16 hrs, and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 46% EA) to obtain the title compound (49 mg, 60.5% yield, yellow solid). LC-MS (ESI) m/z: 575.3 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(3-(羟甲基)苯基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(3-(hydroxymethyl)phenyl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(3-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)-4-(((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(40mg,0.07mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(column：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水；流动相B：CAN；梯度:42-72％B，检测波长：214nm，流速:20mL/min，柱温25℃)分离纯化得到目标化合物(15.15mg,收率47.3％，白色固体)。LC-MS(ESI)m/z:461.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.02(d,J＝9.3Hz,1H),7.50(t,J＝7.9Hz,1H),7.31(d,J＝7.9Hz,1H),6.27(s,1H),5.34(t,J＝5.8Hz,1H),4.68–4.61(m,2H),4.60(d,J＝5.8Hz,2H),4.04–3.97(m,1H),3.94(d,J＝10.7Hz,2H),3.73–3.63(m,4H),3.60–3.47(m,3H),3.00(d,J＝12.6Hz,1H),2.03–1.92(m,4H),1.08(d,J＝6.4Hz,3H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (40 mg, 0.07 mmol) was dissolved in THF (2 mL) and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at 25° C. for 16 hrs, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xtimate The title compound (15.15 mg, 47.3% yield, white solid) was isolated and purified using a C18 column (21.2 x 250 mm, 5 μm; mobile phase A: 0.1% FA/water; mobile phase B: ACN; gradient: 42-72% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C). LC-MS (ESI) m/z: 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.23(s,1H),8.02(d,J＝9.3Hz,1H),7.50(t,J＝7.9Hz,1H),7.31(d,J＝7.9H z,1H),6.27(s,1H),5.34(t,J＝5.8Hz,1H),4.68–4.61(m,2H),4.60(d,J＝5.8H z,2H),4.04–3.97(m,1H),3.94(d,J＝10.7Hz,2H),3.73–3.63(m,4H),3.60–3 .47(m,3H),3.00(d,J＝12.6Hz,1H),2.03–1.92(m,4H),1.08(d,J＝6.4Hz,3H).

实施例88：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(5-甲基-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 88: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(5-methyl-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(200mg,0.56mmol)和3-碘-5-甲基-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑(247mg,0.84mmol)溶解在NMP(6mL)中，再加入Cs2CO3(551mg,1.69mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(80mg,0.56mmol)和CuI(107mg,0.56mmol)，N2保护下，反应混合物在150℃搅拌5hrs，冷却至室温，向反应混合物中加入水(20mL)，用EA(30mL×2)萃取，合并有机相用水(30mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，45％EA)得到目标化合物(100mg,收率34.2％，黄色固体)。LC-MS(ESI)m/z:519.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (200 mg, 0.56 mmol) and 3-iodo-5-methyl-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazole (247 mg, 0.84 mmol) were dissolved in NMP (6 mL), and Cs 2 CO 3 (551 mg, 1.69 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol) and CuI (107 mg, 0.56 mmol) were added. 2 , the reaction mixture was stirred at 150°C for 5 hrs, cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with water (30 mL x 3 ), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 45% EA) to obtain the title compound (100 mg, 34.2% yield, as a yellow solid). LC-MS (ESI) m/z: 519.2 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(5-甲基-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡嗪并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(5-methyl-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazino[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(100mg,0.19mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经反向柱层析分离纯化(H2O：CAN，50％ACN)得到目标化合物(30mg,收率35.8％，白色固体)。LC-MS(ESI)m/z:435.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),6.59(s,1H),6.23(s,1H),4.62(s,2H),4.05–3.97(m,1H),3.96–3.89(m,2H),3.73–3.62(m,4H),3.60–3.55(m,2H),3.53–3.45(m,1H),3.03–2.96(m,1H),2.32(s,3H),2.03–1.89(m,4H),1.07(d,J＝6.5Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (100 mg, 0.19 mmol) was dissolved in THF (2 mL). 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O :ACN, 50% ACN) to afford the title compound (30 mg, 35.8% yield, as a white solid). LC-MS (ESI) m/z: 435.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.75(s,1H),6.59(s,1H),6.23(s,1H),4.62(s,2H),4.05–3.97(m,1H),3.96–3.89(m,2H),3.73–3.62(m,4H) ,3.60–3.55(m,2H),3.53–3.45(m,1H),3.03–2.96(m,1H),2.32(s,3H),2.03–1.89(m,4H),1.07(d,J＝6.5Hz,3H).

实施例89：8-(4-((R)-2,4-二甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3- 氧杂-8-氮杂双环[3.2.1]辛烷
Example 89: 8-(4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3- oxa-8-azabicyclo[3.2.1]octane

步骤1：(R)-2,4-二甲基哌嗪-1-羧酸叔丁酯的合成
Step 1: Synthesis of (R)-tert-butyl 2,4-dimethylpiperazine-1-carboxylate

将(R)-2-甲基哌嗪-1-甲酸叔丁酯(5.00g,24.9mmol)溶于DMF(50mL)中，然后依次加入醋酸(2.25g,37.4mmol)，甲醛(2.25g,74.9mmol)和NaBH(OAc)3(10.60g,49.9mmol)，N2保护下，反应混合物60℃下反应12hrs，冷却至室温，向反应混合物中加入水，用EA(10mL×2)萃取，水(20mL×2)洗涤，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝10：1)得到目标产物(3.41g,收率63％，无色油状物)。LC-MS(ESI)m/z:215.2[M+H]+。(R)-tert-Butyl 2-methylpiperazine-1-carboxylate (5.00 g, 24.9 mmol) was dissolved in DMF (50 mL), followed by the addition of acetic acid (2.25 g, 37.4 mmol), formaldehyde (2.25 g, 74.9 mmol), and NaBH(OAc) ₃ (10.60 g, 49.9 mmol). Under nitrogen , the reaction mixture was reacted at 60°C for 12 hr. After cooling to room temperature, water was added to the reaction mixture, which was extracted with EA (10 mL × 2) and washed with water (20 mL × 2). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to afford the desired product (3.41 g, 63% yield, as a colorless oil). LC-MS (ESI) m/z: 215.2 [M+H] ⁺ .

步骤2：(R)-1,3-二甲基哌嗪的合成
Step 2: Synthesis of (R)-1,3-dimethylpiperazine

将(R)-2,4-二甲基哌嗪-1-羧酸叔丁酯(3.00g,14.0mmol)溶于THF(24mL)中，然后加入4N盐酸/1,4-二氧六环溶液(24mL)，N2保护下，反应混合物在室温下反应12hrs，减压浓缩，向残余物中加入饱和NaHCO3溶液至碱性，用EA(10mL×2)萃取，合并有机相，用水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品，直接进行下一步反应(2g,收率90％，无色油状物)。LC-MS(ESI)m/z:115.2[M+H]+。(R)-tert-Butyl 2,4-dimethylpiperazine-1-carboxylate (3.00 g, 14.0 mmol) was dissolved in THF (24 mL), followed by the addition of a 4N hydrochloric acid/1,4-dioxane solution (24 mL). Under nitrogen , the reaction mixture was allowed to react at room temperature for 12 hours and then concentrated under reduced pressure. Saturated NaHCO₃ solution was added to the residue until alkaline, followed by extraction with EA (10 mL × 2). The combined organic phases were washed with water (20 mL × 2 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the crude product, which was directly used in the next step (2 g, 90% yield, colorless oil). LC-MS (ESI) m/z: 115.2 [M+H] ⁺ .

步骤3：8-(4-(((R)-2,4-二甲基哌嗪-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(3.00g,6.81mmol)溶于甲苯(120mL)中，然后加入(R)-1,3-二甲基哌嗪(1.56g,13.60mmol)，BINAP(0.85g,1.36mmol)，Cs2CO3(6.66g,20.40mmol)和Pd(OAc)2(0.15g,0.68mmol)，N2保护下，反应混合物130℃下反应12hrs，冷却至室温后，加入水(50mL)，用EA(50mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(MeOH:DCM＝1:10)得到目标产物(1.1g,收率37％，黄色固体)。LC-MS(ESI)m/z:427.2[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (3.00 g, 6.81 mmol) was dissolved in toluene (120 mL), and then (R)-1,3-dimethylpiperazine (1.56 g, 13.60 mmol), BINAP (0.85 g, 1.36 mmol), Cs 2 CO 3 (6.66 g, 20.40 mmol) and Pd(OAc) 2 (0.15 g, 0.68 mmol) were added. Under N 2 protection, the reaction mixture was reacted at 130°C for 12 hrs. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EA (50 mL×3). The organic phases were combined and dried over anhydrous Na 2 SO 4. Dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (MeOH:DCM=1:10) to obtain the desired product (1.1 g, 37% yield, yellow solid). LC-MS (ESI) m/z: 427.2 [M+H] + .

步骤4：8-(4-((R)-2,4-二甲基哌嗪-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((R)-2,4-dimethylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(((R)-2,4-二甲基哌嗪-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.10g,2.58mmol)溶于MeOH(10mL)中，然后加入4N盐酸/1,4-二氧六环溶液(10mL)，反应混合物在室温下反应6hrs，减压浓缩，向残余物中加入饱和NaHCO3溶液至碱性，再加入水(50mL)，用EA(50mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(MeOH:DCM＝1:10)得到目标产物(0.42g,收率48％，黄色固体)。LC-MS(ESI)m/z:343.2[M+H]+。8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.10 g, 2.58 mmol) was dissolved in MeOH (10 mL), and then 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. The reaction mixture was reacted at room temperature for 6 hrs and concentrated under reduced pressure. Saturated NaHCO 3 solution was added to the residue to make it alkaline, and then water (50 mL) was added. The mixture was extracted with EA (50 mL×3). The organic phases were combined and anhydrous Na 2 SO 4. Dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (MeOH:DCM=1:10) to obtain the desired product (0.42 g, yield 48%, yellow solid). LC-MS (ESI) m/z: 343.2 [M+H] + .

步骤5：8-(4-((R)-2,4-二甲基哌嗪-1-基)-3-碘-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-((R)-2,4-dimethylpiperazin-1-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-2,4-二甲基哌嗪-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(450mg,1.31mmol)溶于DMF(40mL)中，然后加入KOH(311mg,5.55mmol)，搅拌30min后，向反应体系中缓慢加入I2(221mg,3.94mmol)，反应混合物在室温下搅拌3hrs。向反应混合物中加入饱和Na2SO3溶液，再加入水(30mL)，用EA(30mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析分离纯化(MeOH:DCM＝1:10)得到目标产物(110mg,收率18％，黄色固体)。LC-MS(ESI)m/z:469.0[M+H]+。8-(4-((R)-2,4-dimethylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (450 mg, 1.31 mmol) was dissolved in DMF (40 mL), followed by the addition of KOH (311 mg, 5.55 mmol). After stirring for 30 min, I₂ (221 mg, 3.94 mmol) was slowly added to the reaction system, and the reaction mixture was stirred at room temperature for 3 hrs. Saturated Na₂SO₃ solution was added to the reaction mixture, followed by water (30 mL), and the mixture was extracted with EA (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 1:10) to afford the desired product (110 mg, 18% yield, as a yellow solid). LC-MS(ESI)m/z:469.0[M+H] + .

步骤6：8-(4-(((R)-2,4-二甲基哌嗪-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-2,4-二甲基哌嗪-1-基)-3-碘-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.11mmol)溶于NMP(5mL)中，然后加入(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(83mg,0.43mmol)，吡啶(42mg,0.53mmol)和醋酸铜(38mg,0.21mmol)，反应混合物在O2氛围下50℃下搅拌12hrs，冷却至室温，向反应混合物中加入水(30mL)，用EA(20mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(MeOH:DCM＝1:10)得到目标化合物(20mg,收率30％，黄色固体)。LC-MS(ESI)m/z:619.2[M+H]+。8-(4-((R)-2,4-dimethylpiperazin-1-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.11 mmol) was dissolved in NMP (5 mL), and then (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (83 mg, 0.43 mmol), pyridine (42 mg, 0.53 mmol) and copper acetate (38 mg, 0.21 mmol) were added. The reaction mixture was stirred at 50°C for 12 hrs under an O2 atmosphere and cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL×3). The organic phases were combined and dried over anhydrous Na2SO4 . 4. The product was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM=1:10) to obtain the title compound (20 mg, 30% yield, yellow solid). LC-MS (ESI) m/z: 619.2 [M+H] + .

步骤7：8-(4-(((R)-2,4-二甲基哌嗪-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(((R)-2,4-二甲基哌嗪-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.08mmol)溶于DMF(4mL)中，然后加入三氟甲基(1,10-二氮杂菲)铜(I)(126mg,0.41mmol)，反应混合物在微波130℃下反应3hrs，冷却至室温，加入水(50mL)，用EA(50mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(40mg,收率88％，黄色油状物)，直接进行下一步。LC-MS(ESI)m/z:461.2[M+H]+。8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.08 mmol) was dissolved in DMF (4 mL), and trifluoromethyl(1,10-phenanthroline)copper(I) (126 mg, 0.41 mmol) was added. The reaction mixture was reacted at 130°C in a microwave for 3 hrs, cooled to room temperature, added with water (50 mL), extracted with EA (50 mL×3), and the organic phases were combined and dried over anhydrous Na 2 SO 4. The product was dried, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (40 mg, 88% yield, yellow oil), which was directly used for the next step. LC-MS (ESI) m/z: 461.2 [M+H] + .

步骤8：8-(4-((R)-2,4-二甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(((R)-2,4-二甲基哌嗪-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.07mmol)溶于THF(8mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在30℃下搅拌12hrs，冷却至室温，向反应混合物中加入饱和NaHCO3溶液(30mL)至碱性，用EA(30mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％ FA/水，流动相B：ACN；梯度：28-58％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(5mg,收率14.7％，白色固体)。LC-MS(ESI)m/z:477.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝2.4Hz,1H),6.96(d,J＝2.4Hz,1H),6.62(s,1H),4.68(s,2H),3.86(dd,J＝15.7,10.9Hz,2H),3.68(d,J＝10.9Hz,2H),3.55(d,J＝20.5Hz,1H),3.39(s,1H),3.05(d,J＝10.8Hz,1H),2.94(d,J＝10.2Hz,2H),2.72(d,J＝9.6Hz,1H),2.54(s,3H),2.40(s,1H),2.20–2.05(m,4H),1.05(d,J＝6.2Hz,3H)。8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.07 mmol) was dissolved in THF (8 mL), and 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was stirred at 30°C for 12 hrs, cooled to room temperature, and saturated NaHCO3 solution ( 30 mL) was added to the reaction mixture to make it alkaline. The mixture was extracted with EA (30 mL×3). The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 28-58% B, detection wavelength 214nm, flow rate: 20mL/min, column temperature 25°C) to obtain the title compound (5mg, yield 14.7%, white solid). LC-MS (ESI) m/z: 477.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.81(d,J＝2.4Hz,1H),6.96(d,J＝2.4Hz,1H),6.62(s,1H) ,4.68(s,2H),3.86(dd,J＝15.7,10.9Hz,2H),3.68(d,J＝10.9Hz,2H),3.55(d,J＝2 0.5Hz,1H),3.39(s,1H),3.05(d,J＝10.8Hz,1H),2.94(d,J＝10.2Hz,2H),2.72(d, J＝9.6Hz,1H),2.54(s,3H),2.40(s,1H),2.20–2.05(m,4H),1.05(d,J＝6.2Hz,3H).

实施例90：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2,4-二甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并 [3,4-b]吡啶-3-腈
Example 90: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2,4-二甲基哌嗪-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(4-(((R)-2,4-二甲基哌嗪-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(参考实施例89，步骤6)(60mg,0.09mmol)溶于DMA(5mL)中，加入Zn(CN)2(34mg,0.29mmol)，锌粉(19mg,0.29mmol)，Pd2(dba)3(8.88mg,0.01mmol)和Pd(dppf)Cl2(14.2mg,0.02mmol)，反应混合物在N2保护下在150℃下反应1hr，冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(MeOH:DCM＝1:5)得到目标产物(40mg,收率79％，黄色固体)。LC-MS(ESI)m/z:518.2[M+H]+。8-(4-(((R)-2,4-dimethylpiperazin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Reference Example 89, Step 6) (60 mg, 0.09 mmol) was dissolved in DMA (5 mL), and Zn(CN) 2 (34 mg, 0.29 mmol), zinc powder (19 mg, 0.29 mmol), Pd 2 (dba) 3 (8.88 mg, 0.01 mmol) and Pd(dppf)Cl 2 (14.2 mg, 0.02 mmol) were added. The reaction mixture was stirred under N 2 , reacted at 150°C for 1 hr. Cooled to room temperature, water (30 mL) was added to the reaction mixture, and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 1:5) to obtain the desired product (40 mg, 79% yield, yellow solid). LC-MS (ESI) m/z: 518.2 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2,4-二甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2,4-二甲基哌嗪-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(40mg,0.07mmol)溶于THF(4mL)中，然后加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在室温下反应12hrs，减压浓缩，向残余物中加入饱和NaHCO3溶液(30mL)至碱性，用EA(3mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％ FA/水，流动相B：ACN；梯度：10-35％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(10mg,收率30％，白色固体)。LC-MS(ESI)m/z:434.2[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.08(s,1H),7.89(s,1H),6.83(d,J＝2.1Hz,1H),6.18(s,1H),4.60(s,2H),4.19–4.11(m,1H),3.66(t,J＝10.3Hz,2H),3.56(d,J＝10.8Hz,2H),3.46–3.38(m,1H),3.10(d,J＝12.2Hz,1H),2.81(d,J＝10.6Hz,1H),2.64–2.58(m,1H),2.55(d,J＝3.1Hz,1H),2.26–2.22(m,4H),2.00–1.87(m,4H),1.10(d,J＝6.4Hz,3H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (40 mg, 0.07 mmol) was dissolved in THF (4 mL), and then a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was reacted at room temperature for 12 hrs and concentrated under reduced pressure. Saturated NaHCO 3 solution (30 mL) was added to the residue to make it alkaline, and the mixture was extracted with EA (3 mL×3). The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 10-35% B, detection wavelength 214 nm, flow rate: 20 mL/min, column temperature 25°C) was used to separate and purify the target compound (10 mg, yield 30%, white solid). LC-MS (ESI) m/z: 434.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.08(s,1H),7.89(s,1H),6.83(d,J＝2.1Hz,1H),6.18(s,1H),4.60(s,2H), 4.19–4.11(m,1H),3.66(t,J＝10.3Hz,2H),3.56(d,J＝10.8Hz,2H),3.46–3.38( m,1H),3.10(d,J＝12.2Hz,1H),2.81(d,J＝10.6Hz,1H),2.64–2.58(m,1H),2.55 (d,J＝3.1Hz,1H),2.26–2.22(m,4H),2.00–1.87(m,4H),1.10(d,J＝6.4Hz,3H).

实施例91：6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-(3-氧杂-8-氮杂双环[2.2.1]辛烷-8基)-1-(1H-吡唑-3- 基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 91: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-oxa-8-azabicyclo[2.2.1]octan-8-yl)-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

参考实施例20的合成方法合成实施例91(8.0mg,收率27.2％，白色固体)。LC-MS(ESI)m/z:433.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.89(s,1H),6.83(s,1H),6.19(s,1H),4.61(s,2H),4.34(s,2H),3.89(d,J＝10.7Hz,2H),3.64(d,J＝11.5Hz,4H),3.55(d,J＝10.8Hz,2H),2.00–1.86(m,8H)。Example 91 (8.0 mg, 27.2% yield, white solid) was synthesized using the reference method of Example 20. LC-MS (ESI) m/z: 433.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.07 (s, 1H), 7.89 (s, 1H), 6.83 (s, 1H), 6.19 (s, 1H), 4.61 (s, 2H), 4.34 (s, 2H), 3.89 (d, J=10.7 Hz, 2H), 3.64 (d, J=11.5 Hz, 4H), 3.55 (d, J=10.8 Hz, 2H), 2.00–1.86 (m, 8H).

实施例92：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2-甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-腈
Example 92: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2-methylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine-3-carbonitrile

步骤1：(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成
Step 1: Synthesis of tert-butyl (3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(20a)(3.00g,6.81mmol)和2-甲基丙-2-基(3R)-3-甲基哌嗪-1-羧酸酯(2.05g,10.22mmol)溶于甲苯(60mL)，然后依次加入Cs2CO3(6.66g,20.44mmol)，BINAP(0.85g,1.36mmol)和Pd(OAc)2(0.15g,0.68mmol)，然后反应混合物在N2保护下130℃搅拌过夜，冷却至室温，向反应混合物中加入水和EA稀释，用EA(50mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％ EA)得到目标化合物(1.2g,收率34％，黄色固体)。LC-MS(ESI)m/z:513.2[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20a) (3.00 g, 6.81 mmol) and 2-methylpropan-2-yl (3R)-3-methylpiperazine-1-carboxylate (2.05 g, 10.22 mmol) were dissolved in toluene (60 mL), and then Cs 2 CO 3 (6.66 g, 20.44 mmol), BINAP (0.85 g, 1.36 mmol) and Pd(OAc) 2 (0.15 g, 0.68 mmol) were added in sequence, and the reaction mixture was stirred under N O 2 . 2. Stir at 130°C overnight under the protection of a flask. Cool to room temperature. Dilute with water and EA to the reaction mixture, extract with EA (50 mL x 2). Combine the organic phases, wash with saturated brine, dry over anhydrous Na2SO4 , filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (1.2 g, 34% yield, yellow solid). LC-MS (ESI) m/z: 513.2 [M+H] + .

步骤2：8-(4-((R)-2-甲基哌嗪-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-2-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(6.15g,11.35mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)，然后反应混合物在N2保护下室温搅拌16hrs，加入NaHCO3水溶液调整pH值为11左右,反应液直接用于下一步反应。LC-MS(ESI)m/z:329.2[M+H]+。Dissolve tert-butyl (3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (6.15 g, 11.35 mmol) in THF (10 mL). Add 4N hydrochloric acid/1,4-dioxane solution (10 mL). The reaction mixture is stirred at room temperature under nitrogen for 16 hours. Aqueous NaHCO₃ is added to adjust the pH to approximately 11, and the reaction mixture is used directly in the next step. LC-MS (ESI) m/z: 329.2 [M+H] + .

步骤3：(R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成
Step 3: Synthesis of (R)-tert-butyl 4-(6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate

将上一步反应液(约500mL)置于反应瓶中,然后加入Boc2O(5g)和THF(100mL)，反应液在室温下搅拌过夜，向反应混合物中加入EA(200mL×3)萃取，合并有机相用饱和食盐水(200mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH，6％MeOH)得到目标化合物(580mg,收率74.1％，淡黄色固体)。LC-MS((ESI)m/z:429.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),7.91(s,1H),5.78(s,1H),4.48(s,2H),4.41(s,1H),4.02–3.88(m,1H),3.79(d,J＝13.0Hz,1H),3.70–3.63(m,3H),3.50(d,J＝10.7Hz,2H),3.29–3.19(m,2H),3.17(d,J＝5.3Hz,1H),1.98–1.82(m,4H),1.43(s,9H),1.06(d,J＝6.5Hz,3H).The reaction solution from the previous step (about 500 mL) was placed in a reaction flask, and then Boc2O (5 g) and THF (100 mL) were added. The reaction solution was stirred at room temperature overnight. EA (200 mL×3) was added to the reaction mixture for extraction. The combined organic phases were washed with saturated brine (200 mL× 5 ), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH, 6% MeOH) to obtain the title compound (580 mg, yield 74.1%, light yellow solid). LC-MS((ESI)m/z:429.3[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ12.64(s,1H),7.91(s,1H),5.78(s,1H),4.48(s,2H),4.41(s,1H),4.02–3.88(m,1H),3.79(d,J＝13.0Hz,1H),3.70–3.63(m ,3H),3.50(d,J＝10.7Hz,2H),3.29–3.19(m,2H),3.17(d,J＝5.3Hz,1H),1.98–1.82(m,4H),1.43(s,9H),1.06(d,J＝6.5Hz,3H).

步骤4：(R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成
Step 4: Synthesis of tert-butyl (R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate

将(R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(600mg,1.40mmol)和KOH(236mg,4.20mmol)溶解于DMF(42mL)中，再分批量缓慢加入I2(710mg,2.80mmol)，反应液在25℃下搅拌1小时，加入饱和Na2SO3水溶液淬灭反应，用EA(30mL×2)萃取，合并有机相，用水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相柱层析分离纯化(DCM：MeOH，5％MeOH)得到目标化合物(580mg,收率74.7％，淡黄色固体)。LC-MS(ESI)m/z:555.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),6.08(s,1H),5.76(s,1H),4.54–4.47(m,2H),3.98–3.86(m,2H),3.71–3.57(m,4H),3.51(d,J＝10.7Hz,2H),3.28–3.10(m,2H),2.84–2.76(m,1H),1.99–1.88(m,4H),1.43(s,9H),0.86(d,J＝6.4Hz,3H).(R)-tert-Butyl 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (600 mg, 1.40 mmol) and KOH (236 mg, 4.20 mmol) were dissolved in DMF (42 mL). I₂ (710 mg, 2.80 mmol) was slowly added portionwise. The reaction solution was stirred at 25°C for 1 hour. The reaction was quenched by addition of saturated aqueous Na₂SO₃ solution and extracted with EA (30 mL×2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by normal phase column chromatography (DCM:MeOH, 5% MeOH) to give the title compound (580 mg, yield 74.7%, light yellow solid). LC-MS(ESI)m/z:555.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.16(s,1H),6.08(s,1H),5.76(s,1H),4.54–4.47(m,2H),3.98–3.86(m,2H),3.71–3.57(m,4H),3.51(d, J＝10.7Hz,2H),3.28–3.10(m,2H),2.84–2.76(m,1H),1.99–1.88(m,4H),1.43(s,9H),0.86(d,J＝6.4Hz,3H).

步骤5：(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成
Step 5: Synthesis of tert-butyl (3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate

将(R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(550mg,0.99mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(583mg,2.97mmol)、吡啶(314mg,3.97mmol)和醋酸铜(396mg,1.98mmol)依次加入到NMP(5mL)中。反应混合物在O2氛围下50℃搅拌16hrs，冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×2)萃取，合并有机相用，用饱和食盐水(30mL×3)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，45％EA)，得到目标化合物(620mg,收率88.7％，淡黄色固体)。LC-MS(方法A)：RT＝1.75min，(ESI)m/z:705.2[M+H]+。Tert-butyl (R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (550 mg, 0.99 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (583 mg, 2.97 mmol), pyridine (314 mg, 3.97 mmol), and copper acetate (396 mg, 1.98 mmol) were added sequentially to NMP (5 mL). The reaction mixture was stirred at 50°C under an O atmosphere for 16 hrs, cooled to room temperature, and water (30 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous Na₂SO₄ , and filtered. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA, 45% EA) to afford the title compound (620 mg, 88.7% yield, pale yellow solid). LC-MS (Method A): RT = 1.75 min, (ESI) m/z: 705.2 [M+H] + .

步骤6：(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-氰基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成
Step 6: Synthesis of tert-butyl (3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-cyano-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate

将(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(100mg,0.14mmol)、Zn(CN)2(50mg,0.43mmol)、锌粉(28mg,0.43mmol)、Pd2(dba)3(13mg,0.014mmol)和Pd(dppf)Cl2(21mg,0.028mmol)依次加入到DMA(0.5mL)中。反应混合物在在N2保护下150℃搅拌1hr，冷却至室温，向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，53％EA)得到目标化合物(70mg,收率81.7％，类黄色固体)。LC-MS(ESI)m/z:604.4[M+H]+。(3R)-tert-Butyl 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.14 mmol), Zn(CN) 2 (50 mg, 0.43 mmol), zinc powder (28 mg, 0.43 mmol), Pd2 (dba) 3 (13 mg, 0.014 mmol) and Pd(dppf) Cl2 (21 mg, 0.028 mmol) were added sequentially to DMA (0.5 mL). The reaction mixture was stirred at 150°C for 1 hour under N₂ protection, cooled to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 5 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 53% EA) to obtain the title compound (70 mg, 81.7% yield, off-yellow solid). LC-MS (ESI) m/z: 604.4 [M+H] ⁺ .

步骤7：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-2-甲基哌嗪-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-2-methylpiperazin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(3R)-4-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-氰基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(65mg,0.11mmol)溶于THF(3.5mL)中，加入4N盐酸/1,4-二氧六环溶液(3.5mL),混合物在30℃下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：11-36％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(25.0mg,收率55.3％，白色固体)。LC-MS(ESI)m/z:420.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.19(s,1H),7.88(d,J＝2.0Hz,1H),6.83(d,J＝2.3Hz,1H),6.16(s,1H),4.59(s,2H),4.08–4.00(m,1H),3.68–3.63(m,2H),3.58–3.55(m,2H),3.31–3.30(m,1H),3.20–3.16(m,1H),3.01(d,J＝9.9Hz,2H),2.87–2.74(m,2H),2.02–1.88(m,4H),1.08(d,J＝6.5Hz,3H).tert-Butyl (3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-cyano-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (65 mg, 0.11 mmol) was dissolved in THF (3.5 mL), and a 4N hydrochloric acid/1,4-dioxane solution (3.5 mL) was added. The mixture was stirred at 30° C. for 16 hrs and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 11-36% B, detection wavelength: 214nm, flow rate: 20mL/min, column temperature: 25°C) was used to separate and purify the title compound (25.0mg, 55.3% yield, white solid). LC-MS (ESI) m/z: 420.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.07(s,1H),8.19(s,1H),7.88(d,J＝2.0Hz,1H),6.83(d,J＝2.3Hz,1H),6.16(s,1H),4.59(s,2H),4.08–4.00(m,1H),3.68–3.63(m,2H), 3.58–3.55(m,2H),3.31–3.30(m,1H),3.20–3.16(m,1H),3.01(d,J＝9. 9Hz,2H),2.87–2.74(m,2H),2.02–1.88(m,4H),1.08(d,J＝6.5Hz,3H).

实施例93：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-(1H-吡唑-3-基)-4-[(3R)-3-甲基吗啉基]-3-苯基吡唑并 [3,4-b]吡啶
Example 93: 6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-[(3R)-3-methylmorpholinyl]-3-phenylpyrazolo [3,4-b]pyridine

步骤1：8-(4-((R)-3-甲基吗啉基)-3-苯基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.16mmol)和苯硼酸(40mg,0.33mmol)溶解在1,4-二氧六环(4mL)和水(1mL)中，然后加入Na2CO3(52mg,0.49mmol)和Pd(dppf)Cl2(12mg,0.02mmol)，N2保护下，反应混合物在100℃搅拌16hrs，冷却至室温，加水和EA(10mL×2)萃取，合并有机相，用水(10mL×2)洗涤，干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，45％EA)得到目标化合物(75mg,收率81.7％，白色固体)。LC-MS(ESI)m/z:556.4[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.16 mmol) and phenylboronic acid (40 mg, 0.33 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and then Na 2 CO 3 (52 mg, 0.49 mmol) and Pd(dppf)Cl 2 (12 mg, 0.02 mmol) were added. 2 , the reaction mixture was stirred at 100°C for 16 hours, cooled to room temperature, extracted with water and EA (10 mL x 2), and the combined organic phases were washed with water (10 mL x 2), dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 45% EA) to obtain the title compound (75 mg, 81.7% yield, white solid). LC-MS (ESI) m/z: 556.4 [M+H] + .

步骤2：8-(4-((R)-3-甲基吗啉基)-3-苯基-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((R)-3-methylmorpholinyl)-3-phenyl-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-3-甲基吗啉基)-3-苯基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(75mg,0.13mmol)溶于THF(2mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)，反应混合物在50℃下搅拌2hrs。减压浓缩，残余物经反向柱层析分离纯化(H2O：ACN，58％ACN)得到目标化合物(16.1mg,收率25.3％，白色固体)。LC-MS(ESI)m/z:472.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.83(d,J＝6.9Hz,3H),7.53(t,J＝7.5Hz,2H),7.45(t,J＝7.3Hz,1H),6.81(s,1H),6.16(s,1H),4.68–4.50(m,2H),3.78–3.67(m,2H),3.66–3.47(m,4H),3.31–3.25(m,2H),3.23–3.15(m,1H),3.15–3.08(m,1H),2.86(d,J＝12.4Hz,1H),2.03–1.88(m,4H),0.83(d,J＝6.4Hz,3H).8-(4-((R)-3-methylmorpholinyl)-3-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (75 mg, 0.13 mmol) was dissolved in THF (2 mL). 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added, and the reaction mixture was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (H 2 O:ACN, 58% ACN) to obtain the title compound (16.1 mg, 25.3% yield, as a white solid). LC-MS (ESI) m/z: 472.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.81(s,1H),7.83(d,J＝6.9Hz,3H),7.53(t,J＝7.5Hz,2H),7.45(t,J＝ 7.3Hz,1H),6.81(s,1H),6.16(s,1H),4.68–4.50(m,2H),3.78–3.67(m,2 H),3.66–3.47(m,4H),3.31–3.25(m,2H),3.23–3.15(m,1H),3.15–3.08( m,1H),2.86(d,J＝12.4Hz,1H),2.03–1.88(m,4H),0.83(d,J＝6.4Hz,3H).

实施例94：8-(3-环丙基-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂 双环[3.2.1]辛烷
Example 94: 8-(3-cyclopropyl-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo [3.2.1]octane

步骤1：8-(3-环丙基-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-cyclopropyl-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.13mmol)和环丙基硼酸(22mg,0.26mmol)溶解在1,4-二氧六环(4mL)和水(1mL)中，然后加入Na2CO3(42mg,0.40mmol)和Pd(dppf)Cl2(9mg,0.01mmol)。N2保护下，反应混合物在100℃搅拌16hrs，冷却至室温，加水，EA(10mL×2)萃取，合并有机相，用水(10mL×2)洗涤，干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(40mg,收率58.2％，白色固体)。LC-MS(ESI)m/z:520.2[M+H]+。8-(3-iodo-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.13 mmol) and cyclopropylboronic acid (22 mg, 0.26 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), followed by the addition of Na 2 CO 3 (42 mg, 0.40 mmol) and Pd(dppf)Cl 2 (9 mg, 0.01 mmol). Under N₂ protection, the reaction mixture was stirred at 100°C for 16 hours, cooled to room temperature, and extracted with EA (10 mL x 2). The combined organic phases were washed with water (10 mL x 2), dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (40 mg, 58.2% yield, white solid). LC-MS (ESI) m/z: 520.2 [M+H] + .

步骤2：8-(3-环丙基-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(3-cyclopropyl-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-环丙基-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.06mmol)溶于THF(1mL)中，加入4N盐酸/1,4-二氧六环溶液(1mL)，反应混合物在50℃下搅拌2hrs，减压浓缩，残余物经Prep-HPLC(column：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水；流动相B：ACN；梯度:30-60％B，检测波长：214nm，流速:20mL/min，柱温25℃)分离纯化得到目标化合物(8.0mg,收率31.8％，白色固体)。LC-MS(ESI)m/z:436.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),7.75(s,1H),6.70(s,1H),6.13(s,1H),4.60–4.51(m,2H),4.03–3.95(m,1H),3.91–3.83(m,2H),3.77–3.64(m,3H),3.60–3.45(m,4H),2.93–2.84(m,1H),2.35–2.26(m,1H),2.01–1.84(m,4H),1.35–1.23(m,1H),1.03–0.92(m,5H),0.76–0.69(m,1H)。8-(3-Cyclopropyl-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.06 mmol) was dissolved in THF (1 mL), and a 4N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The reaction mixture was stirred at 50° C. for 2 hrs and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5μm; mobile phase A: 0.1% FA/water; mobile phase B: ACN; gradient: 30-60% B, detection wavelength: 214nm, flow rate: 20mL/min, column temperature 25°C) was used to separate and purify the title compound (8.0mg, 31.8% yield, white solid). LC-MS (ESI) m/z: 436.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.66(s,1H),7.75(s,1H),6.70(s,1H),6.13(s,1H),4.60–4.51(m,2H),4.03–3.95(m,1H),3.91–3.83(m,2H),3.77–3.64(m,3H), 3.60–3.45(m,4H),2.93–2.84(m,1H),2.35–2.26(m,1H),2.01–1.84(m,4H),1.35–1.23(m,1H),1.03–0.92(m,5H),0.76–0.69(m,1H).

实施例95：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(吡啶-2-基)-1H-吡唑并[3,4-b]吡啶 -3-腈
Example 95: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine -3-carbonitrile

向6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.14mmol)的NMP(1.5mL)溶液中加入甲基[(1S，2S)-2-(甲氨基)环己基]胺(40mg,0.28mmol)、2-碘吡啶(43mg,0.21mmol)、CuI(40mg,0.21mmol)和Cs2CO3(138mg,0.42mmol)，在N2保护下，反应混合物在120℃下搅拌3hrs，冷却至室温，加入H2O(10mL)，用EA(10mL×2)萃取，合并有机相，用水(10mL×5)洗涤，干燥，减压浓缩，残余物经反向柱层析(H2O：MeCN，45％MeCN)分离纯化得到目标化合物(12.5mg,收率20.5％，白色固体)。LC-MS(ESI)m/z:432.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.68(dd,J＝4.8,1.1Hz,1H),8.31(d,J＝8.2Hz,1H),8.17–8.11(m,1H),7.57–7.53(m,1H),6.33(s,1H),4.68(s,2H),4.13–4.04(m,1H),4.00(d,J＝11.5Hz,2H),3.78–3.68(m,4H),3.63(d,J＝10.8Hz,2H),3.60–3.53(m,1H),3.08(d,J＝12.6Hz,1H),2.07–1.96(m,4H),1.15(d,J＝6.5Hz,3H).To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.14 mmol) in NMP (1.5 mL) were added methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (40 mg, 0.28 mmol), 2-iodopyridine (43 mg, 0.21 mmol), CuI (40 mg, 0.21 mmol) and Cs 2 CO 3 (138 mg, 0.42 mmol). Under N 2 protection, the reaction mixture was stirred at 120° C. for 3 hrs, cooled to room temperature, H 2 O (10 mL) was added, and the mixture was extracted with EA (10 mL×2). The organic phases were combined, washed with water (10 mL×5), dried, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (H 2 The title compound (12.5 mg, 20.5% yield, white solid) was isolated and purified using 4% MeCN (2:MeCN, 45% MeCN). LC-MS (ESI) m/z: 432.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.68(dd,J＝4.8,1.1Hz,1H),8.31(d,J＝8.2Hz,1H),8.17–8.11(m,1H) ,7.57–7.53(m,1H),6.33(s,1H),4.68(s,2H),4.13–4.04(m,1H),4.00(d ,J＝11.5Hz,2H),3.78–3.68(m,4H),3.63(d,J＝10.8Hz,2H),3.60–3.53( m,1H),3.08(d,J＝12.6Hz,1H),2.07–1.96(m,4H),1.15(d,J＝6.5Hz,3H).

实施例96:6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶 -3-腈
Example 96: 6-(3-Oxo-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine- 3-carbonitrile

步骤1：4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑的合成
Step 1: Synthesis of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

将4-碘-1H-吡唑(1.00g,5.15mmol)和DHP(1.30g,15.4mmol)溶于THF(10mL)中，然后加入对甲基苯磺酸(0.09g,0.52mmol)，反应液在80℃下反应24hrs，冷却至室温。减压浓缩，残余物经正相柱层析(PE：EA，35％EA)分离纯化，得到目标化合物(900mg,收率62.8％，无色油状物)。LC-MS(ESI)m/z:279.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.58(s,1H),5.40(dd,J＝9.9,2.4Hz,1H),3.93–3.87(m,1H),3.65–3.57(m,1H),2.12–2.00(m,1H),1.96–1.83(m,2H),1.71–1.58(m,1H),1.57–1.43(m,2H)。4-Iodo-1H-pyrazole (1.00 g, 5.15 mmol) and DHP (1.30 g, 15.4 mmol) were dissolved in THF (10 mL), followed by the addition of p-toluenesulfonic acid (0.09 g, 0.52 mmol). The reaction mixture was incubated at 80°C for 24 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by normal phase column chromatography (PE:EA, 35% EA) to obtain the title compound (900 mg, 62.8% yield, colorless oil). LC-MS (ESI) m/z: 279.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.08(s,1H),7.58(s,1H),5.40(dd,J＝9.9,2.4Hz,1H),3.93–3.87(m,1H),3.65–3.5 7(m,1H),2.12–2.00(m,1H),1.96–1.83(m,2H),1.71–1.58(m,1H),1.57–1.43(m,2H).

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(200mg,0.56mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(160mg,1.13mmol)、4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑(157mg,0.56mmol)、CuI(107mg,0.56mmol)和Cs2CO3(459mg,1.41mmol)依次加入到NMP(3mL)中。反应混合物在120℃搅拌12hrs，冷却至室温。向反应混合物中加入水(10mL)，用EA(15mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，粗产品经反相柱(H2O：MeCN，55％MeCN)纯化得到目标化合物(100mg,收率35.1％，黄色油状物)。LC-MS(ESI)m/z:505.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (200 mg, 0.56 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (160 mg, 1.13 mmol), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (157 mg, 0.56 mmol), CuI (107 mg, 0.56 mmol), and Cs 2 CO 3 (459 mg, 1.41 mmol) were added sequentially to NMP (3 mL). The reaction mixture was stirred at 120° C. for 12 hrs and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (15 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (H 2 O:MeCN, 55% MeCN) to obtain the title compound (100 mg, 35.1% yield, yellow oil). LC-MS (ESI) m/z: 505.2 [M+H] + .

步骤3：6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Step 3: 6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-腈(100mg,0.20mmol)溶于THF(5mL)，加入4N盐酸/1,4-二氧六环溶液(5mL)。反应混合物在室温下搅拌12hrs。减压浓缩，残余物中加入饱和Na2CO3溶液(20mL)，用EA(20mL×2)萃取，合并有机相用饱和食盐水(80mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC HPLC(柱：Xtimate C18 5um OBD 21.2*250mm；流动相A：0.1％FA/水，流动相B：ACN；梯度：32-62％B，检测波长214nm，流速：20mL/min，柱温25℃)，冻干得到目标化合物(25mg,收率30.0％，白色固体)分离纯化。LC-MS(方法A)：RT＝1.31min，(ESI)m/z:421.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.40(s,1H),8.11(s,1H),6.20(s,1H),4.65(s,2H),4.04–3.95(m,1H),3.94–3.87(m,2H),3.72–3.62(m,4H),3.57(d,J＝11.1Hz,2H),3.52–3.41(m,1H),2.99(d,J＝12.7Hz,1H),2.01–1.90(m,4H),1.05(d,J＝6.5Hz,3H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (100 mg, 0.20 mmol) was dissolved in THF (5 mL), and a 4N hydrochloric acid/1,4-dioxane solution (5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, and saturated Na₂CO₃ solution (20 mL) was added to the residue. The mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C18 5 μm OBD 21.2 x 250 mm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 32-62% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) and lyophilized to afford the title compound (25 mg, 30.0% yield, as a white solid). LC-MS (Method A): RT = 1.31 min, (ESI) m/z: 421.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.16(s,1H),8.40(s,1H),8.11(s,1H),6.20(s,1H),4.65(s,2H),4.04–3.95(m,1H),3.94–3.87(m,2H),3.72–3.6 2(m,4H),3.57(d,J＝11.1Hz,2H),3.52–3.41(m,1H),2.99(d,J＝12.7Hz,1H),2.01–1.90(m,4H),1.05(d,J＝6.5Hz,3H).

实施例97 6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-咪唑-4-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡 啶-3-腈
Example 97 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-imidazol-4-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b] pyridine -3-carbonitrile

步骤1：4-碘-1-(四氢-2H-吡喃-2-基)-1H-咪唑的合成
Step 1: Synthesis of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazole

将4-碘-1H-咪唑(1.00g,5.15mmol)和DHP(1.30g,15.4mmol)溶于THF(10mL)中，然后加入对甲基苯磺酸(0.09g,0.52mmol)。反应液在80℃下反应24hrs，冷却至室温。减压浓缩，残余物经正相柱层析(PE：EA，35％EA)纯化得到目标化合物(950mg,收率66.3％，白色固体)。LC-MS(ESI)m/z:279.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.70(d,J＝1.3Hz,1H),7.44(d,J＝1.4Hz,1H),5.24(dd,J＝8.3,4.0Hz,1H),3.89–3.82(m,1H),3.55–3.46(m,1H),1.86–1.76(m,3H),1.60–1.48(m,1H),1.48–1.41(m,2H)。4-Iodo-1H-imidazole (1.00 g, 5.15 mmol) and DHP (1.30 g, 15.4 mmol) were dissolved in THF (10 mL), followed by the addition of p-toluenesulfonic acid (0.09 g, 0.52 mmol). The reaction mixture was stirred at 80°C for 24 hours, then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by normal phase column chromatography (PE:EA, 35% EA) to afford the title compound (950 mg, 66.3% yield, as a white solid). LC-MS (ESI) m/z: 279.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ7.70(d,J＝1.3Hz,1H),7.44(d,J＝1.4Hz,1H),5.24(dd,J＝8.3,4.0Hz,1H),3.89–3.8 2(m,1H),3.55–3.46(m,1H),1.86–1.76(m,3H),1.60–1.48(m,1H),1.48–1.41(m,2H).

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1-(1-(四氢-2H-吡喃-2-基)-1H-咪唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(200mg,0.56mmol)、(1S，2S)-N1，N2-二甲基环己烷-1,2-二胺(160mg,1.13mmol)、(4-碘-1-(四氢-2H-吡喃-2-基)-1H-咪唑(235mg,0.85mmol)、CuI(107mg,0.56mmol)和Cs2CO3(459mg,1.41mmol)依次加入到NMP(6mL)中，反应混合物在120℃加热反应12hrs，冷却至室温，向反应混合物中加入水(10mL)，用EA(15mL×3)萃取，合并有机相，依次用水(30mL×5)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(80mg,收率28.1％，棕色油状物)。LC-MS(ESI)m/z:505.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (200 mg, 0.56 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (160 mg, 1.13 mmol), (4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazole (235 mg, 0.85 mmol), CuI (107 mg, 0.56 mmol) and Cs 2 CO 3 The 4-hydroxy-2-[4-[[4-(2-[2-[2-[2-[2-[2-[2-[2-[2- ( 2-[2-( 2- (2-1-1-2-2-1 ...

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(1H-咪唑-4-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-imidazol-4-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((R)-3-甲基吗啉基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.10mmol)溶于THF(5mL)中，加入4N盐酸/1,4-二氧六环溶液(5mL)，反应混合物在室温下搅拌12hrs，减压浓缩，残余物经反相柱层析(H2O：MeCN，55％MeCN)纯化，得到目标化合物(5mg,收率12.0％，类白色固体)。LC-MS(方法A)：RT＝1.11min，(ESI)m/z:421.2[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.75–7.49(m,2H),6.13(s,1H),4.58–4.52(m,2H),4.05–3.93(m,3H),3.80–3.73(m,3H),3.70–3.63(m,1H),3.60–3.51(m,3H),3.06–2.85(m,1H),2.10–1.97(m,4H),1.10(d,J＝6.7Hz,3H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.10 mmol) was dissolved in THF (5 mL), and a 4N hydrochloric acid/1,4-dioxane solution (5 mL) was added. The reaction mixture was stirred at room temperature for 12 hr, concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O :MeCN, 55% MeCN) to obtain the title compound (5 mg, 12.0% yield, off-white solid). LC-MS (Method A): RT = 1.11 min, (ESI) m/z: 421.2 [M+H] + . 1 H NMR (400MHz, Methanol-d 4 )δ7.75–7.49(m,2H),6.13(s,1H),4.58–4.52(m,2H),4.05–3.93(m,3H),3.80–3.73(m,3H),3.7 0–3.63(m,1H),3.60–3.51(m,3H),3.06–2.85(m,1H),2.10–1.97(m,4H),1.10(d,J＝6.7Hz,3H).

实施例98:8-(4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶 -6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 98: 8-(4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin -6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(2R)-4-异丙氧基-2-甲基哌啶-1-羧酸苄酯的合成
Step 1: Synthesis of benzyl (2R)-4-isopropoxy-2-methylpiperidine-1-carboxylate

将(2R)-2-甲基六氢吡啶-4-酮(3.74g,15.12mmol)溶于DCM(30mL)，-60℃下加入将2,2,4-三甲基-3-氧-2-硅戊烷(2g,15.12mmol)和Et3SiH(1.76g,15.1mmol)，并立即置换N2三次，反应液在-60℃下反应30mins，0℃下加入TMSOTf(0.34g,1.51mmol)，然后自然升至室温搅拌12hrs。向反应液中加入水用EA(10mL)萃取，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，1％EA到10％EA)分离纯化，得到目标化合物(2.00g,收率45.4％，无色油状物)。LC-MS(ESI)m/z:292.2[M+H]+。(2R)-2-Methylhexahydropyridin-4-one (3.74 g, 15.12 mmol) was dissolved in DCM (30 mL). 2,2,4-Trimethyl-3-oxo-2-silapentane (2 g, 15.12 mmol) and Et₃SiH₄ (1.76 g, 15.1 mmol) were added at -60°C. The atmosphere was immediately replaced with nitrogen three times. The reaction mixture was allowed to react at -60°C for 30 min. TMSOTf (0.34 g, 1.51 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and stirred for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with EA (10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 1% EA to 10% EA) to obtain the title compound (2.00 g, 45.4% yield, as a colorless oil). LC-MS(ESI)m/z:292.2[M+H] + .

步骤2：(2R)-4-异丙氧基-2-甲基哌啶盐酸盐的合成
Step 2: Synthesis of (2R)-4-isopropoxy-2-methylpiperidine hydrochloride

将(2R)-4-异丙氧基-2-甲基哌啶-1-羧酸苄酯(3.50g,12.1mmol)溶于MeOH(30mL)中，加入Pd/C(1.2g)，置换H2后，在室温下反应12hrs，过滤除去Pd/C，减压浓缩得到(2R)-4-异丙氧基-2-甲基哌啶盐酸盐(2g,粗品，无色油状物)。LC-MS(ESI)m/z:158.2[M+H]+。Benzyl (2R)-4-isopropoxy-2-methylpiperidine-1-carboxylate (3.50 g, 12.1 mmol) was dissolved in MeOH (30 mL) and Pd/C (1.2 g) was added. After H₂ displacement, the mixture was reacted at room temperature for 12 hours. The Pd/C was removed by filtration, and the mixture was concentrated under reduced pressure to yield (2R)-4-isopropoxy-2-methylpiperidine hydrochloride (2 g, crude, colorless oil). LC-MS (ESI) m/z: 158.2 [M+H] + .

步骤3：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-[(2R)-2-甲基-4-(丙-2-基氧基)六氢吡啶-1-基]-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶的合成
Step 3: Synthesis of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-[(2R)-2-methyl-4-(propan-2-yloxy)hexahydropyridin-1-yl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(5.00g,11.35mmol)和(2R)-2-甲基-4-(丙-2-基氧基)六氢吡啶(1.96g,12.49mmol)溶于甲苯(100mL)，然后依次加入Cs2CO3(11.10g,34.07mmol)，BINAP(2.83g,4.54mmol)和Pd(OAc)2(0.51g,2.27mmol)。反应混合物在N2保护下130℃搅拌24hrs，冷却至室温。向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取。合并有机相用水洗涤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，23％EA)，得到目标化合物(1.60g,粗品，收率100％，黄色固体)。LC-MS(方法A)：RT＝1.45min，(ESI)m/z:470.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (5.00 g, 11.35 mmol) and (2R)-2-methyl-4-(propan-2-yloxy)piperidine (1.96 g, 12.49 mmol) were dissolved in toluene (100 mL). Cs 2 CO 3 (11.10 g, 34.07 mmol), BINAP (2.83 g, 4.54 mmol), and Pd(OAc) 2 (0.51 g, 2.27 mmol) were then added sequentially. The reaction mixture was stirred at 130° C. under N 2 protection for 24 hours and then cooled to room temperature. The reaction mixture was diluted with water and EA, and extracted with EA (100 mL x 2). The combined organic phases were washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 23% EA) to afford the title compound (1.60 g, crude product, 100% yield, yellow solid). LC-MS (Method A): RT = 1.45 min, (ESI) m/z: 470.2 [M+H] + .

步骤4：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-[(2R)-2-甲基-4-(丙-2-基氧基)六氢吡啶-1-基]-1H-吡唑并[3,4-b]吡啶的合成
Step 4: Synthesis of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-[(2R)-2-methyl-4-(propan-2-yloxy)hexahydropyridin-1-yl]-1H-pyrazolo[3,4-b]pyridine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-[(2R)-2-甲基-4-(丙-2-基氧基)六氢吡啶-1-基]-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(1.50g,1.60mmol)溶于THF(10mL)/MeOH(5mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)，N2保护下，混合物在室温搅拌16hrs，减压浓缩，残余物中加入饱和Na2CO3溶液至碱性，用EA(30mL×2)萃取，合并有机相,用饱和Na2CO3(30mL×2)溶液洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(396mg,收率64.3％，黄色固体)。LC-MS(ESI)m/z:386.3[M+H]+ 6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-[(2R)-2-methyl-4-(propan-2-yloxy)hexahydropyridin-1-yl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (1.50 g, 1.60 mmol) was dissolved in THF (10 mL)/MeOH (5 mL), and 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. Under N2 protection, the mixture was stirred at room temperature for 16 hrs, concentrated under reduced pressure, and saturated Na2CO3 solution was added to the residue to make it alkaline. The residue was extracted with EA (30 mL ×2). The organic phases were combined, washed with saturated Na2CO3 solution (30 mL×2), and anhydrous Na2SO4 . 4. Dry, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the target compound (396 mg, yield 64.3%, yellow solid). LC-MS (ESI) m/z: 386.3 [M+H] +

步骤5：6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-3-碘-4-[(2R,4R)-2-甲基-4-(丙-2-基氧基)六氢吡啶-1-基]-1H-吡唑并[3,4-b]吡啶的合成
Step 5: Synthesis of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-3-iodo-4-[(2R,4R)-2-methyl-4-(propan-2-yloxy)hexahydropyridin-1-yl]-1H-pyrazolo[3,4-b]pyridine

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-[(2R)-2-甲基-4-(丙-2-基氧基)六氢吡啶-1-基]-1H-吡唑并[3,4-b]吡啶(340mg,0.88mmol)和KOH(124mg,2.20mmol)溶于DMF(20mL)中，在25℃下分批量缓慢加入I2(447mg,1.76mmol)。在N2保护下，反应混合物在25℃下搅拌1hr，加入饱和Na2SO3水溶液淬灭反应，用EA(20mL×2)萃取，合并有机相，用水洗涤，，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经正相柱层析(PE：EA，30％EA)分离纯化得到目标化合物(120mg,收率26.6％，黄色固体)。LC-MS m/z:512.2[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-[(2R)-2-methyl-4-(propan-2-yloxy)hexahydropyridin-1-yl]-1H-pyrazolo[3,4-b]pyridine (340 mg, 0.88 mmol) and KOH (124 mg, 2.20 mmol) were dissolved in DMF (20 mL), and I₂ (447 mg, 1.76 mmol) was slowly added portionwise at 25°C. Under N₂ protection, the reaction mixture was stirred at 25°C for 1 hr. The reaction was quenched by addition of saturated aqueous Na₂SO₃ solution and extracted with EA (20 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by normal phase column chromatography (PE:EA, 30% EA) to afford the title compound (120 mg, 26.6% yield, as a yellow solid). LC-MS m/z: 512.2 [M+H] + .

步骤6：8-(3-碘-4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(3-iodo-4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.20mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(115mg,0.59mmol)、吡啶(62mg,0.78mmol)和醋酸铜(78mg,0.39mmol)依次加入到NMP(20mL)中。在O2氛围下置换三次，反应混合物在O2氛围下50℃搅拌16hrs，冷却至室温。向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经反向柱层析(H2O：CH3CN，90％CH3CN)纯化得到目标化合物(67mg,收率51.8％，白色固体)。LC-MS(ESI)m/z:662.2[M+H]+。8-(3-iodo-4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.20 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (115 mg, 0.59 mmol), pyridine (62 mg, 0.78 mmol), and copper acetate (78 mg, 0.39 mmol) were added sequentially to NMP (20 mL). The atmosphere was replaced with O₂ three times, and the reaction mixture was stirred at 50°C under an O₂ atmosphere for 16 hrs and then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 5 ), dried over anhydrous Na₂SO₄ , and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O : CH₃CN , 90% CH₃CN ) to afford the title compound (67 mg, 51.8% yield, white solid). LC-MS (ESI) m/z: 662.2 [M+H] ⁺ .

步骤7：8-(4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(57mg,0.086mmol)溶于DMF(5mL)，加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(166mg,0.86mmol)、六甲基磷酸三胺(154mg,0.86mmol)和CuI(25mg,0.13mmol)。在N2保护下，反应混合物在100℃下搅拌16hrs，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，减压除去溶剂，残余物先经正相柱层析(PE：EA，80％EA)分离纯化，然后再反向柱(H2O：CH3CN，91％CH3CN)纯化得到目标化合物(28mg,收率53.8％，淡黄色固体)。LC-MS(ESI)m/z:604.2[M+H]+。8-(3-iodo-4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (57 mg, 0.086 mmol) was dissolved in DMF (5 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (166 mg, 0.86 mmol), hexamethylphosphoric triamide (154 mg, 0.86 mmol), and CuI (25 mg, 0.13 mmol) were added. Under N protection, the reaction mixture was stirred at 100° C. for 16 hrs and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , and the solvent removed under reduced pressure. The residue was purified by normal phase column chromatography (PE:EA, 80% EA) and then by reverse phase column chromatography ( H₂O : CH₃CN , 91% CH₃CN ) to obtain the title compound (28 mg, 53.8% yield, light yellow solid). LC-MS (ESI) m/z: 604.2 [M+H] ⁺ .

步骤8：8-(4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-异丙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(25mg,0.041mmol)溶于DCM(2mL)中，加入TFA(1mL)，反应混合物在室温下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(柱：SunFire Prep C18 OBD，50*250mm，10um；流动相A：0.1％FA/水，流动相B：ACN；梯度：54-84％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(8.34mg,收率38.8％，白色固体)。LC-MS(方法A)：RT＝1.61min，(ESI)m/z:520.2[M+H]+。1HNMR(400MHz,Methanol-d4)δ7.77(s,1H),6.92(d,J＝2.3Hz,1H),6.58(s,1H),4.62(s,2H),3.88–3.78(m,3H),3.66–3.58(m,3H),3.34–3.32(m,2H),2.64(td,J＝12.0,2.3Hz,1H),2.13–2.03(m,5H),2.00–1.94(m,1H),1.75–1.63(m,1H),1.45–1.37(m,1H),1.18(d,J＝6.1Hz,6H),1.02(d,J＝6.0Hz,3H)。8-(4-((2R)-4-isopropoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (25 mg, 0.041 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 16 hrs and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: SunFire Prep C18 OBD (50 x 250 mm, 10 μm column); mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 54-84% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) was used to isolate and purify the title compound (8.34 mg, 38.8% yield, white solid). LC-MS (Method A): RT = 1.61 min, (ESI) m/z: 520.2 [M+H] + . 1 HNMR (400MHz, Methanol-d 4 )δ7.77(s,1H),6.92(d,J＝2.3Hz,1H),6.58(s,1H),4.62(s,2H),3.88–3.78(m,3H),3.66–3.58(m,3H),3.34–3.32(m,2H),2.64(td,J＝12 .0,2.3Hz,1H),2.13–2.03(m,5H),2.00–1.94(m,1H),1.75–1.63(m,1H),1.45–1.37(m,1H),1.18(d,J＝6.1Hz,6H),1.02(d,J＝6.0Hz,3H).

实施例99:8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡 啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 99: 8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin -6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：苄基(R)-2-甲基-4-氧代哌啶-1-甲酸酯的合成
Step 1: Synthesis of benzyl (R)-2-methyl-4-oxopiperidine-1-carboxylate

将(2R)-2-甲基六氢吡啶-4-酮(50g,441.80mmol)溶于DCM(500mL)中，加入Et3N(223g,2209mmol)，然后0℃下加入氯甲酸苄酯(93.3mL，663.00mmol)，并立即置换N2三次，反应液在室温下反应12hrs。向反应液中加入水，用DCM(10mL)进行萃取，合并有机相，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化(PE：EA，从1％EA到20％EA)得到目标化合物(53g,收率48.5％，无色油状物)。LC-MS(方法A)：RT＝1.25min，(ESI)m/z:248.2[M+H]+。(2R)-2-Methylhexahydropyridin-4-one (50 g, 441.80 mmol) was dissolved in DCM (500 mL), and Et₃N (223 g, 2209 mmol) was added. Benzyl chloroformate (93.3 mL, 663.00 mmol) was then added at 0°C. The nitrogen atmosphere was immediately replaced three times. The reaction mixture was allowed to react at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with DCM (10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 1% EA to 20% EA) to afford the title compound (53 g, 48.5% yield, colorless oil). LC-MS (Method A): RT = 1.25 min, (ESI) m/z: 248.2 [M+H] ⁺ .

步骤2：(2R)-4-羟基-2-甲基哌啶-1-羧酸苄酯的合成
Step 2: Synthesis of benzyl (2R)-4-hydroxy-2-methylpiperidine-1-carboxylate

将苄基(R)-2-甲基-4-氧代哌啶-1-甲酸酯(5.00g,20.20mmol)溶于THF(14mL)中，0℃下缓慢加入NaBH4(1.53g,40.40mmol)，立即置换N2三次，反应混合物在0℃下反应3hrs。向反应混合物中加入水灭反应，用EA(10mL)进行萃取，旋干有机相，无水Na2SO4干燥，得到粗产品(2R)-4-羟基-2-甲基哌啶-1-羧酸苄酯(4.70g,收率96.2％，无色油状物)。LC-MS(ESI)m/z:250.2[M+H]+。Benzyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (5.00 g, 20.20 mmol) was dissolved in THF (14 mL). NaBH₄ (1.53 g, 40.40 mmol) was slowly added at 0°C. The nitrogen atmosphere was immediately replaced three times. The reaction mixture was allowed to react at 0°C for 3 hr. Water was added to the reaction mixture to quench the reaction. The mixture was extracted with EA (10 mL). The organic phase was spin-dried and dried over anhydrous Na₂SO₄ to obtain crude (2R)-benzyl 4-hydroxy-2-methylpiperidine-1-carboxylate (4.70 g, 96.2% yield, colorless oil). LC-MS (ESI) m/z: 250.2 [M+H] ⁺ .

步骤3：苄基(2R)-2-甲基-4-(三氟甲氧基)哌啶-1-甲酸酯的合成
Step 3: Synthesis of benzyl (2R)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate

避光条件下，将AgOTf(6.96g,27.1mmol)，KF(2.33g,40.10mmol)，1-氯甲基-4-氟-1,4-二氮杂双环(5.33g,15.10mmol)加入到三口烧瓶中，置换N2三次，冷却至0℃后，中，然后逐滴滴加(2R)-4-羟基-2-甲基哌啶-1-羧酸苄酯(2.50g,10.10mmol)的EA(30mL)溶液，，在缓慢的滴加2-氟吡啶(2.92g,30.10mmol)和三氟甲基三甲基硅烷(4.28g,30.10mmol)，反应混合物在室温下反应24hrs，，向反应混合物中加入水(30mL)，用EA萃取，合并有机相，减压浓缩，残余物经硅胶柱层析(PE：EA，20％EA)分离纯化，得到目标化合物(300mg,收率9.4％，无色油状物)，LC-MS(ESI)m/z:318.2[M+H]+。Under light-shielding conditions, AgOTf (6.96 g, 27.1 mmol), KF (2.33 g, 40.10 mmol), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo (5.33 g, 15.10 mmol) were added to a three-necked flask to replace N 2 three times, cooled to 0°C, and then a solution of (2R)-4-hydroxy-2-methylpiperidine-1-carboxylic acid benzyl ester (2.50 g, 10.10 mmol) in EA (30 mL) was added dropwise. 2-Fluoropyridine (2.92 g, 30.10 mmol) and trifluoromethyltrimethylsilane (4.28 g, 30.10 mmol) were slowly added dropwise. The reaction mixture was reacted at room temperature for 24 hrs. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA. The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 20% EA) to give the title compound (300 mg, yield 9.4%, colorless oil). LC-MS (ESI) m/z: 318.2 [M+H] + .

步骤4：(2R)-2-甲基-4-(三氟甲氧基)哌啶盐酸盐的合成
Step 4: Synthesis of (2R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride

将Pd/C(100mg)加入到苄基(2R)-2-甲基-4-(三氟甲氧基)哌啶-1-甲酸酯(300mg,0.95mmol)的MeOH(6mL)溶液中，H2置换后，反应液在室温下反应12hrs，，过滤除去Pd/C，减压除去溶剂得到目标产物(200mg,收率96.3％，无色油状物)。LC-MS(ESI)m/z:184.2[M+H]+。Pd/C (100 mg) was added to a solution of benzyl (2R)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate (300 mg, 0.95 mmol) in MeOH (6 mL). After H₂ substitution, the reaction mixture was allowed to react at room temperature for 12 hours. The Pd/C was removed by filtration, and the solvent was removed under reduced pressure to afford the desired product (200 mg, 96.3% yield, colorless oil). LC-MS (ESI) m/z: 184.2 [M+H] ⁺ .

步骤5：8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 5: 8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧-8-氮杂双环[3.2.1]辛烷(375mg,0.85mmol)溶于1,4-二氧六环(30mL)中，依次加入(2R)-2-甲基-4-(三氟甲氧基)哌啶盐酸盐(156mg,0.85mmol)，Ruphods PdG2(66mg,0.08mmol)和CS2CO3(832mg,2.55mmol)，并立即置换氮气三次，反应混合物在110℃下搅拌12hrs，冷却至室温，用EA(20mL×2)萃取，合并有机相，用水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(EA：PE＝1：5)分离纯化得到目标化合物(200mg,收率47.4％，黄色固体)。LC-MS(ESI)m/z:496.2[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxo-8-azabicyclo[3.2.1]octane (375 mg, 0.85 mmol) was dissolved in 1,4-dioxane (30 mL), and (2R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride (156 mg, 0.85 mmol), Ruphods PdG2 (66 mg, 0.08 mmol) and CS2CO3 (832 mg, 2.55 mmol) were added in sequence , and the atmosphere was immediately replaced with nitrogen three times. The reaction mixture was stirred at 110°C for 12 hrs, cooled to room temperature, and extracted with EA (20 mL×2). The organic phases were combined, washed with water (20 mL×2), and anhydrous Na2SO4 was added. 4. Dry, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA:PE=1:5) to obtain the target compound (200 mg, yield 47.4%, yellow solid). LC-MS (ESI) m/z: 496.2 [M+H] + .

步骤6：8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 6: 8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(200mg,0.41mmol)溶于THF(4mL)中，加入4N盐酸/1,4-二氧六环溶液(4mL)，反应混合物在N2保护下在室温下反应12hrs，减压除去有机溶剂，向残余物中加入饱和NaHCO3溶液至碱性，用EA(10mL×2)萃取，合并有机相用水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩经硅胶柱层析(EA：PE＝1：4)分离纯化得到目标化合物(80mg,收率60.2％，黄色固体)。LC-MS(方法A)：RT＝0.66min，(ESI)m/z:412.2[M+H]+。8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (200 mg, 0.41 mmol) was dissolved in THF (4 mL), and a 4N hydrochloric acid/1,4-dioxane solution (4 mL) was added. The reaction mixture was reacted at room temperature under N2 protection for 12 hrs. The organic solvent was removed under reduced pressure, and a saturated NaHCO3 solution was added to the residue until it became alkaline. The mixture was extracted with EA (10 mL×2). The combined organic phases were washed with water (20 mL× 2 ), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE=1:4) to obtain the title compound (80 mg, yield 60.2%, yellow solid). LC-MS (Method A): RT = 0.66 min, (ESI) m/z: 412.2 [M+H] + .

步骤7：8-(3-碘-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(3-iodo-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.19mmol)和KOH(27mg,0.49mmol)溶于DMF(6mL)中，在30℃下，分批量缓慢加入I2(99mg,0.39mmol)的DMF(0.5mL)溶液，在N2保护下，反应混合物在30℃下搅拌1hr。加入饱和Na2SO3水溶液淬灭，用EA(10mL×2)萃取，合并有机相，用水洗涤，无水Na2SO4干燥，过滤。减压除去溶剂，残余物经正相柱层析(PE：EA，50％EA)分离纯化，得到目标化合物(36mg,收率34.5％，白色固体)。LC-MS(ESI)m/z:538.0[M+H]+。8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.19 mmol) and KOH (27 mg, 0.49 mmol) were dissolved in DMF (6 mL). A solution of I (99 mg, 0.39 mmol) in DMF (0.5 mL) was slowly added portionwise at 30°C. Under N protection, the reaction mixture was stirred at 30°C for 1 hr. The mixture was quenched by addition of saturated aqueous Na2SO3 solution and extracted with EA (10 mL x 2). The organic phases were combined, washed with water, dried over anhydrous Na2SO4 , and filtered. The solvent was removed under reduced pressure, and the residue was separated and purified by normal phase column chromatography (PE:EA, 50% EA) to obtain the title compound (36 mg, yield 34.5%, white solid). LC-MS (ESI) m/z: 538.0 [M+H] + .

步骤8：8-(3-碘-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(3-iodo-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(36.0mg,0.067mmol)、(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)硼酸(39.4mg,0.20mmol)、吡啶(21.2mg,0.27mmol)和醋酸铜(26.8mg,0.13mmol)依次加入到NMP(5mL)中。在O2氛围下置换三次，反应液在O2氛围下50℃搅拌16hrs，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析(PE：EA，60％EA)分离纯化得到目标化合物(46mg,收率99.9％，白色固体)。LC-MS(ESI)m/z:688.2[M+H]+。8-(3-iodo-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36.0 mg, 0.067 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (39.4 mg, 0.20 mmol), pyridine (21.2 mg, 0.27 mmol), and copper acetate (26.8 mg, 0.13 mmol) were added sequentially to NMP (5 mL). The atmosphere was replaced with O₂ three times, and the reaction solution was stirred at 50°C under O₂ for 16 hrs before cooling to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (46 mg, 99.9% yield, white solid). LC-MS (ESI) m/z: 688.2 [M+H] + .

步骤9：8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 9: Synthesis of 8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.058mmol)溶于DMF(5mL)，加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(111mg,0.58mmol)、六甲基磷酸三胺(104mg,0.58mmol)和CuI(17mg,0.087mmol)。在N2保护下，反应混合物在100℃下搅拌16hrs，冷却至室温，向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向柱(H2O：CH3CN，90％CH3CN)纯化得到目标化合物(26mg,收率71.0％，黄色固体)。LC-MS(ESI)m/z:630.2[M+H]+。8-(3-iodo-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.058 mmol) was dissolved in DMF (5 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (111 mg, 0.58 mmol), hexamethylphosphoric triamide (104 mg, 0.58 mmol) and CuI (17 mg, 0.087 mmol) were added. Under N₂ protection, the reaction mixture was stirred at 100°C for 16 hrs, cooled to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by reverse column chromatography ( H₂O : CH₃CN , 90% CH₃CN ) to obtain the title compound (26 mg, 71.0% yield, yellow solid). LC-MS (ESI) m/z: 630.2 [M+H] ⁺ .

步骤10：8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 10: Synthesis of 8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.048mmol)溶于THF(4mL)中，加入4N盐酸/1,4-二氧六环溶液(2mL)。反应混合物在室温下搅拌16hrs，减压浓缩，残留物中加入饱和Na2CO3(20mL)水溶液，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(80mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：53-83％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(3.21mg,收率12.4％，白色固体)。LC-MS(方法A)：RT＝1.61min,(ESI)m/z:546.2[M+H]+。1HNMR(400MHz,MeOD-d4)δ7.77(s,1H),6.92(s,1H),6.62(s,0.5H),6.50(s,0.5H),4.80–4.74(m,1H),4.63(s,2H),3.86–3.78(m,2H),3.63(d,J＝10.8Hz,2H),3.28–3.22(m,1H),3.09–3.03(m,0.5H),2.77–2.70(m,0.5H),2.27–1.83(m,8.5H),1.70–1.60(m,0.5H),1.08–1.00(m,3H).8-(4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.048 mmol) was dissolved in THF (4 mL), and a 4N hydrochloric acid/1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Saturated aqueous Na₂CO₃ (20 mL) was added to the residue, and the mixture was extracted with EA (20 mL × 2). The combined organic phases were washed with saturated brine (80 mL × 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 53-83% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (3.21 mg, yield: 12.4%, white solid). LC-MS (Method A): RT = 1.61 min, (ESI) m/z: 546.2 [M+H] + . 1 HNMR(400MHz,MeOD-d 4 )δ7.77(s,1H),6.92(s,1H),6.62(s,0.5H),6.50(s,0.5H),4.80–4.74(m,1H),4.63(s,2H),3.86–3.78(m,2H),3.63(d,J＝10.8Hz ,2H),3.28–3.22(m,1H),3.09–3.03(m,0.5H),2.77–2.70(m,0.5H),2.27–1.83(m,8.5H),1.70–1.60(m,0.5H),1.08–1.00(m,3H).

实施例100和实施例101：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-2-甲基-4-(三氟甲氧基)哌啶-1- 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-2-甲基 -4-(三氟甲氧基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 100 and Example 101: 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-2-methyl -4-(trifluoromethoxy)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.15mmol)、Zn(CN)2(51mg,0.44mmol)、锌粉(28mg,0.44mmol)、Pd2(dba)3(6.6mg,0.007mmol)和Pd(dppf)Cl2(11mg,0.015mmol)依次加入到DMA(10mL)中。N2保护下，反应混合物在150℃搅拌1hr，冷却至室温。向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物硅胶柱层析(PE：EA，50％EA)分离纯化得到目标化合物(70mg,收率82.0％，淡棕色固体)。LC-MS(ESI)m/z:587.2[M+H]+。8-(3-iodo-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.15 mmol), Zn(CN) ( 51 mg, 0.44 mmol), zinc powder (28 mg, 0.44 mmol), Pd (dba) ( 6.6 mg, 0.007 mmol), and Pd(dppf) Cl (11 mg, 0.015 mmol) were added sequentially to DMA (10 mL). Under N protection, the reaction mixture was stirred at 150° C. for 1 hr and then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 5 ), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (70 mg, 82.0% yield, light brown solid). LC-MS (ESI) m/z: 587.2 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,，4R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,，4S)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-2-甲基-4-(三氟甲氧基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(65mg,0.11mmol)溶于DCM(2mL)中，加入TFA(1mL),反应混合物在室温下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：50-80％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物P1(11.68mg,收率20.9％，白色固体)。LC-MS(方法A)：RT＝1.51min，(ESI)m/z:503.2[M+H]+。SFC(方法K):RT＝7.51min。1HNMR(400MHz,Methanol-d4)δ7.77(s,1H),6.96(d,J＝2.4Hz,1H),6.18(s,1H),4.81–4.75(m,1H),4.66–4.59(m,2H),4.43–4.32(m,1H),3.81(t,J＝10.7Hz,2H),3.63(d,J＝11.1Hz,2H),3.48–3.40(m,1H),3.38–3.34(m,1H),2.34–2.25(m,2H),2.15–2.03(m,5H),1.98–1.87(m,1H),1.15(d,J＝6.7Hz,3H)和目标化合物P2(3.30mg,收率5.9％，白色固体)。LC-MS(方法A)：RT＝1.52min，(ESI)m/z:503.2[M+H]+。SFC(方法K):RT＝7.51min。6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (65 mg, 0.11 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 16 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 50-80% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the target compound P1 (11.68 mg, yield: 20.9%, white solid). LC-MS (Method A): RT = 1.51 min, (ESI) m/z: 503.2 [M+H] + . SFC (Method K): RT = 7.51 min. 1 H NMR (400 MHz, Methanol-d 4 )δ7.77(s,1H),6.96(d,J＝2.4Hz,1H),6.18(s,1H),4.81–4.75(m,1H),4.66–4.59(m,2H),4.43–4.32(m,1H),3.81(t,J＝10.7Hz,2H),3.63(d,J＝11.1Hz,2H),3.48–3.40(m,1H),3.38–3.34(m,1H),2.34–2.25(m,2H),2.15–2.03(m,5H),1.98–1.87(m,1H),1.15(d,J＝6.7Hz,3H)and target compound P2 (3.30mg, yield 5.9%, white solid). LC-MS (Method A): RT = 1.52 min, (ESI) m/z: 503.2 [M+H] + . SFC (Method K): RT = 7.51 min.

实施例102和实施例103：8-(4-((2R,4S)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H- 吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4R)-4-(甲氧基-d3)-2-甲基哌啶-1- 基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 102 and Example 103: 8-(4-((2R,4S)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H -pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4R)-4-(methoxy-d3)-2-methylpiperidin-1- yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(3-碘-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(3-iodo-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(240mg，0.39mmol)溶于DMF(5mL)中，在0℃下，加入NaH(28mg，1.16mmol)，反应混合物在0℃下搅拌10mins，然后再缓慢滴加氘代碘甲烷(224mg，1.55mmol)。N2保护下，反应混合物在室温搅拌16hrs。向反应混合物中加入水(20mL)，用EA(20mL×3)萃取，合并有机相用饱和食盐水(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，45％EA)分离纯化，得到目标化合物(170mg，收率68.9％，淡黄色油状物)。LC-MS(ESI)m/z:637.2[M+H]+。(2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (240 mg, 0.39 mmol) was dissolved in DMF (5 mL). NaH (28 mg, 1.16 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 min, and then deuterated iodomethane (224 mg, 1.55 mmol) was slowly added dropwise. Under N protection, the reaction mixture was stirred at room temperature for 16 hrs. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 45% EA) to obtain the title compound (170 mg, 68.9% yield, light yellow oil). LC-MS (ESI) m/z: 637.2 [M+H] + .

步骤2：8-(4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(120mg,0.19mmol)和三氟甲基(1,10-二氮杂菲)铜(I)(236mg，0.75mmol)依次加入到DMF(5mL)中。所得反应混合物微波150℃反应3hrs，冷却至室温，加入水(5mL)，用EA(5mL×3)萃取，合并有机相，用饱和食盐水(5mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经Prep-TLC(PE/EA＝2/1)分离纯化，得到目标化合物(80mg，收率73.3％，黄色固体)。LC-MS(ESI)m/z:579.2[M+H]+。8-(3-iodo-4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.19 mmol) and trifluoromethyl(1,10-phenanthroline)copper(I) (236 mg, 0.75 mmol) were added sequentially to DMF (5 mL). The resulting reaction mixture was microwaved at 150°C for 3 hrs, cooled to room temperature, and water (5 mL) was added. The mixture was extracted with EA (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by Prep-TLC (PE/EA = 2/1) to obtain the title compound (80 mg, 73.3% yield, as a yellow solid). LC-MS (ESI) m/z: 579.2 [M+H] + .

步骤3：8-(4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(130mg，0.11mmol)溶于DCM(2mL)中，加入TFA(2mL)，反应混合物在25℃下搅拌16hrs。减压浓缩，残余物经反向柱层析(H2O：MeCN，64％MeCN)分离纯化得到目标化合物(50mg，收率90.0％，类白色固体)。LC-MS(ESI)m/z:495.2[M+H]+。8-(4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (130 mg, 0.11 mmol) was dissolved in DCM (2 mL). TFA (2 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was isolated and purified by reverse-phase column chromatography ( H2O :MeCN, 64% MeCN) to provide the title compound (50 mg, 90.0% yield, off-white solid). LC-MS (ESI) m/z: 495.2 [M+H] + .

步骤4：8-(4-((2R,4S)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((2R,4S)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg，0.101mmol)经过手性拆分SFC(column：Daicel Chiralpak IE，40mm I.D.*250mm，10um：流动相A：n-Hexane流动相B：乙醇，B％：15％，流速：80mL/min)得到目标化合物P1(7mg，收率14.0％，白色固体)。LC-MS(ESI)m/z:495.2[M+H]+。SFC(方法F):RT＝5.551min。1H NMR(400MHz,Methanol-d4)δ7.76(s,1H),6.92(d,J＝2.2Hz,1H),6.40(s,1H),4.61(s,2H),3.87–3.76(m,3H),3.67–3.58(m,3H),3.24–3.16(m,1H),3.09–2.99(m,1H),2.13–2.01(m,5H),2.00–1.92(m,1H),1.83–1.68(m,2H),0.99(d,J＝6.4Hz,3H).和目标化合物P2(27mg，收率54.0％，白色固体)。LC-MS(ESI)m/z:495.2[M+H]+。SFC(方法F):RT＝6.525min。1H NMR(400MHz,Methanol-d4)δ7.77(d,J＝2.3Hz,1H),6.92(d,J＝2.3Hz,1H),6.58(s,1H),4.62(s,2H),3.83(d,J＝10.9Hz,1H),3.80(d,J＝10.9Hz,1H),3.63(d,J＝11.0Hz,2H),3.49–3.37(m,1H),3.36–3.32(m,2H),2.71–2.59(m,1H),2.24–2.00(m,6H),1.73–1.61(m,1H),1.44–1.34(m,1H),1.03(d,J＝6.0Hz,3H).Chiral separation of 8-(4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.101 mmol) by SFC (column: Daicel Chiralpak IE, 40 mm ID*250 mm, 10 μm; mobile phase A: n-Hexane; mobile phase B: ethanol, B%: 15%; flow rate: 80 mL/min) afforded the title compound P1 (7 mg, 14.0% yield, white solid). LC-MS (ESI) m/z: 495.2 [M+H] + . SFC (Method F): RT = 5.551 min. 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.76 (s, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.40 (s, 1H), 4.61 (s, 2H), 3.87–3.76 (m, 3H), 3.67–3.58 (m, 3H), 3.24–3.16 (m, 1H), 3.09–2.99 (m, 1H), 2.13–2.01 (m, 5H), 2.00–1.92 (m, 1H), 1.83–1.68 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H). The target compound P2 (27 mg, yield 54.0%) was obtained as a white solid. LC-MS (ESI) m/z: 495.2 [M+H] + . SFC (Method F): RT = 6.525 min. 1 H NMR (400MHz, Methanol-d 4 )δ7.77(d,J＝2.3Hz,1H),6.92(d,J＝2.3Hz,1H),6.58(s,1H),4.62(s,2H),3.83(d,J＝10.9Hz,1H),3.80(d,J＝10.9Hz,1H),3.63(d,J＝11.0Hz, 2H),3.49–3.37(m,1H),3.36–3.32(m,2H),2.71–2.59(m,1H),2.24–2. 00(m,6H),1.73–1.61(m,1H),1.44–1.34(m,1H),1.03(d,J＝6.0Hz,3H).

实施例104和实施例105：8-(4-((2S，4R)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲 脂)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-甲氧基-2-(三氟甲基)哌啶 -1-基)-1-(1H-吡唑-3-基)-3-(三氟甲脂)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 104 and Example 105: 8-(4-((2S,4R)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-methoxy-2-(trifluoromethyl)piperidin- 1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：2-(三氟甲基)哌啶-4-醇的合成
Step 1: Synthesis of 2-(trifluoromethyl)piperidin-4-ol

将2-(三氟甲基)吡啶-4-醇(1000mg，6.13mmol)溶于异丙醇(12mL)中，加入浓盐酸(0.20mL，6.47mmol)和PtO2(139.23mg,0.61mmol)，反应混合物在50℃下H2氛围(50psi)中搅拌18hrs，冷却至室温，过滤，减压浓缩，得到目标化合物(950mg,收率91.6％，无色油状物，粗品)。LC-MS(ESI)m/z:170.0[M+H]+。2-(Trifluoromethyl)pyridin-4-ol (1000 mg, 6.13 mmol) was dissolved in isopropanol (12 mL), and concentrated hydrochloric acid (0.20 mL, 6.47 mmol) and PtO₂ (139.23 mg, 0.61 mmol) were added. The reaction mixture was stirred at 50°C under a H₂ atmosphere (50 psi) for 18 hr, cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the title compound (950 mg, 91.6% yield, crude colorless oil). LC-MS (ESI) m/z: 170.0 [M+H] ⁺ .

步骤2：4-((叔丁基二甲基甲硅烷基)氧基)-2-(三氟甲基)哌啶的合成
Step 2: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-2-(trifluoromethyl)piperidine

将2-(三氟甲基)六氢吡啶-4-醇(1000mg，5.91mmol)溶于DCM(10mL)中，加入TBSCl(1.07g，7.09mmol)和咪唑(800mg，11.82mmol)，N2保护下，反应混合物在室温搅拌4hrs。向反应混合物中加入水(5mL)用EA(10mL×2)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，7％EA)分离纯化，得到目标化合物(850mg，收率50.7％，淡黄色油状物)。LC-MS(ESI)m/z:284.2[M+H]+。1HNMR(400MHz,CDCl3)δ4.54(s,1H),3.76–3.66(m,1H),3.18(m,1H),3.07–2.99(m,1H),2.57(m,1H),1.94(m,1H),1.79(m,1H),1.40–1.32(m,1H),1.31–1.23(m,1H),0.89–0.81(m,9H),0.04(s,6H)。2-(Trifluoromethyl)hexahydropyridin-4-ol (1000 mg, 5.91 mmol) was dissolved in DCM (10 mL), and TBSCl (1.07 g, 7.09 mmol) and imidazole (800 mg, 11.82 mmol) were added. Under N₂ protection, the reaction mixture was stirred at room temperature for 4 hr. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE:EA, 7% EA) to obtain the title compound (850 mg, 50.7% yield, as a light yellow oil). LC-MS (ESI) m/z: 284.2 [M+H] ⁺ . 1 HNMR (400MHz, CDCl 3 )δ4.54(s,1H),3.76–3.66(m,1H),3.18(m,1H),3.07–2.99(m,1H),2.57(m,1H),1.94(m, 1H),1.79(m,1H),1.40–1.32(m,1H),1.31–1.23(m,1H),0.89–0.81(m,9H),0.04(s,6H).

步骤3：8-(4-((叔丁基二甲基甲硅烷基)氧基)-2-(三氟甲基)哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((tert-butyldimethylsilyl)oxy)-2-(trifluoromethyl)piperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3，4，5，6-四氢-2H-吡喃-2-基)吡唑并[3，4-b]吡啶(1.3g，2.95mmol)溶于1,4-二氧六环(10mL)中，加入4-((叔丁基二甲基甲硅烷基)氧基)-2-(三氟甲基)哌啶(0.92g，3.25mmol)、Cs2CO3(2.89g，8.86mmol)和Ruphos Pd G2(0.23g，0.30mmol)，反应混合物在N2保护下在110℃下搅拌16hrs，冷却至室温，向反应混合物中加入水(15mL)，用EA(50mL×3)萃取，合并有机相，用饱和食盐水(50mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，40％EA)，得到目标化合物(900mg,收率51.2％，淡黄色固体)。LC-MS(ESI)m/z:596.3[M+H]+。(6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (1.3 g, 2.95 mmol) was dissolved in 1,4-dioxane (10 mL), and 4-((tert-butyldimethylsilyl)oxy)-2-(trifluoromethyl)piperidine (0.92 g, 3.25 mmol), Cs 2 CO 3 (2.89 g, 8.86 mmol) and Ruphos Pd G2 (0.23 g, 0.30 mmol) were added. The reaction mixture was stirred at 110° C. for 16 hrs under N 2 protection, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL×2). Anhydrous Na 2 The residue was dried over SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 40% EA) to obtain the title compound (900 mg, 51.2% yield, light yellow solid). LC-MS (ESI) m/z: 596.3 [M+H] + .

步骤4：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇的合成
Step 4: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol

把8-(4-((叔丁基二甲基甲硅烷基)氧基)-2-(三氟甲基)哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(580mg，0.97mmol)和4N盐酸/1,4-二氧六环溶液(5mL)依次加入到MeOH(1mL)中。所得反应混合物30℃搅拌16hrs。向反应混合物中加入饱和Na2CO3水溶液(10mL)调pH大于8，用EA(10mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物通过硅胶柱层析(DCM：MeOH，7％MeOH)分离纯化，得到目标化合物(180mg，收率46.5％，淡黄色固体)。LC-MS(ESI)m/z:398.2[M+H]+。8-(4-((tert-Butyldimethylsilyl)oxy)-2-(trifluoromethyl)piperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (580 mg, 0.97 mmol) and a 4N hydrochloric acid/1,4-dioxane solution (5 mL) were added sequentially to MeOH (1 mL). The resulting reaction mixture was stirred at 30°C for 16 hours. Saturated aqueous Na₂CO₃ solution (10 mL) was added to the reaction mixture to adjust the pH to greater than 8. The mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH, 7% MeOH) to obtain the title compound (180 mg, 46.5% yield, light yellow solid). LC-MS (ESI) m/z: 398.2 [M+H] + .

步骤5：1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇的合成
Step 5: Synthesis of 1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇(290mg，0.73mmol)溶解在DMF(20mL)中，向溶液中加入KOH(123mg，2.19mmol)，然后缓慢加入I2(370mg，1.46mmol)，N2保护下，反应混合物在30℃下搅拌下1hr。向反应混合物中加入饱和Na2SO3水溶液(5mL)淬灭反应，用EA(10mL×3)萃取，合并有机相，依次用水(30mL×3)和饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(DCM：MeOH，10％MeOH)分离纯化得到目标化合物(250mg,收率65.4％，淡黄色固体)。LC-MS(ESI)m/z:524.0[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol (290 mg, 0.73 mmol) was dissolved in DMF (20 mL), KOH (123 mg, 2.19 mmol) was added to the solution, and then I2 (370 mg, 1.46 mmol) was slowly added. Under N2 protection, the reaction mixture was stirred at 30°C for 1 hr. Saturated aqueous Na₂SO₃ (5 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EA (10 mL × 3). The combined organic phases were washed sequentially with water (30 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (DCM:MeOH, 10% MeOH) to obtain the title compound (250 mg, 65.4% yield, light yellow solid). LC-MS (ESI) m/z: 524.0 [M+H] + .

步骤6：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇的合成
Step 6: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol

将1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇(150mg,0.28mmol)，醋酸铜(114mg,0.57mmol)，无水吡啶(1mg,1.15mmol)和[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(168mg,0.86mmol)依次加入到NMP(2mL)中。N2保护下，反应混合物50℃搅拌16hrs，冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×2)萃取，合并有机相用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，55％EA)得到目标化合物(120mg，收率62.1％，淡黄色固体)。LC-MS(ESI)m/z:674.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝2.5Hz,1H),6.80(d,J＝2.4Hz,1H),6.62(s,1H),5.42(dd,J＝9.9,2.2Hz,1H),4.96(d,J＝3.7Hz,1H),4.66–4.53(m,3H),3.98–3.87(m,2H),3.72–3.53(m,6H),3.02–2.91(m,1H),2.36–2.24(m,1H),2.19–2.08(m,1H),2.01–1.87(m,6H),1.84–1.61(m,4H),1.59–1.51(m,2H).1-(6-(3-Oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol (150 mg, 0.28 mmol), copper acetate (114 mg, 0.57 mmol), anhydrous pyridine (1 mg, 1.15 mmol) and [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (168 mg, 0.86 mmol) were added sequentially to NMP (2 mL). Under N₂ protection, the reaction mixture was stirred at 50°C for 16 hr, cooled to room temperature, and water (30 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 55% EA) to obtain the title compound (120 mg, 62.1% yield, light yellow solid). LC-MS (ESI) m/z: 674.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ7.97(d,J＝2.5Hz,1H),6.80(d,J＝2.4Hz,1H),6.62(s,1H),5.42(dd,J＝9.9,2.2Hz,1H),4.96(d,J＝3.7Hz,1H),4.66–4.53(m,3H),3.98–3.87 (m,2H),3.72–3.53(m,6H),3.02–2.91(m,1H),2.36–2.24(m,1H),2.19 –2.08(m,1H),2.01–1.87(m,6H),1.84–1.61(m,4H),1.59–1.51(m,2H).

步骤7：8-(3-碘-4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(3-iodo-4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-(三氟甲基)哌啶-4-醇(150mg，0.22mmol)溶解在DMF(2mL)中，将溶液置于0℃下，N2保护下，分批次加入NaH(26mg，0.66mmol)，搅拌5mins之后，加入CH3I(0.069mL，1.11mmol)，室温下搅拌过夜，加入冷水淬灭反应，用EA萃取3次，合并有机相减压浓缩，残余物经硅胶柱层析(PE：EA，60％EA)分离纯化得到目标化合物(90mg，收率58.7％，淡黄色固体)。LC-MS(ESI)m/z:688.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)piperidin-4-ol (150 mg, 0.22 mmol) was dissolved in DMF (2 mL). The solution was placed at 0°C under N2 protection. NaH (26 mg, 0.66 mmol) was added portionwise. After stirring for 5 min, CH3I (0.069 mL, 1.11 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched by adding cold water and extracted three times with EA. The combined organic phases were concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 60% EA) to give the title compound (90 mg, yield 58.7%, light yellow solid). LC-MS(ESI)m/z:688.2[M+H] + .

步骤8：8-(4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲酯)-1H-吡喃并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(60mg，0.087mmol)和三氟甲基(1,10-二氮杂菲)铜(I)(109mg，0.35mmol)依次加入到DMF(2mL)中。所得反应混合物N2保护下微波150℃反应3hrs，冷却至室温。反应混合物中加入水(5mL)，用EA(5mL×3)萃取，合并有机相，用饱和食盐水(5mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经TLC(PE/EA＝2/1)分离纯化，得到目标化合物(60mg，收率65.5％，黄色固体，纯度60％)。LC-MS(ESI)m/z:630.2[M+H]+。8-(3-iodo-4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.087 mmol) and trifluoromethyl(1,10-phenanthroline)copper(I) (109 mg, 0.35 mmol) were added sequentially to DMF (2 mL). The resulting reaction mixture was microwaved at 150° C. for 3 hrs under N protection and cooled to room temperature. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by TLC (PE/EA = 2/1) to obtain the title compound (60 mg, yield 65.5%, yellow solid, purity 60%). LC-MS (ESI) m/z: 630.2 [M+H] + .

步骤9：8-(4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲酯)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 9: Synthesis of 8-(4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲酯)-1H-吡喃并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg，0.079mmol)溶于DCM(2mL)中，加入TFA(2mL)。反应混合物在室温下搅拌16hrs，减压浓缩，残余物经Prep-HPLC(柱：Xtimate C18，21.2*250mm，5um；流动相A：0.1％FA/水，流动相B：ACN；梯度：45-75％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化得到目标化合物(25mg,收率72.1％，类白色固体)。LC-MS(ESI)m/z:546.2[M+H]+。8-(4-(4-Methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrano[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.079 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was isolated and purified by Prep-HPLC (column: Xtimate C18, 21.2 x 250 mm, 5 μm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 45-75% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the title compound (25 mg, 72.1% yield, off-white solid). LC-MS (ESI) m/z: 546.2 [M+H] + .

步骤10：8-(4-((2S，4R)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲脂)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲脂)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 10: Synthesis of 8-(4-((2S,4R)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-(4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲酯)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(25mg,0.046mmol)经过手性拆分SFC(column：Daicel ChiralCel AD，40mm I.D.*250mm，10um：流动相A：n-Hexane；流动相B：异丙醇，B％:5％流速：90mL/min)得到目标化合物P1(7mg,收率28.0％，白色固体)。LC-MS(ESI)m/z:546.2[M+H]+。SFC(方法G):RT＝5.603min，1H NMR(400MHz,Methanol-d4)δ7.77(d,J＝2.3Hz,1H),6.92(d,J＝2.4Hz,1H),6.74(s,1H),4.63(s,2H),4.33–4.23(m,1H),3.83(d,J＝10.9Hz,1H),3.77(d,J＝10.9Hz,1H),3.63(d,J＝11.0Hz,2H),3.60–3.47(m,2H),3.40(s,3H),2.97–2.88(m,1H),2.39–2.31(m,1H),2.14–1.99(m,5H),1.90–1.81(m,1H),1.76–1.66(m,1H).和P2(8mg,收率32.0％，白色固体)。LC-MS(ESI)m/z:546.2[M+H]+。SFC(方法G):RT＝8.614min，1H NMR(400MHz,Methanol-d4)δ7.80–7.73(m,1H),6.92(d,J＝2.4Hz,1H),6.74(s,1H),4.63(s,2H),4.33–4.22(m,1H),3.83(d,J＝10.8Hz,1H),3.77(d,J＝10.9Hz,1H),3.63(d,J＝11.4Hz,2H),3.60–3.46(m,2H),3.40(s,3H),2.98–2.88(m,1H),2.39–2.30(m,1H),2.15–2.09(m,2H),2.09–1.96(m,3H),1.91–1.81(m,1H),1.77–1.66(m,1H).Chiral separation of 8-(4-(4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (25 mg, 0.046 mmol) by SFC (column: Daicel ChiralCel AD, 40 mm ID x 250 mm, 10 μm; mobile phase A: n-Hexane; mobile phase B: isopropanol, B%: 5%; flow rate: 90 mL/min) afforded the title compound P1 (7 mg, 28.0% yield, white solid). LC-MS (ESI) m/z: 546.2 [M+H] + . SFC (Method G): RT = 5.603 min, 1 H NMR (400 MHz, Methanol-d 4 )δ7.77(d,J＝2.3Hz,1H),6.92(d,J＝2.4Hz,1H),6.74(s,1H),4.63(s,2H),4.33–4.23(m,1H),3.83(d,J＝10.9Hz,1H),3.77(d,J＝10.9Hz,1H),3.63(d,J＝11.0Hz,2H),3.60–3.47(m,2H),3.40(s,3H),2.97–2.88(m,1H),2.39–2.31(m,1H),2.14–1.99(m,5H),1.90–1.81(m,1H),1.76–1.66(m,1H).And P2 (8 mg, yield 32.0%, white solid). LC-MS (ESI) m/z: 546.2 [M+H] + . SFC (Method G): RT = 8.614 min, 1 H NMR (400 MHz, Methanol-d 4 )δ7.80–7.73(m,1H),6.92(d,J＝2.4Hz,1H),6.74(s,1H),4.63(s,2H),4.33– 4.22(m,1H),3.83(d,J＝10.8Hz,1H),3.77(d,J＝10.9Hz,1H),3.63(d,J＝11.4H z,2H),3.60–3.46(m,2H),3.40(s,3H),2.98–2.88(m,1H),2.39–2.30(m,1H) ,2.15–2.09(m,2H),2.09–1.96(m,3H),1.91–1.81(m,1H),1.77–1.66(m,1H).

实施例106和实施例107：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S，4R)-4-甲氧基-2-(三氟甲基)哌啶-1- 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S，4S)-4-甲氧 基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 106 and Example 107: 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S,4R)-4-methoxy-2-(trifluoromethyl)piperidin-1- yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S,4S)-4-methoxy -2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：6-(-3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((2S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(70mg,0.10mmol)，Zn(CN)2(35mg,0.30mmol)，锌粉(20mg,0.31mmol)，Pd2(dba)3(9.3mg,0.010mmol)和Pd(dppf)Cl2(14.9mg,0.020mmol)加于DMA(2mL)中，N2保护下，反应混合物在150℃下反应1hr。向反应混合物中加入水(10mL)，用EA(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱(PE：EA，53％EA)分离纯化得到目标化合物(50mg,收率83.7％，淡黄色固体)。LC-MS(ESI)m/z:587.2[M+H]+。8-(3-iodo-4-((2S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (70 mg, 0.10 mmol), Zn(CN) 2 (35 mg, 0.30 mmol), zinc powder (20 mg, 0.31 mmol), Pd2 (dba) 3 (9.3 mg, 0.010 mmol) and Pd(dppf) Cl2 (14.9 mg, 0.020 mmol) were added to DMA (2 mL), and the reaction mixture was reacted at 150°C for 1 hr under N2 protection. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (PE:EA, 53% EA) to obtain the title compound (50 mg, 83.7% yield, light yellow solid). LC-MS (ESI) m/z: 587.2 [M+H] + .

步骤2：6-(-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(50mg,0.085mmol)溶于DCM(2mL)中，加入TFA(2mL)。反应混合物在室温下搅拌16hrs。减压浓缩，经残余物经反向柱层析(H2O：MeCN，64％MeCN)分离纯化得到目标化合物(30mg,收率70.0％，类白色固体)。LC-MS(方法A)：RT＝1.38min，(ESI)m/z:503.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (50 mg, 0.085 mmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was isolated and purified by reverse-phase column chromatography ( H₂O :MeCN, 64% MeCN) to afford the title compound (30 mg, 70.0% yield, off-white solid). LC-MS (Method A): RT = 1.38 min, (ESI) m/z: 503.2 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S，4R)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S，4S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2S,4R)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2S,4S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2S)-4-甲氧基-2-(三氟甲基)哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(30mg,0.06mmol)经过手性拆分SFC(column：Daicel Chiralpak IG，40mm I.D.*250mm，10um：n-Hexane；B％：8％，溶剂：乙醇，流速：80mL/min，21.5/25.3min)得到目标化合物P1(6mg,收率20.0％，白色固体)。LC-MS(方法A)：RT＝1.43min，(ESI)m/z:503.2[M+H]+。SFC(方法J):RT＝10.037min。1H NMR(400MHz,MeOD-d4)δ7.78(d,J＝2.3Hz,1H),6.97(d,J＝2.4Hz,1H),6.39(s,1H),4.67–4.58(m,3H),3.89–3.76(m,3H),3.72–3.67(m,1H),3.63(d,J＝10.9Hz,2H),3.38(s,3H),3.29–3.24(m,1H),2.48–2.39(m,1H),2.32–2.25(m,1H),2.14–1.93(m,6H).和目标化合物P2(6mg,收率20.0％，白色固体)。LC-MS(方法A)：RT＝1.42min，(ESI)m/z:503.2[M+H]+。SFC(方法J):RT＝12.371min。1H NMR(400MHz,MeOD-d4)δ7.78(d,J＝2.3Hz,1H),6.97(d,J＝2.4Hz,1H),6.39(s,1H),4.67–4.55(m,4H),3.89–3.75(m,4H),3.73–3.66(m,1H),3.63(d,J＝10.9Hz,3H),3.38(s,3H),3.31–3.22(m,2H),2.49–2.38(m,2H),2.34–2.25(m,2H),2.15–1.90(m,9H).Chiral separation of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2S)-4-methoxy-2-(trifluoromethyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (30 mg, 0.06 mmol) by SFC (column: Daicel Chiralpak IG, 40 mm ID x 250 mm, 10 μm: n-Hexane; B%: 8%, solvent: ethanol, flow rate: 80 mL/min, 21.5/25.3 min) afforded the title compound P1 (6 mg, 20.0% yield, white solid). LC-MS (Method A): RT = 1.43 min, (ESI) m/z: 503.2 [M+H] + . SFC (Method J): RT = 10.037 min. 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.78 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.39 (s, 1H), 4.67–4.58 (m, 3H), 3.89–3.76 (m, 3H), 3.72–3.67 (m, 1H), 3.63 (d, J = 10.9 Hz, 2H), 3.38 (s, 3H), 3.29–3.24 (m, 1H), 2.48–2.39 (m, 1H), 2.32–2.25 (m, 1H), 2.14–1.93 (m, 6H). The target compound P2 (6 mg, yield 20.0%) was obtained as a white solid. LC-MS (Method A): RT = 1.42 min, (ESI) m/z: 503.2 [M+H] + . SFC (Method J): RT = 12.371 min. 1 H NMR (400MHz, MeOD-d 4 )δ7.78(d,J＝2.3Hz,1H),6.97(d,J＝2.4Hz,1H),6.39(s,1H),4.67–4.55(m,4H),3.89–3.75(m,4H),3.73–3.66(m,1H ),3.63(d,J＝10.9Hz,3H),3.38(s,3H),3.31–3.22(m,2H),2.49–2.38(m,2H),2.34–2.25(m,2H),2.15–1.90(m,9H).

实施例108和实施例109：8-(4-((2R,4R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡 唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑 -3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 108 and Example 109: 8-(4-((2R,4R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol -3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(-3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(100mg，0.16mmol)溶于DMF(6mL)，然后在0℃下加入NaH(11mg，0.48mmol)，所得反应混合物在0℃下搅拌30mins,再缓慢滴加CH3I(125mg，0.81mmol)。反应混合物在N2保护下室温搅拌12hrs。向反应混合物中加入水(10mL)，用EA(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(PE：EA，30％EA)分离纯化得到目标化合物(75mg，收率71.7％，黄色固体)。LC-MS(ESI)m/z:648.2[M+H]+。(2R)-1-(6-(-3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (100 mg, 0.16 mmol) was dissolved in DMF (6 mL), and NaH (11 mg, 0.48 mmol) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes, and then CH3I (125 mg, 0.81 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours under N2 protection. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 30% EA) to obtain the title compound (75 mg, 71.7% yield, yellow solid). LC-MS (ESI) m/z: 648.2 [M+H] + .

步骤2：8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxo-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(120mg，0.18mmol)和三氟甲基(1,10-二氮杂菲)铜(I)(289mg，0.93mmol)依次加入到DMF(6mL)中。所得反应混合物微波130℃反应3hrs，冷却至室温，向反应混合物中加入水(20mL)，用EA(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化得到目标化合物(80mg，收率73.3％，黄色固体)。LC-MS(ESI)m/z:590.2[M+H]+。8-(4-((2R)-4-Ethoxy-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.18 mmol) and trifluoromethyl(1,10-phenanthroline)copper(I) (289 mg, 0.93 mmol) were added sequentially to DMF (6 mL). The resulting reaction mixture was microwaved at 130°C for 3 hrs, cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (80 mg, yield 73.3%, yellow solid). LC-MS (ESI) m/z: 590.2 [M+H] + .

步骤3：8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧-8-氮杂双环[3.2.1]辛烷(80mg，0.14mmol)溶于DCM(3mL)中，加入TFA(3mL)。反应混合物在25℃下搅拌12hrs。减压浓缩，残余物经反向柱层析(H2O：MeCN，55％MeCN)纯化得到目标化合物(30mg，收率43.7％，类白色固体)。LC-MS(ESI)m/z:506.2[M+H]+。8-(4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxo-8-azabicyclo[3.2.1]octane (80 mg, 0.14 mmol) was dissolved in DCM (3 mL), and TFA (3 mL) was added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography ( H₂O :MeCN, 55% MeCN) to afford the title compound (30 mg, 43.7% yield, off-white solid). LC-MS (ESI) m/z: 506.2 [M+H] + .

步骤4：8-(4-((2R,4R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((2R,4R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(50mg,0.101mmol)经过手性拆分SFC(column：Daicel Chiralpak IG，40mm I.D.*250mm，10um：流动相A：n-Hexane；流动相B：乙醇，B％：5％，90mL/min)得到目标化合物P1(2mg,收率6.6％，白色固体)。LC-MS(ESI)m/z:506.2[M+H]+。SFC(方法F):RT＝6.373min，1H NMR(400MHz,Methanol-d4)δ7.79(s,1H),6.94(s,1H),6.40(s,1H),4.61(d,J＝12.5Hz,2H),3.91–3.73(m,4H),3.70–3.54(m,4H),3.26–3.18(m,1H),3.11–3.03(m,1H),2.15–2.03(m,5H),2.02–1.94(m,1H),1.87–1.67(m,2H),1.24(t,J＝7.0Hz,3H),1.02(d,J＝6.4Hz,3H).和P2(3mg,收率10％，白色固体)。LC-MS(ESI)m/z:506.2[M+H]+。SFC(方法F):RT＝7.782min。1H NMR(400MHz,Methanol-d4)δ7.78(s,1H),6.94(d,J＝2.2Hz,1H),6.60(s,1H),4.64(s,2H),3.83(dd,J＝15.2,10.9Hz,2H),3.68–3.58(m,4H),3.57–3.50(m,1H),3.40–3.33(m,2H),2.66(t,J＝11.4Hz,1H),2.21–2.02(m,6H),1.76–1.66(m,1H),1.47–1.39(m,1H),1.23(t,J＝7.0Hz,3H),1.05(d,J＝6.0Hz,3H).Chiral separation of 8-(4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (50 mg, 0.101 mmol) by SFC (column: Daicel Chiralpak IG, 40 mm ID x 250 mm, 10 μm; mobile phase A: n-Hexane; mobile phase B: ethanol, B%: 5%, 90 mL/min) afforded the title compound P1 (2 mg, 6.6% yield, white solid). LC-MS (ESI) m/z: 506.2 [M+H] + . SFC (Method F): RT = 6.373 min, 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.79 (s, 1H), 6.94 (s, 1H), 6.40 (s, 1H), 4.61 (d, J = 12.5 Hz, 2H), 3.91-3.73 (m, 4H), 3.70-3.54 (m, 4H), 3.26-3.18 (m, 1H), 3.11-3.03 (m, 1H), 2.15-2.03 (m, 5H), 2.02-1.94 (m, 1H), 1.87-1.67 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). And P2 (3 mg, yield 10%), white solid. LC-MS (ESI) m/z: 506.2 [M+H] + . SFC (Method F): RT = 7.782 min. 1 H NMR (400MHz, Methanol-d 4 )δ7.78(s,1H),6.94(d,J＝2.2Hz,1H),6.60(s,1H),4.64(s,2H),3.83(dd,J＝15.2,10.9Hz,2H),3.68–3.58(m,4H),3.57–3.50(m,1H),3.40– 3.33(m,2H),2.66(t,J＝11.4Hz,1H),2.21–2.02(m,6H),1.76–1.66(m,1H),1.47–1.39(m,1H),1.23(t,J＝7.0Hz,3H),1.05(d,J＝6.0Hz,3H).

实施例110：8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b] 吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 110: 8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

实施例111和实施例112：8-(4-((2R,4R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲 基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-(二氟甲氧基)-2-甲基哌啶 -1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Example 111 and Example 112: 8-(4-((2R,4R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-( trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-(difluoromethoxy)-2-methylpiperidin -1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶的合成
Step 1: Synthesis of (2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine

将(2R)-1-苄基-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶(25.0g,78.23mmol)溶于MeOH(250mL)中，加入Pd/C(10％)(5.0g)。反应混合物在H2氛围下25℃搅拌16hrs。过滤，减压浓缩，得到目标化合物(16.50g,粗品，收率98.8％，无色油状物)。LC-MS(ESI)m/z:230.4[M+H]+。(2R)-1-Benzyl-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine (25.0 g, 78.23 mmol) was dissolved in MeOH (250 mL) and Pd/C (10%) (5.0 g) was added. The reaction mixture was stirred at 25°C under a H₂ atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to afford the title compound (16.50 g, crude product, 98.8% yield, colorless oil). LC-MS (ESI) m/z: 230.4 [M+H] ⁺ .

步骤2：8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(10.00g，22.71mmol)和((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶(5.73g，24.98mmol)溶于干燥的DMF(200mL)中，然后依次加入Cs2CO3(22.21g，68.14mmol)和Ruphos Pd G2(0.88g,1.14mmol)。反应混合物在N2保护下130℃搅拌16hrs，冷却至室温，向反应混合物中加入水和EA稀释，用EA(200mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，得到粗品目标化合物(12.30g，收率100％，黄色油状物)。LC-MS(ESI)m/z:542.4[M+H]+。6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (10.00 g, 22.71 mmol) and ((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine (5.73 g, 24.98 mmol) were dissolved in dry DMF (200 mL), and then Cs 2 CO 3 (22.21 g, 68.14 mmol) and Ruphos Pd G2 (0.88 g, 1.14 mmol) were added in sequence. The reaction mixture was stirred at 130° C. for 16 hrs under N 2 protection, cooled to room temperature, diluted with water and EA, extracted with EA (200 mL×2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4. The residue was dried, filtered, and concentrated under reduced pressure to obtain the crude target compound (12.30 g, 100% yield, yellow oil). LC-MS (ESI) m/z: 542.4 [M+H] + .

步骤3：(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(12.30g，22.70mmol)溶于MeOH(40mL)中，加入4N盐酸/1,4-二氧六环溶液(20mL)，然后反应混合物在N2保护下50℃搅拌16hrs，冷却至室温，减压浓缩，加入饱和Na2CO3水溶液至碱性，用DCM(100mL×2)萃取。合并有机相，用饱和Na2CO3水溶液(100mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析(PE：EA，0％～100％EA to DCM：MeOH，10％MeOH)分离纯化得到目标化合物(5.31g，收率68.1％，黄色固体)。LC-MS(ESI)m/z:344.2[M+H]+。8-(4-((2R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (12.30 g, 22.70 mmol) was dissolved in MeOH (40 mL), and a 4N hydrochloric acid/1,4-dioxane solution (20 mL) was added. The reaction mixture was then stirred at 50°C for 16 hrs under N2 protection, cooled to room temperature, concentrated under reduced pressure, and saturated aqueous Na2CO3 solution was added to make it alkaline. The mixture was extracted with DCM (100 mL × 2). The combined organic phases were washed with saturated aqueous Na2CO3 solution (100 mL × 2), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA, 0%-100% EA to DCM:MeOH, 10% MeOH) to obtain the title compound (5.31 g, 68.1% yield, yellow solid). LC-MS (ESI) m/z: 344.2 [M+H] + .

步骤4：(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 4: Synthesis of (2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(6.27g，18.26mmol)和KOH(2.56g，45.64mmol)加入DMF(400mL)中，再分批量缓慢加入I2(9.27g，36.51mmol)。反应混合物在N2保护下在30℃下搅拌1hr，冷却至室温。加入饱和Na2SO3水溶液淬灭反应，用EA(400mL×2)萃取，合并有机相，用水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相柱层析分离纯化(PE：EA，78％EA)得到目标化合物(2.90g，收率33.8％，黄色固体)。LC-MS(ESI)m/z:470.0[M+H]+。(2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (6.27 g, 18.26 mmol) and KOH (2.56 g, 45.64 mmol) were added to DMF (400 mL), followed by the slow addition of I₂ (9.27 g, 36.51 mmol) in portions. The reaction mixture was stirred at 30°C for 1 hr under N₂ protection and then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous Na₂SO₃ solution and extracted with EA (400 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (PE:EA, 78% EA) to afford the title compound (2.90 g, 33.8% yield, as a yellow solid). LC-MS(ESI)m/z:470.0[M+H] + .

步骤5：(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 5: Synthesis of (2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

将(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(2.90g,6.18mmol)和[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]硼二醇(4.84g,24.71mmol)溶于NMP(60mL)中，再加入吡啶(2.44g，30.89mmol)、醋酸铜(2.47g，12.36mmol)。反应混合物O2氛围下在50℃下搅拌16hrs，冷却至室温，向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取，合并有机相，用水(150mL×3)洗涤，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，45％EA)，得到目标化合物(2.40g，收率62.7％，黄色固体)。LC-MS(ESI)m/z:620.2[M+H]+。(2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (2.90 g, 6.18 mmol) and [1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]boranediol (4.84 g, 24.71 mmol) were dissolved in NMP (60 mL), and pyridine (2.44 g, 30.89 mmol) and copper acetate (2.47 g, 12.36 mmol) were added. The reaction mixture was stirred at 50°C under an O₂ atmosphere for 16 hours, cooled to room temperature, diluted with water and EA, and extracted with EA (100 mL x 2). The combined organic phases were washed with water (150 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 45% EA) to obtain the title compound (2.40 g, 62.7% yield, as a yellow solid). LC-MS (ESI) m/z: 620.2 [M+H] ⁺ .

步骤6：8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(3-氧-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(300mg，0.48mmol)溶于DCM(5mL)和H2O(15mL)中，在25℃下，加入氟氢化钾(151mg，1.94mmol)，然后再缓慢滴加(溴二氟甲基)三甲基硅烷(984mg，4.84mmol)。反应混合物在N2保护下25℃搅拌16hrs。向反应混合物中加入水(30mL)，用DCM(30mL×2)萃取，合并有机相，用饱和食盐水(50mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，55％EA)得到目标化合物(152mg，收率46.9％，白色固体)。LC-MS(ESI)m/z:670.2[M+H]+。(2R)-1-(6-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (300 mg, 0.48 mmol) was dissolved in DCM (5 mL) and H 2 O (15 mL). Potassium bifluoride (151 mg, 1.94 mmol) was added at 25° C., followed by the slow dropwise addition of (bromodifluoromethyl)trimethylsilane (984 mg, 4.84 mmol). The reaction mixture was stirred at 25° C. under N 2 protection for 16 hrs. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with DCM (30 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 55% EA) to obtain the title compound (152 mg, 46.9% yield, white solid). LC-MS (ESI) m/z: 670.2 [M+H] + .

步骤7：8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(135mg，0.20mmol)溶于DMF(10mL)，加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(387mg，2.02mmol)、六甲基磷酸三胺(361mg，2.02mmol，0.35mL)和CuI(58mg，0.30mmol)。反应混合物在N2保护下置在100℃下搅拌16hrs，冷却至室温，向反应混合物中加入水(10mL)，用EA(10mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩，残余物先经硅胶柱层析(正向柱(PE：EA，80％ EA))，分离纯化然后反向柱(H2O：CH3CN，85％CH3CN)纯化得到目标化合物(80mg，收率64.9％，黄色固体)。LC-MS(ESI)m/z:612.4[M+H]+。8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (135 mg, 0.20 mmol) was dissolved in DMF (10 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (387 mg, 2.02 mmol), hexamethylphosphoric triamide (361 mg, 2.02 mmol, 0.35 mL) and CuI (58 mg, 0.30 mmol) were added. The reaction mixture was stirred at 100°C under N₂ protection for 16 hr, cooled to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (forward phase column (PE:EA, 80% EA)) and then by reverse phase column chromatography ( H₂O : CH₃CN , 85% CH₃CN ) to obtain the title compound (80 mg, yield 64.9%, yellow solid). LC-MS (ESI) m/z: 612.4 [M+H] ⁺ .

步骤8：(1R,5S)-8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of (1R,5S)-8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(70mg，0.11mmol)溶于THF(10mL)中，然后加入4N盐酸/1,4-二氧六环溶液(5mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，残余物中加入饱和Na2CO3(20mL)溶液，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(80mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-TLC(PE/EA＝1/1)分离得到目标化合物(25mg，收率41.4％，白色固体)。LC-MS(ESI)m/z:528.2[M+H]+。1HNMR(400MHz,MeOD-d4)δ7.77(s,1H),6.92(d,J＝2.2Hz,1H),6.60(s,1H),6.47(t,J＝76Hz,1H),4.64–4.62(m,2H),4.32–4.27(m,1H),3.85–3.78(m,2H),3.65–3.62(m,2H),3.33–3.30(m,2H),2.73–2.68(m,1H),2.19–2.13(m,3H),2.07–2.04(m,3H),1.89–1.86(m,1H),1.62–1.54(m,1H),1.03(d,J＝6.1Hz,3H)。8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (70 mg, 0.11 mmol) was dissolved in THF (10 mL), and then a 4N hydrochloric acid/1,4-dioxane solution (5 mL) was added. The reaction mixture was stirred at 25°C for 16 hours, then concentrated under reduced pressure. Saturated Na₂CO₃ solution (20 mL ) was added to the residue, followed by extraction with EA (20 mL × 2). The combined organic phases were washed with saturated brine (80 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by Prep-TLC (PE/EA = 1/1) to obtain the title compound (25 mg, 41.4% yield, white solid). LC-MS (ESI) m/z: 528.2 [M+H] ⁺ . 1 HNMR(400MHz,MeOD-d 4 )δ7.77(s,1H),6.92(d,J＝2.2Hz,1H),6.60(s,1H),6.47(t,J＝76Hz,1H) ,4.64–4.62(m,2H),4.32–4.27(m,1H),3.85–3.78(m,2H),3.65–3.62(m ,2H),3.33–3.30(m,2H),2.73–2.68(m,1H),2.19–2.13(m,3H),2.07–2. 04(m,3H),1.89–1.86(m,1H),1.62–1.54(m,1H),1.03(d,J＝6.1Hz,3H).

步骤9：8-(4-((2R,4R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((2R,4S)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 9: Synthesis of 8-(4-((2R,4R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((2R,4S)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(20mg，0.04mmol)经过手性拆分SFC(column：Daicel ChiralPak IH，40mm I.D.×250mm，10μm；B％：8％，溶剂：正己烷、EtOH，流速：80mL/min)得到目标化合物P2(9.77mg，收率48.9％，白色固体)。LC-MS(ESI)m/z:528.2[M+H]+。SFC(方法H):RT＝6.392min，1HNMR(400MHz,MeOD-d4)δ7.67(s,1H),6.83(d,J＝2.3Hz,1H),6.51(s,1H),6.36(t,J＝76Hz,1H),4.54–4.52(m,2H),4.23–4.17(m,1H),3.75–3.68(m,2H),3.55–3.52(m,2H),3.30–3.23(m,2H),2.64–2.55(m,1H),2.09–1.93(m,6H),1.80–1.77(m,1H),1.53–1.44(m,1H),0.94(d,J＝6.1Hz,3H)和目标化合物P1(1.79mg,收率9.0％，白色固体)。LC-MS(ESI)m/z:528.2[M+H]+。SFC(方法H):RT＝4.966min。Chiral separation of 8-(4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20 mg, 0.04 mmol) by SFC (column: Daicel ChiralPak IH, 40 mm ID × 250 mm, 10 μm; B%: 8%, solvent: n-hexane, EtOH, flow rate: 80 mL/min) afforded the title compound P2 (9.77 mg, 48.9% yield, white solid). LC-MS (ESI) m/z: 528.2 [M+H] + . SFC (Method H): RT = 6.392 min, 1 H NMR (400 MHz, MeOD-d 4 )δ7.67(s,1H),6.83(d,J＝2.3Hz,1H),6.51(s,1H),6.36(t,J＝76Hz,1H),4.54–4.52(m,2H),4.23–4.17(m,1H),3.75–3.68(m,2H),3.55–3.52(m,2H),3.30–3.23(m,2H),2.64–2.55(m,1H),2.09–1.93(m,6H),1.80–1.77(m,1H),1.53–1.44(m,1H),0.94(d,J＝6.1Hz,3H)and target compound P1 (1.79 mg, yield 9.0%, white solid). LC-MS (ESI) m/z: 528.2 [M+H] + . SFC (Method H): RT=4.966 min.

实施例113：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H- 吡唑并[3,4-b]吡啶-3-腈
Example 113: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H -pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Step 1: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(80mg,0.12mmol)溶于DMA(5mL)中，将氰化锌(43.5mg,0.37mmol)、锌粉(24.2mg,0.37mmol)、Pd2(dba)3(11.3mg,0.01mmol)和Pd(dppf)Cl2(18.1mg,0.02mmol)依次加入到反应体系中，，然后混合物在N2保护下150℃搅拌1hr。反应结束后，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到粗产品(40mg,收率59.2％，黄色油状物)。LC-MS(ESI)m/z:547.5[M+H]+。8-(4-((2R)-4-Ethoxy-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (80 mg, 0.12 mmol) was dissolved in DMA (5 mL), and zinc cyanide (43.5 mg, 0.37 mmol), zinc powder (24.2 mg, 0.37 mmol), Pd2 (dba) 3 (11.3 mg, 0.01 mmol) and Pd(dppf) Cl2 (18.1 mg, 0.02 mmol) were added to the reaction system in sequence, and then the mixture was stirred at 150°C for 1 hr under N2 protection. After the reaction, water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to give the crude product (40 mg, 59.2% yield, yellow oil). LC-MS (ESI) m/z: 547.5 [M+H] ⁺ .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Step 2: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-乙氧基-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(40mg,0.07mmol)溶于DCM(3mL)中，加入TFA(3mL)。反应混合物在25℃下搅拌12hrs。减压浓缩，残余物经Prep-HPLC分离纯化(柱：Xtimate C18 5um OBD 21.2*250mm；流动相A：0.1％FA/水，流动相B：ACN；梯度：45-75％B，检测波长214nm，流速：20mL/min，柱温25℃)，得到目标化合物HQ-19-242(20mg,收率59.1％，白色固体)。LC-MS(方法A)：RT＝1.48min，(ESI)m/z:463.2[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.04(s,1H),7.86(s,1H),6.80(d,J＝2.2Hz,1H),6.28(s,1H),4.57(d,J＝11.9Hz,2H),3.90–3.80(m,1H),3.65–3.57(m,3H),3.55(s,1H),3.53–3.42(m,4H),2.93–2.85(m,1H),2.12–2.04(m,1H),1.97–1.92(m,2H),1.91–1.82(m,4H),1.68–1.60(m,1H),1.14–1.08(m,6H)。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-ethoxy-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (40 mg, 0.07 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) was added. The reaction mixture was stirred at 25° C. for 12 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18 5um OBD 21.2*250mm; mobile phase A: 0.1% FA/water, mobile phase B: ACN; gradient: 45-75% B, detection wavelength: 214 nm, flow rate: 20 mL/min, column temperature: 25°C) to obtain the target compound HQ-19-242 (20 mg, 59.1% yield, white solid). LC-MS (Method A): RT = 1.48 min, (ESI) m/z: 463.2 [M+H] + . 1 HNMR (400MHz, DMSO-d 6 )δ13.04(s,1H),7.86(s,1H),6.80(d,J＝2.2Hz,1H),6.28(s,1H),4.57(d,J＝11.9Hz,2H),3.90–3.80(m,1H),3.65–3.57(m,3H),3.55(s,1 H),3.53–3.42(m,4H),2.93–2.85(m,1H),2.12–2.04(m,1H),1.97–1.92(m,2H),1.91–1.82(m,4H),1.68–1.60(m,1H),1.14–1.08(m,6H).

实施例114和实施例115：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-(二氟甲氧基)-2-甲基哌啶-1- 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-(二氟 甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 114 and Example 115: 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R , 4R)-4-(difluoromethoxy)-2-methylpiperidin-1- yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R , 4S)-4-(difluoromethoxy )-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(160mg，0.24mmol)、Zn(CN)2(84mg，0.72mmol)、锌粉(47mg，0.72mmol)、Pd2(dba)3(10.9mg，0.012mmol)和Pd(dppf)Cl2(17.5mg，0.024mmol)依次加入到DMA(15mL)中。反应混合物在N2保护下150℃搅拌1hr,冷却至室温，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相，用饱和食盐水(50mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)，然后减压浓缩目标化合物(91mg，收率67.0％，淡棕色固体)。LC-MS(ESI)m/z:569.2[M+H]+。8-(4-((2R)-4-(Difluoromethoxy)-2-methylpiperidin-1-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (160 mg, 0.24 mmol), Zn(CN) 2 (84 mg, 0.72 mmol), zinc powder (47 mg, 0.72 mmol), Pd2 (dba) 3 (10.9 mg, 0.012 mmol) and Pd(dppf) Cl2 (17.5 mg, 0.024 mmol) were added sequentially to DMA (15 mL). The reaction mixture was stirred at 150°C for 1 hour under N₂ protection, then cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 5 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA), and then concentrated under reduced pressure to yield the title compound (91 mg, 67.0% yield, light brown solid). LC-MS (ESI) m/z: 569.2 [M+H] ⁺ .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(86mg,0.15mmol)溶于THF(10mL)中，加入4N盐酸/1,4-二氧六环溶液(5mL)。反应混合物在室温下搅拌16hrs，减压浓缩，残余物中加入饱和NaHCO3溶液(20mL)，用EA(2mL×2)萃取，合并有机相，用饱和食盐水(80mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，82％EA)得到目标化合物(59mg，收率80.5％，白色固体)。LC-MS(ESI)m/z:485.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (86 mg, 0.15 mmol) was dissolved in THF (10 mL), and a 4N hydrochloric acid/1,4-dioxane solution (5 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. Saturated NaHCO₃ solution (20 mL) was added to the residue, followed by extraction with EA (2 mL × 2). The combined organic phases were washed with saturated brine (80 mL × 2 ), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 82% EA) to obtain the title compound (59 mg, 80.5% yield, white solid). LC-MS (ESI) m/z: 485.2 [M+H] ⁺ .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(二氟甲氧基)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(59mg,0.12mmol)经过手性拆分SFC(column：Daicel ChiralPak IH，40mm I.D.×250mm，10μm；流动相A：正己烷，流动相B：EtOH，B％：20％，流速：80mL/min)得到目标化合物P1(22.03mg,收率37.3％，白色固体)。LC-MS(ESI)m/z:485.2[M+H]+。SFC(方法D):RT＝3.236min.1HNMR(400MHz,DMSO-d6)δ13.08(s,1H),7.93–7.85(m,1H),6.80(t,J＝76.4Hz,2H),6.36(s,1H),4.62(d,J＝10.6Hz,2H),4.50–4.42(m,1H),3.96–3.87(m,1H),3.66(t,J＝10.8Hz,2H),3.61–3.47(m,3H),3.05–2.95(m,1H),2.28-2.22(m,1H),2.03–1.90(m,6H),1.79–1.70(m,1H),1.12(d,J＝6.4Hz,3H)和目标化合物P2(4.85mg,收率8.2％，白色固体)。LC-MS(ESI)m/z:485.2[M+H]+。SFC(方法D):RT＝4.090min。1HNMR(400MHz,DMSO-d6)δ13.08(s,1H),7.90(s,1H),7.01–6.60(m,2H),6.19(s,1H),4.66–4.53(m,3H),4.37–4.27(m,1H),3.71–3.61(m,2H),3.57(d,J＝10.9Hz,2H),3.40–3.33(m,2H),2.03–1.87(m,6H),1.78–1.69(m,1H),1.09(d,J＝6.7Hz,3H)。Chiral separation of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(difluoromethoxy)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (59 mg, 0.12 mmol) by SFC (column: Daicel ChiralPak IH, 40 mm ID × 250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: EtOH, B%: 20%, flow rate: 80 mL/min) afforded the title compound P1 (22.03 mg, 37.3% yield, white solid). LC-MS (ESI) m/z: 485.2 [M+H] + . SFC (method D): RT = 3.236 min. 1 H NMR (400 MHz, DMSO-d 6 )δ13.08(s,1H),7.93–7.85(m,1H),6.80(t,J＝76.4Hz,2H),6.36(s,1H),4.62(d,J＝10.6Hz,2H),4.50–4.42(m,1H),3.96–3.87(m,1H),3.66(t,J＝10.8Hz,2H),3.61–3.47(m,3H),3.05–2.95(m,1H),2.28-2.22(m,1H),2.03–1.90(m,6H),1.79–1.70(m,1H),1.12(d,J＝6.4Hz,3H)and target compound P2 (4.85mg, yield 8.2%, white solid). LC-MS(ESI)m/z:485.2[M+H] + . SFC (Method D): RT=4.090min. 1 HNMR (400MHz, DMSO-d 6 )δ13.08(s,1H),7.90(s,1H),7.01–6.60(m,2H),6.19(s,1H),4.66–4.53(m,3H),4.37–4.27(m,1H),3.71–3.61 (m,2H),3.57(d,J＝10.9Hz,2H),3.40–3.33(m,2H),2.03–1.87(m,6H),1.78–1.69(m,1H),1.09(d,J＝6.7Hz,3H).

实施例116和实施例117：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-(甲氧基-d3)-2-甲基哌啶-1- 基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈，和 6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑 并[3,4-b]吡啶-3-腈
Example 116 and Example 117: 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-4-(methoxy-d3)-2-methylpiperidin-1- yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, and 6-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile

步骤1：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 1: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.14mmol)、Zn(CN)2(39mg,0.33mmol)、锌粉(22mg,0.33mmol)、Pd2(dba)3(10mg,0.011mmol)和Pd(dppf)Cl2(16mg,0.022mmol)溶于DMA(1mL)中，氮气保护下，混合物在150℃反应1hr，冷却至室温。向反应混合物中加入水(10mL)，用EA(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗产品经硅胶柱层析(PE：EA，63％EA)分离纯化得到目标化合物(50mg,收率84.8％，白色固体)。LC-MS(ESI)m/z:536.4[M+H]+。8-(3-iodo-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.14 mmol), Zn(CN) 2 (39 mg, 0.33 mmol), zinc powder (22 mg, 0.33 mmol), Pd2 (dba) 3 (10 mg, 0.011 mmol) and Pd(dppf) Cl2 (16 mg, 0.022 mmol) were dissolved in DMA (1 mL). Under nitrogen protection, the mixture was reacted at 150°C for 1 hr and then cooled to room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (PE:EA, 63% EA) to obtain the title compound (50 mg, 84.8% yield, white solid). LC-MS (ESI) m/z: 536.4 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(60mg,0.11mmol)溶于DCM(1mL)中，加入TFA(1mL)。反应混合物在室温下搅拌16hrs。浓缩反应液，经残余物经反向柱层析(H2O：MeCN，64％MeCN)分离纯化得到目标化合物(25mg,收率49.4％，白色固体)。LC-MS(ESI)m/z:452.2[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (60 mg, 0.11 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was isolated and purified by reverse-phase column chromatography ( H2O :MeCN, 64% MeCN) to obtain the title compound (25 mg, 49.4% yield, as a white solid). LC-MS (ESI) m/z: 452.2 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R,4S)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((2R,4S)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((2R)-4-(甲氧基-d3)-2-甲基哌啶-1-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(30mg,0.066mmol)经过手性拆分SFC(column：Daicel Chiralpak IC，40mm I.D.*250mm，10um：Supercritical CO2；B％：50％，溶剂：MeOH，流速：140mL/min，14.7/19.4min)，得到目标化合物P1(25mg,收率83.3％，白色固体)。LC-MS(方法A)：RT＝1.39min，(ESI)m/z:452.2[M+H]+。SFC(方法I):RT＝3.30min。1H NMR(400MHz,MeOD-d4)δ7.76(s,1H),6.96(d,J＝2.4Hz,1H),6.26(s,1H),4.61(s,2H),3.92–3.75(m,3H),3.67–3.53(m,4H),2.99–2.89(m,1H),2.31–2.18(m,1H),2.17–1.96(m,6H),1.78–1.67(m,1H),1.19(d,J＝6.4Hz,3H).和目标化合物P2(2mg,收率6.7％，白色固体)。LC-MS(方法A)：RT＝1.39min，(ESI)m/z:452.2[M+H]+。SFC(方法I)：RT＝4.349min。Chiral separation of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((2R)-4-(methoxy-d3)-2-methylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (30 mg, 0.066 mmol) by SFC (column: Daicel Chiralpak IC, 40 mm ID*250 mm, 10 μm: Supercritical CO 2 ; B%: 50%, solvent: MeOH, flow rate: 140 mL/min, 14.7/19.4 min) afforded the title compound P1 (25 mg, 83.3% yield, white solid). LC-MS (Method A): RT = 1.39 min, (ESI) m/z: 452.2 [M+H] + . SFC (Method I): RT = 3.30 min. 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.76 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.26 (s, 1H), 4.61 (s, 2H), 3.92–3.75 (m, 3H), 3.67–3.53 (m, 4H), 2.99–2.89 (m, 1H), 2.31–2.18 (m, 1H), 2.17–1.96 (m, 6H), 1.78–1.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H). The target compound P2 (2 mg, yield 6.7%) was obtained as a white solid. LC-MS (Method A): RT = 1.39 min, (ESI) m/z: 452.2 [M+H] + . SFC (Method I): RT = 4.349 min.

实施例216：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-(1-吗啉代乙基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-腈
Example 216: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-morpholinoethyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine-3-carbonitrile

步骤1：8-(4-(1-乙氧基乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(1-ethoxyvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向6-[8-氮杂-3-氧杂双环[3.2.1]辛烷-8-基]-4-碘-1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑并[3,4-b]吡啶(500mg,1.022mmol)的甲苯溶液(20.0mL)中加入TEA(0.426mL,3.06mmol)、Pd(PPh3)2Cl2(71.7mg,0.102mmol)和三丁基(1-乙氧基乙烯基)锡(492mg,1.36mmol)，N2保护下，反应混合物在100℃搅拌6hrs，冷却至室温，减压浓缩，得到目标化合物(400mg,收率71.2％，黑色油状物)(粗品)。LC-MS(ESI)m/z:385.2[M+H]+。To a toluene solution (20.0 mL) of 6-[8-aza-3-oxabicyclo[3.2.1]octan-8-yl]-4-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (500 mg, 1.022 mmol) was added TEA (0.426 mL, 3.06 mmol), Pd(PPh 3 ) 2 Cl 2 (71.7 mg, 0.102 mmol), and tributyl(1-ethoxyvinyl)tin (492 mg, 1.36 mmol). Under nitrogen , the reaction mixture was stirred at 100°C for 6 hr, cooled to room temperature, and concentrated under reduced pressure to afford the title compound (400 mg, 71.2% yield, as a black oil) (crude product). LC-MS (ESI) m/z: 385.2 [M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙-1-酮的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethan-1-one

向(8-(4-(1-乙氧基乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(400mg,1.04mmol)的THF溶液(20.0mL)中加入1N HCl(2.00mL)，反应混合物在室温下搅拌1hr，用饱和NaHCO3水溶液调节pH值至7，然后用EA(20mL×3)萃取。合并有机相，用饱和NaCl溶液(20mL×3)洗涤，用无水Na2SO4干燥，过滤，减压浓缩，残留物经硅胶柱层析(PE/EA＝10/1)纯化，得到目标化合物(320mg,收率86.3％，黄色固体)。LC-MS(ESI)m/z:357.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.29(s,1H),5.85-5.82(m,1H),4.75(s,2H),3.93(d,J＝12.0Hz,1H),3.72–3.60(m,5H),2.69(s,3H),2.45–2.43(m,1H),2.05–1.91(m,5H),1.86-1.82(m,1H),1.76–1.71(m,1H),1.58-1.54(m,2H).To a THF solution (20.0 mL) of (8-(4-(1-ethoxyvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400 mg, 1.04 mmol) was added 1N HCl (2.00 mL). The reaction mixture was stirred at room temperature for 1 hr, adjusted to pH 7 with saturated aqueous NaHCO₃ , and then extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 10/1) to obtain the title compound (320 mg, yield 86.3%) as a yellow solid. LC-MS (ESI) m/z: 357.2 [M+ H ] ⁺ . NMR(400MHz,DMSO-d 6 )δ8.13(s,1H),7.29(s,1H),5.85-5.82(m,1H),4.75(s,2H),3.93(d,J＝12.0Hz,1H),3.72–3.60(m,5H),2. 69(s,3H),2.45–2.43(m,1H),2.05–1.91(m,5H),1.86-1.82(m,1H),1.76–1.71(m,1H),1.58-1.54(m,2H).

步骤3：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙-1-醇的合成
Step 3: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethan-1-ol

向1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙-1-酮(730mg,1.84mmol)的MeOH(20.0mL)溶液中加入NaBH4(77.5mg,2.05mmol)，在室温下搅拌反应1hr后，加入1N HCl淬灭反应，然后减压浓缩，残余物在DCM中搅拌，过滤，滤液减压浓缩得到目标化合物(720mg,收率98.1％,黄色油状物)(粗品)。LC-MS(ESI)m/z:359.2[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethan-1-one (730 mg, 1.84 mmol) in MeOH (20.0 mL) was added NaBH₄ (77.5 mg, 2.05 mmol). After stirring at room temperature for 1 hour, the reaction was quenched by the addition of 1N HCl and then concentrated under reduced pressure. The residue was stirred in DCM, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (720 mg, 98.1% yield, yellow oil) (crude product). LC-MS (ESI) m/z: 359.2 [M+H] ⁺ .

步骤4：1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙基甲磺酸酯的合成
Step 4: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethyl methanesulfonate

1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙-1-醇(720mg,1.81mmol)的THF(20.0mL)溶液中加入TEA(0.754mL，5.42mmol)和MsCl(414mg,3.61mmol)，反应混合物在室温下搅拌2hrs，加水淬灭反应，用EA(20mL×3)萃取，合并有机相，用饱和NaCl溶液(20mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，得到目标化合物(750mg,收率85.5％，黄色油状物)。LC-MS(ESI)m/z:437.2[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethan-1-ol (720 mg, 1.81 mmol) in THF (20.0 mL) were added TEA (0.754 mL, 5.42 mmol) and MsCl (414 mg, 3.61 mmol). The reaction mixture was stirred at room temperature for 2 hrs, quenched with water, and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the title compound (750 mg, 85.5% yield, as a yellow oil). LC-MS (ESI) m/z: 437.2 [M+H] ⁺ .

步骤5：8-(4-(1-吗啉乙基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-(1-morpholinoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向1-(6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)乙基甲磺酸酯(750mg,1.55mmol)的NMP(15.0mL)溶液中加入1,4-恶嗪烷(0.542mL，6.19mmol)和KI(257mg,1.55mmol)，反应混合物在80℃下搅拌1h，冷却至室温，加水淬灭反应，用EA(20mL×3)萃取，合并有机相，用饱和NaCl溶液(20mL×3)洗涤，无水Na2SO4干燥，过滤并减压浓缩，残余物经硅胶柱层析(PE/EA＝10/1)分离纯化，得到目标化合物(500mg,收率68.1％，黄色油状物)。LC-MS(ESI)m/z:428.3[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethyl methanesulfonate (750 mg, 1.55 mmol) in NMP (15.0 mL) were added 1,4-oxazinane (0.542 mL, 6.19 mmol) and KI (257 mg, 1.55 mmol). The reaction mixture was stirred at 80°C for 1 h, cooled to room temperature, quenched by addition of water, and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3 ), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE/EA = 10/1) to give the title compound (500 mg, yield 68.1%, yellow oil). LC-MS(ESI)m/z:428.3[M+H] + .

步骤6：8-(4-(1-吗啉乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(1-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(1-吗啉乙基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(950mg,2.00mmol)的MeOH(10.0mL)溶液中加入4N HCl/二噁烷(10.0mL)，反应混合物在室温下搅拌1hr，然后加入饱和NaHCO3水溶液调节pH值至7，用EA(20mL×3)萃取，用饱和NaCl溶液(20mL×3)洗涤，合并有机相，用无水Na2SO4干燥，过滤并减压浓缩，得到目标化合物(720mg,收率89.1％，黄色油状物)。LC-MS(ESI)m/z:344.2[M+H]+。To a solution of 8-(4-(1-morpholinoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (950 mg, 2.00 mmol) in MeOH (10.0 mL) was added 4N HCl/dioxane (10.0 mL). The reaction mixture was stirred at room temperature for 1 hr, then the pH was adjusted to 7 by adding saturated aqueous NaHCO₃ . The mixture was extracted with EA (20 mL × 3) and washed with saturated NaCl solution (20 mL × 3 ). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the title compound (720 mg, 89.1% yield, as a yellow oil). LC-MS (ESI) m/z: 344.2 [M+H] ⁺ .

步骤7：8-(3-碘-4-(1-吗啉基乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(3-iodo-4-(1-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(1-吗啉乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(670mg,1.75mmol)的DMF(50.0mL)溶液中加入KOH(443mg,7.90mmol)粉末，然后分批加入碘(1.78g,7.02mmol)，反应混合物在室温下搅拌1h，加水淬灭反应，用EA(40.0mL×3)萃取，合并有机相，用饱和NaCl溶液水(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤并减压浓缩，残余物经硅胶柱层析(DCM/MeOH＝20/1)分离纯化，得到目标化合物(310mg,收率37.6％，黄色固体)。LC-MS(ESI)m/z:470.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.42(br,1H),6.83(br,1H),4.53(brs,4H),3.75–3.45(m,9H),2.06–1.86(m,6H),1.80–1.52(m,3H).To a solution of 8-(4-(1-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (670 mg, 1.75 mmol) in DMF (50.0 mL) was added powdered KOH (443 mg, 7.90 mmol), followed by the addition of iodine (1.78 g, 7.02 mmol) in portions. The reaction mixture was stirred at room temperature for 1 h, quenched with water, and extracted with EA (40.0 mL × 3). The combined organic phases were washed with saturated NaCl solution (20.0 mL × 3 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (DCM/MeOH = 20/1) to obtain the title compound (310 mg, 37.6% yield, as a yellow solid). LC-MS (ESI) m/z: 470.1 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 ) δ13.42(br,1H),6.83(br,1H),4.53(brs,4H),3.75–3.45(m,9H),2.06–1.86(m,6H),1.80–1.52(m,3H).

步骤8：8-(3-碘-4-(1-吗啉乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(3-iodo-4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(3-碘-4-(1-吗啉基乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(0.260g,0.499mmol)的吡啶(15.0mL)溶液中加入1-(3,4,5,6-四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(1.39g,4.99mmol)和醋酸铜(0.220g,1.10mmol)，反应混合物在80℃下搅拌16hrs，冷却至室温，减压浓缩，残余物通过硅胶柱层析(DCM/EA＝10/1)分离纯化，得到目标化合物(285mg,收率73.8％，黄色固体)。LC-MS(ESI)m/z:620.3[M+H]+。To a solution of 8-(3-iodo-4-(1-morpholinylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.260 g, 0.499 mmol) in pyridine (15.0 mL) were added 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.39 g, 4.99 mmol) and copper acetate (0.220 g, 1.10 mmol). The reaction mixture was stirred at 80° C. for 16 hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (DCM/EA=10/1) to give the title compound (285 mg, yield 73.8%) as a yellow solid. LC-MS(ESI)m/z:620.3[M+H] + .

步骤9：6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-(1-吗啉乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 9: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

向8-(3-碘-4-(1-吗啉乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(265mg,0.428mmol)的DMA(15.0mL)溶液中加入Zn(CN)2(151mg,1.284mmol)、Zn(83.9mg,1.28mmol)、Pd2(dba)3(39.2mg,0.043mmol)和Pd(dppf)Cl2(62.6mg,0.086mmol)，反应混合物在150℃下搅拌1hr，冷却至室温，加水，用EA(30mL×3)萃取，合并有机相，用饱和NaCl溶液(20mL×3)洗涤，无水Na2SO4干燥，过滤，减压下浓缩，残留物通过硅胶柱层析(PE/EA＝5/1)分离纯化，得到目标化合物(125mg,收率50.7％，黄色固体)。LC-MS(ESI)m/z:519.2[M+H]+。To a solution of 8-(3-iodo-4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (265 mg, 0.428 mmol) in DMA (15.0 mL) was added Zn(CN) 2 (151 mg, 1.284 mmol), Zn (83.9 mg, 1.28 mmol), Pd 2 (dba) 3 (39.2 mg, 0.043 mmol) and Pd(dppf)Cl 2 The reaction mixture was stirred at 150°C for 1 hour, cooled to room temperature, added with water, and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE/EA = 5/1) to obtain the title compound (125 mg, 50.7% yield, as a yellow solid). LC-MS (ESI) m/z: 519.2 [M+H] + .

步骤10：6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-(1-吗啉乙基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 10: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-morpholinoethyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

向6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-(1-吗啉乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(105mg,0.202mmol)的DCM(1.00mL)溶液中加入TFA(4.00mL)，反应混合物在室温下搅拌4hr，然后加入饱和NaHCO3水溶液，调节pH值至7，加入MeOH溶解并过滤，滤液用Pre-HPLC(Triart C18,250*20.0mm l.D.,S-5um,12nm，流动相A：H2O(10mmol NH4HCO3)，流动相B:CH3CN，流速：17mL/min，检测波长:254nm/220nm，柱温25℃)分离纯化，得到目标化合物(35.83mg,收率40.7％，白色固体)。LC-MS(方法C)：RT＝0.96min，(ESI)m/z:435.1[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.09(s,1H),7.91(s,1H),6.95(s,1H),6.83(s,1H),4.64(brs,2H),3.76–3.73(m,1H),3.71–3.58(m,8H),2.57–2.51(m,2H),2.37–2.34(m,2H),2.01–1.93(m,4H),1.44(d,J＝8.0Hz,3H)。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (105 mg, 0.202 mmol) in DCM (1.00 mL) was added TFA (4.00 mL). The reaction mixture was stirred at room temperature for 4 hr, and then saturated aqueous NaHCO 3 solution was added to adjust the pH to 7. MeOH was added to dissolve the product and the product was filtered. The filtrate was purified by Pre-HPLC (Triart C18, 250*20.0 mm ID, S-5 μm, 12 nm, mobile phase A: H 2 O (10 mmol NH 4 HCO 3 ), mobile phase B: CH 3 CN, flow rate: 17 mL/min, detection wavelength: 254 nm/220 nm, column temperature 25°C) to separate and purify the title compound (35.83 mg, yield 40.7%, white solid). LC-MS (Method C): RT = 0.96 min, (ESI) m/z: 435.1 [M+H] + . 1 HNMR (400MHz, DMSO-d 6 )δ13.09(s,1H),7.91(s,1H),6.95(s,1H),6.83(s,1H),4.64(brs,2H),3.76–3.73(m,1H),3.7 1–3.58(m,8H),2.57–2.51(m,2H),2.37–2.34(m,2H),2.01–1.93(m,4H),1.44(d,J＝8.0Hz,3H).

实施例217：6-(8-氮杂-3-氧杂双环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-4-[甲基(3,4,5,6-四氢-2H-吡喃-4-基)氨 基]吡唑并[3,4-b]吡啶-3-甲腈
Example 217: 6-(8-Aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-4-[methyl(3,4,5,6-tetrahydro-2H-pyran-4-yl) amino ]pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-甲基-1-(四氢-2H-吡喃-2-基)-N-(四氢-2,H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2,H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(3.00g,6.81mmol)和N-甲基四氢-2H-吡喃-4-胺(940mg,8.18mmol)溶于干燥的DMF(40mL)中，然后依次加入Cs2CO3(4.44g,13.63mmol)和Ruphos Pd G2(260mg,0.34mmol)。反应混合物在氮气氛围下130℃搅拌2hrs，冷却至室温，向反应混合物中加入水(250mL)和EA(250mL)稀释，用EA(150mL×2)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经正相硅胶柱层析分离纯化(PE：EA，50％EA)，得到目标化合物(1.67g,收率57.3％，淡黄色固体)。LC-MS(ESI)m/z:428.3[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (3.00 g, 6.81 mmol) and N-methyltetrahydro-2H-pyran-4-amine (940 mg, 8.18 mmol) were dissolved in dry DMF (40 mL), and then Cs 2 CO 3 (4.44 g, 13.63 mmol) and Ruphos Pd G2 (260 mg, 0.34 mmol) were added in sequence. The reaction mixture was stirred at 130°C for 2 hours under a nitrogen atmosphere, cooled to room temperature, and diluted with water (250 mL) and EA (250 mL). The mixture was extracted with EA (150 mL x 2). The combined organic phases were washed three times with saturated aqueous NaCl, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (1.67 g, 57.3% yield, as a pale yellow solid). LC-MS (ESI) m/z: 428.3 [M+H] ⁺ .

步骤2：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-甲基-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-甲基-1-(四氢-2H-吡喃-2-基)-N-(四氢-2,H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺(1.67g,3.90mmol)溶于MeOH(20mL)中，加入4N盐酸/1,4-二氧六环溶液(10mL)，反应混合物在氮气氛围下50℃搅拌16hrs，冷却至室温，减压除去溶剂，加入饱和Na2CO3(100mL)溶液，用DCM(100mL×2)萃取，合并有机相，用饱和Na2CO3(100mL)溶液洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(100％EA to DCM：MeOH，10％MeOH)得到目标化合物(1.00g,收率74.5％，黄色固体)。LC-MS(ESI)m/z:344.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2,H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.67 g, 3.90 mmol) was dissolved in MeOH (20 mL), and 4N hydrochloric acid/1,4-dioxane solution (10 mL) was added. The reaction mixture was stirred at 50°C for 16 hrs under nitrogen atmosphere, cooled to room temperature, and the solvent was removed under reduced pressure. Saturated Na2CO3 solution (100 mL ) was added, and the mixture was extracted with DCM (100 mL×2) . The organic phases were combined, washed with saturated Na2CO3 solution (100 mL), dried over anhydrous Na2SO4 , filtered , and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (100% EA to The title compound (1.00 g, yield 74.5%, yellow solid) was obtained by the addition of DCM:MeOH, 10% MeOH). LC-MS (ESI) m/z: 344.2 [M+H] + .

步骤3：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-甲基-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-甲基-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺(750mg,2.18mmol)和KOH(306mg,5.46mmol)溶解于DMF(20mL)中，再分批量缓慢加入碘(1.11g,4.37mmol)。在氮气氛围下置换三次，反应混合物在25℃下搅拌1hr，加入饱和Na2SO3水溶液(50mL)淬灭反应，用EA(75mL×2)萃取，合并有机相，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)，得到目标化合物(370mg,收率36.1％，黄色固体)。LC-MS(ESI)m/z:470.1[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (750 mg, 2.18 mmol) and KOH (306 mg, 5.46 mmol) were dissolved in DMF (20 mL), and iodine (1.11 g, 4.37 mmol) was slowly added portionwise. The atmosphere was replaced three times under nitrogen. The reaction mixture was stirred at 25°C for 1 hr and quenched with saturated aqueous Na₂SO₃ (50 mL). The reaction was extracted with EA (75 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to obtain the title compound (370 mg, 36.1% yield) as a yellow solid. LC-MS(ESI)m/z:470.1[M+H] + .

步骤4：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2,H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 4: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2,H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-甲基-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺(370mg,0.788mmol)的吡啶(10.0mL)溶液中加入1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(1.10g,3.94mmol)和醋酸铜(0.286g,1.57mmol)，反应混合物在80℃下搅拌4hrs，冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA，0％～100％EA)，得到目标化合物(340mg,收率69.6％，淡黄色固体)。LC-MS(ESI)m/z:620.3[M+H]+。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (370 mg, 0.788 mmol) in pyridine (10.0 mL) was added 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3, The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0% to 100% EA) to obtain the title compound (340 mg, 69.6% yield, pale yellow solid). LC-MS (ESI) m/z: 620.3 [M+H] + .

步骤5：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-(甲基(四氢-2H-吡喃-4-基)氨基)-1-(1-(四氢-2,H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1-(1-(tetrahydro-2,H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2,H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-4-胺(340mg,0.55mmol)溶于DMF(10mL)中，加入Zn(CN)2(151mg,1.284mmol)、Zn(83.9mg,1.28mmol)，Pd2(dba)3(39.2mg,0.043mmol)和Pd(dppf)Cl2(62.6mg,0.086mmol)，反应混合物在氮气氛围下25℃搅拌1hr。向反应混合物中加入水(50mL)，用EA(30mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，60％EA)，得到目标化合物(174mg,收率61.1％，淡黄色液体)。LC-MS(ESI)m/z:519.3[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2,H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (340 mg, 0.55 mmol) was dissolved in DMF (10 mL), and Zn(CN) 2 (151 mg, 1.284 mmol), Zn (83.9 mg, 1.28 mmol), Pd2 (dba) 3 (39.2 mg, 0.043 mmol) and Pd(dppf) Cl2 (62.6 mg, 0.086 mmol) were added. The reaction mixture was stirred at 25°C for 1 hr under nitrogen atmosphere. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 60% EA) to obtain the title compound (174 mg, 61.1% yield, light yellow liquid). LC-MS (ESI) m/z: 519.3 [M+H] + .

步骤6：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-(甲基(四氢-2H-吡喃-4-基)氨基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-(甲基(四氢-2H-吡喃-4-基)氨基)-1-(1-(四氢-2,H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈(266mg,0.46mmol)溶于DCM(5mL)中，加入TFA(5mL)，反应混合物在25℃下搅拌16hrs。然后加入饱和NaHCO3水溶液，调节pH值至7，有机层分离浓缩，残余物用Prep-HPLC(Triart C18,50*4.6mm,5um；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％ TFA；检测波长214nm,254nm，流速：2.5mL/min，柱温40℃)分离纯化得到目标化合物(24.3mg,收率16.7％，白色固体)。LC-MS(方法C)：RT＝1.4min，(ESI)m/z:435.2[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.07(s,1H),7.89(s,1H),6.83(d,J＝2.3Hz,1H),6.13(s,1H),4.58(s,2H),4.09–3.98(m,1H),3.93(dd,J＝11.1,3.8Hz,2H),3.66(d,J＝10.8Hz,2H),3.56(d,J＝10.7Hz,2H),3.41(t,J＝11.1Hz,2H),2.86(s,3H),2.01–1.86(m,6H),1.70(d,J＝10.2Hz,2H)。6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-1-(1-(tetrahydro-2,H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (266 mg, 0.46 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The reaction mixture was stirred at 25 °C for 16 hrs. Saturated aqueous NaHCO₃ was then added, and the pH was adjusted to 7. The organic layer was separated and concentrated, and the residue was purified using Prep-HPLC (Triart C18, 50*4.6 mm, 5 μm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; detection wavelengths 214 nm and 254 nm, flow rate: 2.5 mL/min, column temperature 40°C) to obtain the title compound (24.3 mg, 16.7% yield, white solid). LC-MS (Method C): RT = 1.4 min, (ESI) m/z: 435.2 [M+H] ⁺ . 1 HNMR (400MHz, DMSO-d 6 )δ13.07(s,1H),7.89(s,1H),6.83(d,J＝2.3Hz,1H),6.13(s,1H),4.58(s,2H),4.09–3.98(m,1H),3.93(dd,J＝11.1,3.8Hz,2H), 3.66(d,J＝10.8Hz,2H), 3.56(d,J＝10.7Hz,2H), 3.41(t,J＝11.1Hz,2H), 2.86(s,3H), 2.01–1.86(m,6H), 1.70(d,J＝10.2Hz,2H).

实施例218：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基吗啉-4-羰基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b] 吡啶-3-甲腈
Example 218: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methylmorpholine-4-carbonyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b] pyridine-3-carbonitrile

步骤1：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-羧酸甲酯的合成
Step 1: Synthesis of methyl 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1.5g,3.41mmol)和Pd(dppf)Cl2(0.25g,0.34mmol)溶于干燥的MeOH(20mL)，然后加入TEA(1.42mL,10.22mmol)。在CO氛围下置换三次，然后反应混合物在CO氛围下60℃搅拌2hrs。冷却至室温，向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA,20％EA)，得到目标化合物(1.2g,收率94.58％，白色固体)。LC-MS(ESI)m/z:373.1[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.5 g, 3.41 mmol) and Pd(dppf) Cl₂ (0.25 g, 0.34 mmol) were dissolved in dry MeOH (20 mL), followed by the addition of TEA (1.42 mL, 10.22 mmol). The reaction mixture was replaced three times under a CO atmosphere, and then stirred at 60°C under a CO atmosphere for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with water and EA, and extracted with EA (100 mL x 2). The combined organic phases were washed three times with saturated aqueous NaCl, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 20% EA) to obtain the title compound (1.2 g, 94.58% yield, as a white solid). LC-MS(ESI)m/z:373.1[M+H] + .

步骤2：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-羧酸的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-羧酸甲酯(1.2g,3.22mmol)溶于THF(10mL)/H2O(3mL)中，然后加入LiOH(0.14g,3.22mmol)，反应混合物在室温下搅拌2hrs。向反应混合物中加入水和EA稀释，用HCl(1M)酸化至pH～4，用EA(100mL×2)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤。减压除去溶剂，得到粗品(1g,收率86.60％，白色固体)，粗产物无需纯化直接用于下一步。LC-MS(ESI)m/z:358.2[M+H]+。Methyl 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.2 g, 3.22 mmol) was dissolved in THF (10 mL)/ H₂O (3 mL), followed by the addition of LiOH (0.14 g, 3.22 mmol). The reaction mixture was stirred at room temperature for 2 hr. Water and EA were added to the reaction mixture, acidified to pH ~4 with HCl (1 M), and extracted with EA (100 mL x 2). The combined organic phases were washed three times with saturated aqueous NaCl, dried over anhydrous Na₂SO₄ , and filtered. The solvent was removed under reduced pressure to yield a crude product (1 g, 86.60% yield, white solid), which was used in the next step without purification. LC-MS (ESI) m/z: 358.2 [M+H] ⁺ .

步骤3：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮的合成
Step 3: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone

0℃下，将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-羧酸(1g,2.79mmol)和HATU(1.59g,4.18mmol)、3-甲基吗啉(0.42g,4.18mmol)、DIEA(0.72g,5.58mmol)溶于干燥的DMF(10mL)中，反应混合物在N2氛围下室温搅拌2hrs。向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(DCM:MeOH，7％MeOH)，得到目标化合物(700mg,收率56.82％，白色固体)LC-MS(ESI)m/z:442.1[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1 g, 2.79 mmol), HATU (1.59 g, 4.18 mmol), 3-methylmorpholine (0.42 g, 4.18 mmol) and DIEA (0.72 g, 5.58 mmol) were dissolved in dry DMF (10 mL) at 0°C, and the reaction mixture was stirred at room temperature under N2 atmosphere for 2 hrs. The reaction mixture was diluted with water and EA, and extracted with EA (100 mL × 2). The combined organic phases were washed three times with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 7% MeOH) to give the title compound (700 mg, yield 56.82%, white solid) (LC-MS (ESI) m/z: 442.1 [M+H] +) .

步骤4：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮的合成
Step 4: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮(700mg,1.58mmol)溶于MeOH(10mL)中，加入4N盐酸/1,4-二氧六环溶液(57.80mg)，反应混合物在N2氛围下室温搅拌0.5hr。减压浓缩得到粗产品(500mg,收率88.24％，黄色固体)，粗产物无需纯化直接用于下一步。LC-MS(ESI)m/z:358.2[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone (700 mg, 1.58 mmol) was dissolved in MeOH (10 mL). 4N hydrochloric acid/1,4-dioxane solution (57.80 mg) was added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hr. The mixture was concentrated under reduced pressure to afford the crude product (500 mg, 88.24% yield, yellow solid), which was used in the next step without purification. LC-MS (ESI) m/z: 358.2 [M+H] + .

步骤5：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮的合成
Step 5: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮(500mg,1.39mmol)和KOH(78.50mg,1.39mmol)溶解于DMF(9mL)中，再分批量缓慢加入碘(355.5mg，1.39mmol)。在N2氛围下置换三次，反应混合物在25℃下搅拌1hr。然后加入饱和Na2SO3水溶液淬灭反应，用EA(100mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)，得到目标化合物(300mg,收率44.37％，黄色固体)。LC-MS(ESI)m/z:470.0[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone (500 mg, 1.39 mmol) and KOH (78.50 mg, 1.39 mmol) were dissolved in DMF (9 mL), and iodine (355.5 mg, 1.39 mmol) was slowly added portionwise. The atmosphere was replaced three times with nitrogen , and the reaction mixture was stirred at 25°C for 1 hr. The reaction was then quenched with saturated aqueous Na₂SO₃ solution and extracted with EA (100 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to obtain the title compound (300 mg, 44.37% yield, as a yellow solid). LC-MS(ESI)m/z:470.0[M+H] + .

步骤6：(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮的合成
Step 6: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮(300mg,0.62mmol)、1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2基)-1H-邻二氮杂茂(1.7g,6.20mmol)、醋酸铜(247.8mg,1.24mmol)依次加入到吡啶(30mL)中，反应混合物在空气氛围下80℃搅拌16hrs。向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相用饱和食盐水(200mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，100％EA)，得到目标化合物(200mg,收率50.86％，黄色固体)。LC-MS(ESI)m/z:634.20[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholine)methanone (300 mg, 0.62 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-o-diazolidine (1.7 g, 6.20 mmol), and copper acetate (247.8 mg, 1.24 mmol) were added sequentially to pyridine (30 mL), and the reaction mixture was stirred at 80 ° C. under air atmosphere for 16 hrs. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (60 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 100% EA) to obtain the title compound (200 mg, 50.86% yield, yellow solid). LC-MS (ESI) m/z: 634.20 [M+H] + .

步骤7：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基吗啉-4-羰基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methylmorpholine-4-carbonyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将(6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)(3-甲基吗啉)甲酮(200mg,0.31mmol)、Zn粉(60.12mg,0.31mmol)、Zn(CN)2(35.14mg,0.31mmol)、Pd2(dba)3(28.91mg,0.03mmol)、Pd(dppf)Cl2(46.20mg,0.06mmol)依次加入到DMA(5mL)中。在N2氛围下置换三次，反应混合物在N2氛围下100℃搅拌1hrs。冷却至室温，向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相，用饱和NaCl水溶液(200mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩得到粗产品(120mg,收率71.36％，黄色固体)，粗产物直接用于下一步。LC-MS(ESI)m/z:533.42[M+H]+。(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(3-methylmorpholino)methanone (200 mg, 0.31 mmol), Zn powder (60.12 mg, 0.31 mmol), Zn(CN) ₂ (35.14 mg, 0.31 mmol), Pd₂ (dba) ₃ (28.91 mg, 0.03 mmol), and Pd(dppf) Cl₂ (46.20 mg, 0.06 mmol) were added sequentially to DMA (5 mL). The atmosphere was replaced with N₂ three times, and the reaction mixture was stirred at 100°C under N₂ atmosphere for 1 hr. After cooling to room temperature, water (60 mL) was added to the reaction mixture, which was then extracted with EA (60 mL × 2). The combined organic phases were washed with saturated aqueous NaCl (200 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude product (120 mg, 71.36% yield, yellow solid). The crude product was used directly in the next step. LC-MS (ESI) m/z: 533.42 [M+H] + .

步骤8：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基吗啉-4-羰基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
Step 8: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methylmorpholine-4-carbonyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基吗啉-4-羰基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈(120mg,0.22)溶于DCM(5mL)中，加入TFA(5mL)，反应混合物在25℃下搅拌16hrs，减压浓缩，残留物中加入饱和Na2CO3(50mL)溶液，用DCM(50mL×2)萃取，合并有机相，用饱和Na2CO3(50mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)得到粗产品，粗产品经Prep-HPLC(柱：Triart c18，250*20.0mm.d,S-5um，12nm；流动相A：10mmol NH4CO3/水，流动相B：CH3CN；梯度：梯度：0-95％B，检测波长214nm，流速：17mL/min，柱温25℃)分离纯化，得到目标化合物(23.27mg,收率23.03％，白色固体)。LC-MS(方法C)：RT＝1.48min，(ESI)m/z:449.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),7.93(s,1H),7.11,7.03(s,1H),6.85(s,1H),4.69(s,2H),4.28,3.96(d,J＝8.8Hz,1H),3.82–3.55(m,7H),3.52(d,J＝11.3Hz,1H),3.45–3.39(m,1H),3.26–3.17(m,1H),2.09–1.91(m,4H),1.38,1.26(d,J＝6.6Hz,3H).6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methylmorpholine-4-carbonyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (120 mg, 0.22) was dissolved in DCM (5 mL), and TFA (5 mL) was added. The reaction mixture was stirred at 25°C for 16 hrs, concentrated under reduced pressure, and saturated Na2CO3 solution (50 mL) was added to the residue, and the mixture was extracted with DCM (50 mL×2). The organic phases were combined, washed with saturated Na2CO3 (50 mL×2), dried over anhydrous Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 75% EA) to give a crude product. The crude product was then purified by Prep-HPLC (column: Triart c18, 250*20.0 mm d, S-5 μm, 12 nm; mobile phase A: 10 mmol NH 4 CO 3 /water, mobile phase B: CH 3 CN; gradient: 0-95% B, detection wavelength: 214 nm, flow rate: 17 mL/min, column temperature: 25°C) to give the title compound (23.27 mg, yield: 23.03%, white solid). LC-MS (Method C): RT = 1.48 min, (ESI) m/z: 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.15(s,1H),7.93(s,1H),7.11,7.03(s,1H),6.85(s,1H),4.69(s,2H),4.28,3.96(d,J＝8.8Hz,1H),3.82–3.55( m,7H),3.52(d,J＝11.3Hz,1H),3.45–3.39(m,1H),3.26–3.17(m,1H),2.09–1.91(m,4H),1.38,1.26(d,J＝6.6Hz,3H).

实施例219：8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶 -6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 219: 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin -6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of (8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2气氛下，在室温下向(2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶(1.50g,6.54mmol)的DMF(20mL)中加入8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.80g,6.34mmol)、Cs2CO3(6.20g,19.0mmol)和RuPhos Pd G2(0.254g,0.327mmol)。然后，反应混合物在130℃下搅拌2hrs，反应混合物冷却加入H2O(100mL)，用EA(80mL×3)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，20％EA)得到目标化合物(2.60g,收率73.4％，黄色油状液体)。LC-MS(ESI)m/z:542.4[M+H]+。To a solution of (2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine (1.50 g, 6.54 mmol) in DMF (20 mL) was added 8-(4-iodo-1-(tetrahydro-2H-pyran- 2 -yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.80 g, 6.34 mmol), Cs2CO3 (6.20 g , 19.0 mmol) and RuPhosPdG2 (0.254 g, 0.327 mmol) at room temperature under N2 atmosphere. The reaction mixture was then stirred at 130°C for 2 hours. H₂O (100 mL) was added to the reaction mixture after cooling, and the mixture was extracted with EA (80 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 20% EA) to obtain the title compound (2.60 g, 73.4% yield, yellow oily liquid). LC-MS (ESI) m/z: 542.4 [M+H] + .

步骤2：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 2: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

在室温下向8-(4-((2R)-4-((叔丁基二甲基甲硅烷基)氧基)-2-甲基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.60g,4.80mmol)的MeOH(20mL)中的溶液中滴加4NHCl/二氧六环溶液(5mL)。然后，将反应混合物在50℃下搅拌3hrs。加入H2O，用EA(80mL×3)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH＝10：1)得到目标化合物(1.50g,收率91.0％，黄色油状液体)。LC-MS(ESI)m/z:344.2[M+H]+。To a solution of 8-(4-((2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.60 g, 4.80 mmol) in MeOH (20 mL) was added dropwise a 4N HCl/dioxane solution (5 mL) at room temperature. The reaction mixture was then stirred at 50°C for 3 hrs. H₂O was added, and the mixture was extracted with EA (80 mL x 3 ). The combined organic phases were dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford the title compound (1.50 g, 91.0% yield, as a yellow oily liquid). LC-MS(ESI)m/z:344.2[M+H] + .

步骤3：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

在室温下，向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(1.50g,4.37mmol)的DMF(15mL)溶液中加入KOH(0.734g,13.1mmol)，分批加入I2(2.20g,8.70mmol)。在N2氛围下置换三次，反应混合物在25℃下搅拌1hr，加入饱和Na2SO3水溶液(50mL)淬灭反应，用EA(75mL×2)萃取，合并有机相，水洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1：5)，得到目标化合物(500mg,收率24.4％，黄色固体)。LC-MS(ESI)m/z:470.1[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (1.50 g, 4.37 mmol) in DMF (15 mL) was added KOH (0.734 g, 13.1 mmol) and I₂ (2.20 g, 8.70 mmol) portionwise at room temperature. The atmosphere was replaced with N₂ three times, and the reaction mixture was stirred at 25°C for 1 hr. The reaction was quenched by addition of saturated aqueous Na₂SO₃ (50 mL) and extracted with EA (75 mL x 2). The combined organic phases were washed with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:5) to afford the title compound (500 mg, 24.4% yield) as a yellow solid. LC-MS(ESI)m/z:470.1[M+H] + .

步骤4：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 4: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

向2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(500mg,1.07mmol)的吡啶(10mL)溶液中加入1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(1.48g,5.33mmol)和醋酸铜(387mg,2.13mmol)，在80℃下搅拌反应4hrs，反应混合物冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1：5)得到目标化合物(400mg,收率60.6％，黄色液体)。LC-MS(ESI)m/z:620.2[M+H]+。To a solution of 2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (500 mg, 1.07 mmol) in pyridine (10 mL) were added 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.48 g, 5.33 mmol) and copper acetate (387 mg, 2.13 mmol). The reaction mixture was stirred at 80°C for 4 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA=1:5) to give the title compound (400 mg, yield 60.6%, yellow liquid). LC-MS(ESI)m/z:620.2[M+H] + .

步骤5：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇的合成
Step 5: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol

在微波管中，将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(200mg,0.323mmol)溶于DMF(4mL)，再加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(303mg,1.78mmol)，向微波管中鼓N2 3mins后密封，微波管在微波仪器中80℃下搅拌3hrs。反应混合物冷却至室温，加入水(20mL)，用EA(30mL×2)萃取，合并有机相，用水(20mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向硅胶柱层析分离纯化(H2O：CH3CN＝1：8)，得到目标化合物(60.0mg,收率33.1％，黄色固体)。LC-MS(ESI)m/z:562.3[M+H]+。In a microwave tube, (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (200 mg, 0.323 mmol) was dissolved in DMF (4 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (303 mg, 1.78 mmol) was added. N2 was bubbled into the microwave tube for 3 mins and then sealed. The microwave tube was stirred at 80°C in a microwave instrument for 3 hrs. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (30 mL × 2). The combined organic phases were washed with water (20 mL × 5), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H 2 O:CH 3 CN=1:8) to obtain the title compound (60.0 mg, 33.1% yield, yellow solid). LC-MS (ESI) m/z: 562.3 [M+H] + .

步骤6：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-基甲磺酸酯的合成
Step 6: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-yl methanesulfonate

0℃下，向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-醇(60.0mg,0.107mmol)的DCM(5mL)溶液中加入Et3N(18.0μL，0.128mmol)、MsCl(14.7mg,0.128mmol)，反应混合物在25℃下搅拌2hrs。向反应混合物中加入饱和NaCl水溶液(20mL)，用DCM(20mL×2)萃取，合并有机相用无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(65.0mg,收率95.1％，淡黄色液体)。LC-MS(ESI)m/z:640.3[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidin-4-ol (60.0 mg, 0.107 mmol) in DCM (5 mL) at 0°C were added Et3N (18.0 μL, 0.128 mmol) and MsCl (14.7 mg, 0.128 mmol), and the reaction mixture was stirred at 25°C for 2 hrs. Saturated aqueous NaCl solution (20 mL) was added to the reaction mixture, and the mixture was extracted with DCM (20 mL x 2). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the title compound (65.0 mg, 95.1% yield, light yellow liquid). LC-MS (ESI) m/z: 640.3 [M+H] + .

步骤7：8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向[(2R)-1-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]-3-(三氟甲基)吡唑并[3,4-b]吡啶-4-基]-2-甲基六氢吡啶-4-基]甲磺酸酯(65.0mg,0.102mmol)的DMF(3mL)溶液中，加入甲硫醇钠(14.2mg,0.203mmol)，反应混合物在100℃下搅拌2hrs，冷却至室温，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相用饱和NaCl水溶液(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(38.0mg,收率63.2％，黄色固体)。LC-MS(ESI)m/z:592.3[M+H]+。To a solution of [(2R)-1-[6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-4-yl]-2-methylhexahydropyridin-4-yl] methanesulfonate (65.0 mg, 0.102 mmol) in DMF (3 mL) was added sodium thiomethoxide (14.2 mg, 0.203 mmol). The reaction mixture was stirred at 100° C. for 2 hrs and cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL×2). The combined organic phases were washed with saturated aqueous NaCl solution (20 mL×2) and anhydrous Na 2 SO 4. The product was dried, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (38.0 mg, yield 63.2%, yellow solid). LC-MS (ESI) m/z: 592.3 [M+H] + .

步骤8：8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(19.0mg,0.032mmol)的DCM(2mL)溶液中，加入TFA(2mL)。混合物在25℃下搅拌16hrs。然后加入饱和NaHCO3水溶液，调节pH值至7，分离有机层并浓缩，残余物经Prep-HPLC((柱：Triart C18,250*20.0mml.D.,S-5um；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；梯度：20-95％B，检测波长220nm,254nm，流速：17mL/min，柱温25℃))分离纯化，得到目标化合物(4.65mg,收率28.5％，白色固体)。LC-MS(方法C)：RT＝1.98min，(ESI)m/z:508.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.89(s,1H),6.79(d,J＝1.9Hz,1H),6.74(s,1H),4.62(s,2H),3.70–3.62(m,2H),3.61–3.56(m,2H),3.24–3.18(m,1H),2.79–2.69(m,1H),2.68–2.59(m,1H),2.11(s,3H),2.09–1.90(m,6H),1.64–1.53(m,1H),1.35–1.24(m,2H),0.94(d,J＝5.9Hz,3H)。To a solution of 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (19.0 mg, 0.032 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 16 hrs. Saturated aqueous NaHCO₃ was then added, and the pH was adjusted to 7. The organic layer was separated and concentrated, and the residue was purified by Prep-HPLC (Triart C18 column, 250 x 20.0 mm L/D, S-5 μm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; gradient: 20-95% B, detection wavelengths 220 nm and 254 nm, flow rate 17 mL/min, column temperature 25°C) to obtain the title compound (4.65 mg, 28.5% yield, as a white solid). LC-MS (Method C): RT = 1.98 min, (ESI) m/z: 508.2 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.02(s,1H),7.89(s,1H),6.79(d,J＝1.9Hz,1H),6.74(s,1H),4.62(s,2H),3.70–3.62(m,2H),3.61–3.56(m,2H),3.24–3.18(m,1H ),2.79–2.69(m,1H),2.68–2.59(m,1H),2.11(s,3H),2.09–1.90(m,6H),1.64–1.53(m,1H),1.35–1.24(m,2H),0.94(d,J＝5.9Hz,3H).

实施例220：8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡 啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷
Example 220: 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin -4-yl)-1-oxa-8-azaspiro[4.5]decane

步骤1：8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 1: Synthesis of 8-(6-(-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

向1-氧杂-8-氮杂螺[4.5]癸烷盐酸盐(1.90g,10.7mmol)、8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(4.73g,10.7mmol)和Cs2CO3(7.00g,21.5mmol)的DMF(20.0mL)溶液加入RuPhos Pd G2(0.420g,0.537mmol)，N2氛围下，反应混合物在130℃反应2hrs，冷却至室温，加入水(100mL)，用EA(100mL×3)萃取，无水Na2SO4干燥，减压浓缩，经硅胶柱层析(PE/EA＝1/1)分离纯化，得到目标产物(3.00g,收率61.6％，黄色固体)。LC-MS(ESI)m/z:454.3[M+H]+。1H NMR(400MHz,CDCl3)δ7.82(s,1H),5.97–5.81(m,1H),5.67(s,1H),4.59–4.40(m,2H),4.16–4.04(m,1H),3.95–3.83(m,4H),3.78–3.56(m,5H),3.54–3.42(m,2H),2.63–2.44(m,1H),2.12–1.86(m,8H),1.79–1.58(m,9H).To a solution of 1-oxa-8-azaspiro[4.5]decane hydrochloride (1.90 g, 10.7 mmol), 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (4.73 g, 10.7 mmol) and Cs 2 CO 3 (7.00 g, 21.5 mmol) in DMF (20.0 mL) was added RuPhos Pd G 2 (0.420 g, 0.537 mmol). Under N 2 atmosphere, the reaction mixture was reacted at 130° C. for 2 hrs, cooled to room temperature, added with water (100 mL), extracted with EA (100 mL×3), and dried over anhydrous Na 2 SO 3 . The residue was dried, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA = 1/1) to obtain the desired product (3.00 g, 61.6% yield, as a yellow solid). LC-MS (ESI) m/z: 454.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H), 5.97–5.81 (m, 1H), 5.67 (s, 1H), 4.59–4.40 (m, 2H), 4.16–4.04 (m, 1H), 3.95–3.83 (m, 4H), 3.78–3.56 (m, 5H), 3.54–3.42 (m, 2H), 2.63–2.44 (m, 1H), 2.12–1.86 (m, 8H), 1.79–1.58 (m, 9H).

步骤2：8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 2: Synthesis of 8-(6-(-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

向8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷(3.00g,6.61mmol)的MeOH(10mL)溶液中加入HCl/二噁烷(20mL,4M)，并在50℃下反应3hrs。将混合物减压浓缩，得到目标产物(2.50g,收率102.3％，淡黄色固体)。LC-MS(ESI)m/z:370.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),7.88(s,1H),5.83(s,1H),4.60–4.40(m,2H),3.76(t,J＝6.6Hz,2H),3.71–3.65(m,2H),3.63–3.55(m,2H),3.52–3.41(m,4H),1.97–1.83(m,6H),1.76–1.62(m,6H).To a solution of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane (3.00 g, 6.61 mmol) in MeOH (10 mL) was added HCl/dioxane (20 mL, 4 M) and reacted at 50°C for 3 hr. The mixture was concentrated under reduced pressure to afford the desired product (2.50 g, 102.3% yield, light yellow solid). LC-MS (ESI) m/z: 370.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ12.62(s,1H),7.88(s,1H),5.83(s,1H),4.60–4.40(m,2H),3.76(t,J＝6.6Hz,2H),3.71 –3.65(m,2H),3.63–3.55(m,2H),3.52–3.41(m,4H),1.97–1.83(m,6H),1.76–1.62(m,6H).

步骤3：8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 3: Synthesis of 8-(6-(-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

将8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷(2.50g,6.77mmol)和KOH(1.14g,20.3mmol)加入到DMF(40mL)中，室温下滴加I2(3.43g,13.5mmol)的DMF(10mL)溶液，滴加过程持续2hrs，滴加完毕，继续搅拌1hrs，加入H2O(150mL)，用EA(100mL×3)萃取，合并有机相，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(DCM/MeOH＝20/1)分离纯化，得到目标产物(2.00g,收率59.7％，黄色固体)。LC-MS(ESI)m/z:496.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),6.03(s,1H),4.53–4.48(m,2H),3.76(t,J＝6.6Hz,2H),3.67–3.64(m,2H),3.53–3.50(m,2H),3.19–3.12(m,4H),1.98–1.78(m,12H).8-(6-(-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane (2.50 g, 6.77 mmol) and KOH (1.14 g, 20.3 mmol) were added to DMF (40 mL). A solution of I 2 (3.43 g, 13.5 mmol) in DMF (10 mL) was added dropwise at room temperature over 2 hrs. After the addition was complete, stirring was continued for 1 hr. H 2 O (150 mL) was added and the mixture was extracted with EA (100 mL×3). The organic phases were combined, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain the target product (2.00 g, yield 59.7%, yellow solid). LC-MS(ESI)m/z:496.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.10(s,1H),6.03(s,1H),4.53–4.48(m,2H),3.76(t,J＝6.6Hz,2H),3. 67–3.64(m,2H),3.53–3.50(m,2H),3.19–3.12(m,4H),1.98–1.78(m,12H).

步骤4：8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 4: Synthesis of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

向8-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷(300mg,0.606mmol)和1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(842mg,3.03mmol)的吡啶(10.0mL)溶液中加入醋酸铜(219mg,1.21mmol)，空气氛围下，反应混合物于80℃搅拌16hrs，冷却至室温，加入H2O(100mL)，用DCM(100mL×3)萃取，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(PE/EA＝1/1)分离纯化，得到目标产物(260mg,收率66.5％，黄色固体)。LC-MS(ESI)m/z:646.3[M+H]+。To a solution of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane (300 mg, 0.606 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (842 mg, 3.03 mmol) in pyridine (10.0 mL) was added copper acetate (219 mg, 1.21 mmol). The reaction mixture was stirred at 80°C for 16 hrs under air atmosphere, cooled to room temperature, and H2O (100 mL) was added. The mixture was extracted with DCM (100 mL×3) and anhydrous Na2SO4 . 4 was dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE/EA=1/1) to obtain the target product (260 mg, yield 66.5%, yellow solid). LC-MS (ESI) m/z: 646.3 [M+H] + .

步骤5：8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 5: Synthesis of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

将8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷(100mg,0.155mmol)和(1,10-菲罗啉)(三氟甲基)铜(I)(96.4mg,0.310mmol)加入到DMF(4.00mL)中，N2置换三次，反应混合物在微波下于100℃下搅拌6hrs，冷却至室温，加入H2O(10mL)，用EA(20mL×3)萃取，合并有机相，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(PE/EA＝1/1)分离纯化，得到目标产物(80.0mg,收率87.9％，黄色固体)。LC-MS(ESI)m/z:588.3[M+H]+。8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane (100 mg, 0.155 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (96.4 mg, 0.310 mmol) were added to DMF (4.00 mL), and the atmosphere was replaced with N2 three times. The reaction mixture was stirred at 100°C under microwave for 6 hrs, cooled to room temperature, added with H2O (10 mL), extracted with EA (20 mL×3), and the organic phases were combined and dried over anhydrous Na2SO4 . 4. The residue was dried and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE/EA=1/1) to obtain the target product (80.0 mg, yield 87.9%, yellow solid). LC-MS (ESI) m/z: 588.3 [M+H] + .

步骤6：8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷的合成
Step 6: Synthesis of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane

向8-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-1-氧杂-8-氮杂螺[4.5]癸烷(80.0mg,0.136mmol)的DCM(5mL)溶液中加入TFA(5mL)，室温下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(方法A)纯化得到目标化合物，得到目标产物(23.4mg,收率34.2％，白色固体)。LC-MS(方法C)：RT＝1.874min，(ESI)m/z:504.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.93–7.80(m,1H),6.84–6.71(m,1H),6.32(s,1H),4.60(s,2H),3.76(t,J＝6.6Hz,2H),3.70–3.63(m,2H),3.59–3.53(m,2H),3.18–3.07(m,4H),2.00–1.87(m,6H),1.79–1.70(m,6H).To a solution of 8-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-oxa-8-azaspiro[4.5]decane (80.0 mg, 0.136 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Method A) to afford the desired product (23.4 mg, 34.2% yield, as a white solid). LC-MS (Method C): RT = 1.874 min, (ESI) m/z: 504.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.02(s,1H),7.93–7.80(m,1H),6.84–6.71(m,1H),6.32(s,1H),4.60(s,2H),3.76(t,J＝6.6Hz, 2H),3.70–3.63(m,2H),3.59–3.53(m,2H),3.18–3.07(m,4H),2.00–1.87(m,6H),1.79–1.70(m,6H).

实施例221：8-(4-((2R)-2-甲基-4-(甲基磺酰基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
 Example 221: 8-(4-((2R)-2-methyl-4-(methylsulfonyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向[(2R)-1-[6-(8-氮杂-3-氧杂双环[3.2.1]辛-8-基)-1-[1-(3,4,5,6-四氢-2H-吡喃-2-基)吡唑-3-基]-3-(三氟甲基)吡唑并[3,4-b]吡啶-4-基]-2-甲基六氢吡啶-4-基]甲磺酸酯(65.0mg,0.102mmol)的DMF(3mL)溶液中，加入甲硫醇钠(14.2mg,0.203mmol)，反应混合物在100℃下搅拌2hrs，冷却至室温，向反应混合物中加入水(20mL)，用EA(20mL×2)萃取，合并有机相用饱和NaCl水溶液(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(38.0mg,收率63.2％，黄色固体)。LC-MS(ESI)m/z:592.3[M+H]+。To a solution of [(2R)-1-[6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-1-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-4-yl]-2-methylhexahydropyridin-4-yl] methanesulfonate (65.0 mg, 0.102 mmol) in DMF (3 mL) was added sodium thiomethoxide (14.2 mg, 0.203 mmol). The reaction mixture was stirred at 100° C. for 2 hrs and cooled to room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL×2). The combined organic phases were washed with saturated aqueous NaCl solution (20 mL×2) and anhydrous Na 2 SO 4. The product was dried, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (38.0 mg, yield 63.2%, yellow solid). LC-MS (ESI) m/z: 592.3 [M+H] + .

步骤2：8-(4-((2R)-2-甲基-4-(甲基磺酰基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-((2R)-2-methyl-4-(methylsulfonyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((2R)-2-甲基-4-(甲硫基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(30.0mg,0.051mmol)的DCM(5mL)溶液中，加入间氯过氧苯甲酸(35.0mg,0.203mmol)，反应混合物在25℃下搅拌2hrs。向反应混合物中加入DCM(20mL)，用饱和Na2SO3水溶液(20mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到目标化合物(20.0mg,收率63.2％，黄色固体)。LC-MS(ESI)m/z:624.3[M+H]+。To a solution of 8-(4-((2R)-2-methyl-4-(methylthio)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30.0 mg, 0.051 mmol) in DCM (5 mL) was added m-chloroperbenzoic acid (35.0 mg, 0.203 mmol). The reaction mixture was stirred at 25°C for 2 hrs. DCM (20 mL) was added to the reaction mixture, which was washed with saturated aqueous Na₂SO₃ (20 mL x 2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (20.0 mg, 63.2% yield, as a yellow solid). LC-MS(ESI)m/z:624.3[M+H] + .

步骤3：8-(4-((2R)-2-甲基-4-(甲基磺酰基)哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((2R)-2-methyl-4-(methylsulfonyl)piperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((2R)-2-甲基-4-(甲基磺酰基)哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(20.0mg,0.032mmol)的DCM(2mL)溶液中，加入TFA(2mL)，混合物在25℃下搅拌16hrs。然后加入饱和NaHCO3水溶液，调节pH值至7，分离有机层并浓缩，残余物用Prep-HPLC(Triart C18,250*20.0mml.D.,S-5um,12nm；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；检测波长220nm,254nm，流速：17mL/min，柱温25℃)分离纯化，得到目标化合物(4.00mg,收率23.1％，白色固体)。LC-MS(方法C)：RT＝1.44min，(ESI)m/z:540.3[M+H]+。HPLC(方法A)：97.9％purity(254nm)，98.3％purity(214nm)。1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),7.89(s,1H),6.80(d,J＝1.8Hz,1H),6.77(s,1H),4.62(s,2H),3.72–3.56(m,4H),3.31–3.23(m,2H),3.02(s,3H),2.70–2.62(m,1H),2.21(d,J＝12.4Hz,1H),2.14–1.90(m,6H),1.82–1.72(m,1H),1.49–1.42(m,1H),1.00(d,J＝5.9Hz,3H)。To a solution of 8-(4-((2R)-2-methyl-4-(methylsulfonyl)piperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (20.0 mg, 0.032 mmol) in DCM (2 mL) was added TFA (2 mL), and the mixture was stirred at 25° C. for 16 hrs. Saturated aqueous NaHCO₃ was then added, and the pH was adjusted to 7. The organic layer was separated and concentrated, and the residue was purified using Prep-HPLC (Triart C18, 250*20.0 mm L.D., S-5 μm, 12 nm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; detection wavelengths 220 nm and 254 nm, flow rate: 17 mL/min, column temperature 25°C) to obtain the title compound (4.00 mg, 23.1% yield, white solid). LC-MS (Method C): RT = 1.44 min, (ESI) m/z: 540.3 [M+H] ⁺ . HPLC (Method A): 97.9% purity (254 nm), 98.3% purity (214 nm). 1 H NMR (400MHz, DMSO-d 6 )δ13.03(s,1H),7.89(s,1H),6.80(d,J＝1.8Hz,1H),6.77(s,1H),4.62(s,2H),3.72–3.56(m,4H),3.31–3.23(m,2H),3.02(s,3 H),2.70–2.62(m,1H),2.21(d,J＝12.4Hz,1H),2.14–1.90(m,6H),1.82–1.72(m,1H),1.49–1.42(m,1H),1.00(d,J＝5.9Hz,3H).

实施例222：8-(4-(4-甲氧基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8- 氮杂二环[3.2.1]辛烷
Example 222: 8-(4-(4-methoxypiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8- azabicyclo[3.2.1]octane

步骤1：8-(4-(4-甲氧基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(4-methoxypiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(1.15g,2.61mmol)的DMF溶液(15.0mL)中加入Cs2CO3(2.54mg,7.81mmol)、4-甲氧基哌啶(300mg,2.61mmol)和RuphosPd G2(202mg,0.260mmol)，在N2氛围下置换三次，反应混合物在130℃搅拌3hrs，冷却至室温，加水淬灭反应，用EA(30.0mL×3)萃取，合并有机相，用饱和NaCl水溶液(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤并减压浓缩，经硅胶柱层析(DCM/MeOH＝20/1)分离纯化，得到目标化合物(950mg,收率85.3％，棕色油状物)。LC-MS，(ESI)m/z:428.3[M+H]+。To a solution of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.15 g, 2.61 mmol) in DMF (15.0 mL) were added Cs 2 CO 3 (2.54 mg, 7.81 mmol), 4-methoxypiperidine (300 mg, 2.61 mmol) and RuphosPd G 2 (202 mg, 0.260 mmol). The atmosphere was replaced with N 2 three times. The reaction mixture was stirred at 130 ° C for 3 hrs, cooled to room temperature, quenched by adding water, and extracted with EA (30.0 mL×3). The organic phases were combined, washed with saturated aqueous NaCl solution (20.0 mL×3), and washed with anhydrous Na 2 SO 4 was dried, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain the target compound (950 mg, yield 85.3%, brown oil). LC-MS, (ESI) m/z: 428.3 [M+H] + .

步骤2：8-(4-(4-甲氧基哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(4-methoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(4-甲氧基哌啶-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(950mg,2.22mmol)的MeOH(8.00mL)溶液中加入4N的HCl/二噁烷溶液(4.00mL)，反应混合物在室温下搅拌16hrs，然后加入饱和NaHCO3水溶液，调节pH值至7，用EA(20.0mL×3)萃取，合并有机相，用饱和NaCl水溶液(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤，减压浓缩，得到棕色油状的目标化合物(800mg,2.33mmol,104％)。LC-MS(ESI)m/z:344.2[M+H]+。To a solution of 8-(4-(4-methoxypiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (950 mg, 2.22 mmol) in MeOH (8.00 mL) was added 4N HCl/dioxane solution (4.00 mL). The reaction mixture was stirred at room temperature for 16 hrs, then saturated aqueous NaHCO₃ was added to adjust the pH to 7. The mixture was extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (20.0 mL × 3 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the title compound (800 mg, 2.33 mmol, 104%) as a brown oil. LC-MS (ESI) m/z: 344.2 [M+H] ⁺ .

步骤3：8-(3-碘-4-(4-甲氧基哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(3-iodo-4-(4-methoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(4-甲氧基哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(800mg,2.33mmol)的DMF(10.0mL)溶液中加入KOH(398mg,7.09mmol)，在2hrs内分批加入I2(1.12g,4.72mmol)，然后在室温下搅拌反应1hr，加水淬灭反应，用EA(40.0mL×3)萃取，合并有机相，用饱和NaCl溶液(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析(DCM/MeOH＝15/1)分离纯化，得到目标化合物(960mg,2.05mmol,收率87.8％，棕色固体)。LC-MS(ESI)m/z:470.1[M+H]+。To a solution of 8-(4-(4-methoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (800 mg, 2.33 mmol) in DMF (10.0 mL) was added KOH (398 mg, 7.09 mmol), and I (1.12 g, 4.72 mmol) was added portionwise over 2 hrs. The reaction was stirred at room temperature for 1 hr, quenched by water, and extracted with EA (40.0 mL×3). The combined organic phases were washed with saturated NaCl solution (20.0 mL×3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=15/1) to give the title compound (960 mg, 2.05 mmol, yield 87.8%, brown solid). LC-MS(ESI)m/z:470.1[M+H] + .

步骤4：8-(3-碘-4-(4-甲氧基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(3-iodo-4-(4-methoxypiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(3-碘-4-(4-甲氧基哌啶-1-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(500mg,1.07mmol)的吡啶(20.0mL)溶液中加入1-(3,4,5,6-四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(1.50g,5.06mmol)和醋酸铜(386mg,1.06mmol)，在80℃敞口搅拌16hrs，反应混合物减压浓缩，残余物通过硅胶柱层析(DCM/MeOH＝15/1)分离纯化，得到目标化合物(700mg,收率106％，棕色固体)。LC-MS(ESI)m/z:620.2[M+H]+。To a solution of 8-(3-iodo-4-(4-methoxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (500 mg, 1.07 mmol) in pyridine (20.0 mL) were added 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 5.06 mmol) and copper acetate (386 mg, 1.06 mmol). The mixture was stirred at 80° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure and the residue was isolated and purified by silica gel column chromatography (DCM/MeOH=15/1) to give the title compound (700 mg, yield 106%, brown solid). LC-MS(ESI)m/z:620.2[M+H] + .

步骤5：8-(4-(4-甲氧基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-(4-methoxypiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2氛围下，在室温下向8-(3-碘-4-(4-甲氧基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(700mg,1.13mmol)的DMF(10.0mL)溶液中滴加(1,10-菲罗啉)(三氟甲基)铜(I)(1.06g,3.40mmol)。然后，将反应混合物微波下130℃下搅拌3hrs，冷却至室温，加入水并用EA(80.0mL×3)萃取，合并有机相，用Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(用0％-3％ MeOH/DCM洗脱)，得到目标化合物(500mg,收率78.8％，黄色固体)。LC-MS(ESI)m/z:562.3[M+H]+。To a solution of 8-(3-iodo-4-(4-methoxypiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[ 3,4 -b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (700 mg, 1.13 mmol) in DMF (10.0 mL) was added (1,10-phenanthroline)(trifluoromethyl)copper(I) (1.06 g, 3.40 mmol) dropwise under N2 atmosphere at room temperature. The reaction mixture was then stirred at 130°C for 3 hours under microwave conditions, cooled to room temperature, and water was added, followed by extraction with EA (80.0 mL x 3). The organic phases were combined, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0%-3% MeOH/DCM) to obtain the title compound (500 mg, 78.8% yield, as a yellow solid). LC-MS (ESI) m/z: 562.3 [M+H] + .

步骤6：8-(4-(4-甲氧基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-(4-methoxypiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在室温下，向8-(4-(4-甲氧基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(500mg,0.890mmol)的DCM(5.00mL)溶液中滴加TFA(5.00mL)。滴加完毕，反应混合物在室温下搅拌16hrs。减压除去溶剂，残余物经pre-HPLC(Triart C18,50*4.6mm,5um；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％ TFA；检测波长214nm,254nm，流速：2.5mL/min，柱温40℃)纯化得到目标化合物(108.6mg,收率25.55％，白色固体)。LC-MS(方法C)：RT＝1.73min，(ESI)m/z:478.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.88(s,1H),6.80(d,J＝2.1Hz,1H),6.31(s,1H),4.60(s,2H),3.66(d,J＝10.8Hz,2H),3.57(d,J＝10.7Hz,2H),3.43–3.38(m,1H),3.35-3.25(m,2H),3.30(s,3H),2.96–2.89(m,2H),2.03–1.95(m,4H),1.94–1.88(m,2H),1.70–1.62(m,2H).To a solution of 8-(4-(4-methoxypiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (500 mg, 0.890 mmol) in DCM (5.00 mL) was added TFA (5.00 mL) dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure, and the residue was purified by pre-HPLC (Triart C18, 50*4.6 mm, 5 μm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; detection wavelengths 214 nm and 254 nm, flow rate: 2.5 mL/min, column temperature 40°C) to yield the title compound (108.6 mg, 25.55% yield, white solid). LC-MS (Method C): RT = 1.73 min, (ESI) m/z: 478.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.88(s,1H),6.80(d,J＝2.1Hz,1H),6.31(s,1H),4.60(s,2H),3.66(d,J＝10.8Hz,2H),3.57(d,J＝10.7Hz,2H), 3.43–3.38(m,1H),3.35-3.25(m,2H),3.30(s,3H),2.96–2.89(m,2H),2.03–1.95(m,4H),1.94–1.88(m,2H),1.70–1.62(m,2H).

实施例223：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-3-(三氟 甲基)-1H-吡唑并[3,4-b]吡啶-4-胺
Example 223: 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-4-amine

步骤1：N-甲基四氢-2H-吡喃-3-甲胺的合成
Step 1: Synthesis of N-methyltetrahydro-2H-pyran-3-methylamine

向四氢-2H-吡喃-3-酮(3g,29.96mmol)的MeOH(50ml)溶液中依次加入甲胺盐酸盐(1.5g,44.95mmol)、Et3N(12.49ml，89.89mmol)，反应混合物在室温搅拌12hrs，将混合物过滤后得到N-甲基四氢-2H-吡喃-3-甲胺(2g,收率57.95％，黄色油状物)，直接用于下一步。LC-MS(ESI)m/z:116.1[M+H]+。To a solution of tetrahydro-2H-pyran-3-one (3 g, 29.96 mmol) in MeOH (50 ml) were added methylamine hydrochloride (1.5 g, 44.95 mmol) and Et₃N (12.49 ml, 89.89 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered to afford N-methyltetrahydro-2H-pyran-3-methanamine (2 g, 57.95% yield, yellow oil), which was used directly in the next step. LC-MS (ESI) m/z: 116.1 [M+H] ⁺ .

步骤2：甲基(四氢-2H-吡喃-3-基)氨基甲酸叔丁基酯的合成
Step 2: Synthesis of tert-butyl methyl(tetrahydro-2H-pyran-3-yl)carbamate

向N-甲基四氢-2H-吡喃-3-甲胺(2g,17.364mmol)的DCM(10mL)溶液中，加入Boc酸酐(7.58g,34.72mmol)、Et3N(7.24ml，52.09mmol),反应混合液在室温下搅拌2hrs。向反应混合物中加入水和EA稀释，用EA(100mL×3)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝9:1)得到目标化合物(2g,收率53.50％，黄色油状物)。LC-MS(ESI)m/z:216.2[M+H]+。To a solution of N-methyltetrahydro-2H-pyran-3-methylamine (2 g, 17.364 mmol) in DCM (10 mL) were added Boc anhydride (7.58 g, 34.72 mmol) and Et₃N (7.24 mL, 52.09 mmol). The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and EA and extracted with EA (100 mL x 3). The combined organic phases were washed three times with saturated aqueous NaCl, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 9:1) to afford the title compound (2 g, 53.50% yield, yellow oil). LC-MS (ESI) m/z: 216.2 [M+H] ⁺ .

步骤3：N-甲基四氢-2H-吡喃-3-甲胺盐酸盐的合成
Step 3: Synthesis of N-methyltetrahydro-2H-pyran-3-methylamine hydrochloride

向甲基(四氢-2H-吡喃-3-基)氨基甲酸叔丁基酯(2g,9.290mmol)的DCM(10mL)溶液中，加入4N盐酸/1,4-二氧六环溶液(10mL)，反应混合物在N2保护下27℃搅拌4hrs。减压除去溶剂，残余物中加入饱和NaHCO3淬灭反应，用DCM(100mL*3)萃取，合并有机相，用饱和NaHCO3(100mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(1g,收率88.24％，白色固体)，直接用于下一步。LC-MS(ESI)m/z:116.2[M+H]+。To a solution of tert-butyl methyl(tetrahydro-2H-pyran-3-yl)carbamate (2 g, 9.290 mmol) in DCM (10 mL) was added a 4N hydrochloric acid/1,4-dioxane solution (10 mL). The reaction mixture was stirred at 27°C for 4 hr under N₂ protection. The solvent was removed under reduced pressure, and the residue was quenched with saturated NaHCO₃ . The mixture was then extracted with DCM (100 mL x 3). The combined organic phases were washed with saturated NaHCO₃ (100 mL x 3), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford the crude product (1 g, 88.24% yield, white solid), which was used directly in the next step. LC-MS (ESI) m/z: 116.2 [M+H] ⁺ .

步骤4：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(四氢-2H-吡喃-2-基)-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 4: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

在N2保护下，向8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1g,2.27mmol)的DMF(10mL)溶液中，并加入N-甲基四氢-2H-吡喃-3-甲胺(0.52g,4.54mmol)、Cs2CO3(2.22g,6.81mmol)和RuPhos Pd G2(0.18g,0.10mmol)。反应混合物在130℃下搅拌12hrs，冷却至室温，用EA(10mL×3)萃取，合并有机相，减压除去溶剂，残余物经硅胶柱层析分离纯化(PE:EA，78％ EA)得到目标化合物(500mg,收率51.49％，淡黄色固体)。LC-MS(ESI)m/z:428.56[M+H]+。Under N₂ protection, to a solution of 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1 g, 2.27 mmol) in DMF (10 mL) were added N-methyltetrahydro-2H-pyran-3-methylamine (0.52 g, 4.54 mmol), Cs₂CO₃ (2.22 g, 6.81 mmol) , and RuPhosPdG₂ (0.18 g, 0.10 mmol). The reaction mixture was stirred at 130°C for 12 hrs, cooled to room temperature, and extracted with EA (10 mL x 3). The organic phases were combined, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 78% EA) to afford the title compound (500 mg, 51.49% yield, as a pale yellow solid). LC-MS(ESI)m/z:428.56[M+H] + .

步骤5：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(四氢-2H-吡喃-2-基)-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺(500mg,1.17mmol)的MeOH(5mL)溶液中，加入4N盐酸/1,4-二氧六环溶液(5mL)，反应混合物在N2保护下50℃搅拌16hrs。冷却至室温，减压除去溶剂，残余物中加入饱和NaHCO3水溶液，用DCM(20mL×3)萃取，合并有机相，用饱和NaHCO3(20mL×3)水溶液洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到粗产品(400mg,收率99.60％，黄色固体)，直接用于下一步。LC-MS(ESI)m/z:344.43[M+H]+。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (500 mg, 1.17 mmol) in MeOH (5 mL) was added 4N hydrochloric acid/1,4-dioxane solution (5 mL). The reaction mixture was stirred at 50°C under N₂ protection for 16 hr. After cooling to room temperature, the solvent was removed under reduced pressure. Saturated aqueous NaHCO₃ was added to the residue, and the mixture was extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated aqueous NaHCO₃ (20 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the crude product (400 mg, 99.60% yield, as a yellow solid), which was used directly in the next step. LC-MS(ESI)m/z:344.43[M+H] + .

步骤6：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-N-甲基-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺(400mg,1.17mmol)和KOH(196.06mg,3.50mmol)溶解于DMF(9mL)中，再分批量缓慢加入I2(295.62mg,1.16mmol)。在N2氛围下置换三次，反应液在25℃下搅拌1hrs，加入饱和Na2SO3水溶液淬灭反应，用EA(30mL×3)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1：4)得到目标化合物(200mg,收率29.58％，黄色固体)。LC-MS(ESI)m/z:470.20[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (400 mg, 1.17 mmol) and KOH (196.06 mg, 3.50 mmol) were dissolved in DMF (9 mL), and I₂ (295.62 mg, 1.16 mmol) was slowly added portionwise. The atmosphere was replaced with N₂ three times, and the reaction mixture was stirred at 25°C for 1 hr. The reaction was quenched by addition of saturated aqueous Na₂SO₃ and extracted with EA (30 mL x 3). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to afford the title compound (200 mg, 29.58% yield, as a yellow solid). LC-MS(ESI)m/z:470.20[M+H] + .

步骤7：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-N-甲基-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺(200mg,0.42mmol)、1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2基)-1H-邻二氮杂茂(1.42g,5.10mmol)、醋酸铜(170.16mg,0.85mmol)依次加入到吡啶(30mL)中。反应混合物在空气氛围下80℃搅拌16hrs。冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×3)萃取，合并有机相，用饱和NaCl水溶液(30mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，100％EA)，得到目标化合物(150mg,收率56.82％，黄色固体)。LC-MS(ESI)m/z:620.51[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (200 mg, 0.42 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-diazol (1.42 g, 5.10 mmol), and copper acetate (170.16 mg, 0.85 mmol) were added sequentially to pyridine (30 mL). The reaction mixture was stirred at 80°C under air atmosphere for 16 hours. After cooling to room temperature, water (30 mL) was added to the reaction mixture, which was then extracted with EA (30 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 100% EA) to obtain the title compound (150 mg, 56.82% yield, as a yellow solid). LC-MS (ESI) m/z: 620.51 [M+H] + .

步骤8：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 8: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-3-碘-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺(100mg,0.16mmol)溶于DMF(3mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(151.58mg,0.48mmol)，反应混合物中鼓N2 3mins，在微波下80℃下搅拌6hrs。冷却至室温，向反应混合物中加入水(20mL)，用EA(20mL×3)萃取，合并有机相，用饱和NaCl水溶液(20mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经反向硅胶柱层析分离纯化(H2O：CH3CN，90％CH3CN)得到目标化合物(40mg,收率44.11％，黄色固体)。LC-MS(ESI)m/z:562.3[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (100 mg, 0.16 mmol) was dissolved in DMF (3 mL) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (151.58 mg, 0.48 mmol) was added. N2 was bubbled through the reaction mixture for 3 mins and stirred at 80°C under microwave for 6 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (20 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (20 mL × 3 ), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography ( H₂O : CH₃CN , 90% CH₃CN ) to obtain the title compound (40 mg, 44.11% yield, yellow solid). LC-MS (ESI) m/z: 562.3 [M+H] ⁺ .

步骤9：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 9: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-N-(四氢-2H-吡喃-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺(40mg,0.071mmol)的DCM(5mL)溶液中，加入TFA(5mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残留物中加入饱和NaHCO3(50mL)水溶液，用DCM(30mL×2)萃取，合并有机相，用饱和NaHCO3(50mL×2)水溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，减压浓缩，残余物经Prep-HPLC(柱：Triart c18250*20.0mm.d,S-5um，12nm；流动相A：10mmolNH4HCO3/水，流动相B：CH3CN；梯度：0-95％B，检测波长214nm，流速：17mL/min，柱温25℃)分离纯化，得到目标化合物(9.41mg,收率27.67％，白色固体)。LC-MS(方法C)：RT＝1.48min，(ESI)m/z:478.20[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.94–7.85(m,1H),6.80(t,J＝2.1Hz,1H),6.37(s,1H),4.58(s,2H),3.81–3.72(m,2H),3.70–3.65(m,2H),3.59–3.55(m,2H),3.53–3.42(m,2H),3.28–3.17(m,1H),2.80(s,3H),2.02–1.84(m,4H),1.80–1.45(m,4H).To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine (40 mg, 0.071 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25° C. for 16 hrs. The mixture was concentrated under reduced pressure. A saturated aqueous NaHCO₃ solution (50 mL) was added to the residue, and the mixture was extracted with DCM (30 mL × 2). The combined organic phases were washed with a saturated aqueous NaHCO₃ solution ( 50 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 75% EA) and concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (column: Triart c18250*20.0 mm.d, S-5 um, 12 nm; mobile phase A: 10 mmol NH₄HCO₃ /water, mobile phase B: CH₃CN ; gradient: 0-95% B, detection wavelength: 214 nm, flow rate: 17 mL/min, column temperature: 25°C) to obtain the target compound (9.41 mg, yield: 27.67%, white solid). LC-MS (Method C): RT = 1.48 min, (ESI) m/z: 478.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 7.94–7.85 (m, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.37 (s, 1H), 4.58 (s, 2H), 3.81–3.72 (m, 2H), 3.70–3.65 (m, 2H), 3.59–3.55 (m, 2H), 3.53–3.42 (m, 2H), 3.28–3.17 (m, 1H), 2.80 (s, 3H), 2.02–1.84 (m, 4H), 1.80–1.45 (m, 4H).

实施例224和实施例225：(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲 基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺和(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8- 基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺
Example 224 and Example 225: (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-( trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine and (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

步骤1：(2R)-4-(二甲氨基)-2-甲基哌啶-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl (2R)-4-(dimethylamino)-2-methylpiperidine-1-carboxylate

向二甲胺的EtOH溶液(2mol/L，70mL)中加入(R)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(4.00g,18.7mmol)。反应混合物在室温下搅拌2hrs。然后将反应混合物冷却至0℃，并分批加入氰基硼氢化钠(2.36g,37.5mmol)，然后加入乙酸至pH值为6左右。将反应混合物在室温下搅拌16hrs。加入1N NaOH溶液(30mL)，用DCM(100mL×2)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩，得到目标产物(3.00g,收率66.0％，黄色液体)。To a solution of dimethylamine in EtOH (2 mol/L, 70 mL) was added tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (4.00 g, 18.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0°C, and sodium cyanoborohydride (2.36 g, 37.5 mmol) was added portionwise. Acetic acid was then added until the pH was approximately 6. The reaction mixture was stirred at room temperature for 16 hours. 1N NaOH solution (30 mL) was added, and the mixture was extracted with DCM (100 mL x 2). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to yield the desired product (3.00 g, 66.0% yield, as a yellow liquid).

步骤2：(2R)-N,N,2-三甲基哌啶-4-胺盐酸盐的合成
Step 2: Synthesis of (2R)-N,N,2-trimethylpiperidin-4-amine hydrochloride

向(2R)-4-(二甲氨基)-2-甲基哌啶-1-甲酸叔丁酯(3.00g,12.3mmol)中加入4MHCl/二噁烷溶液(20mL)。反应混合物在室温下搅拌6hrs。然后将反应混合物过滤，滤饼用EA(50mL)洗涤，真空干燥得到目标产物(2.00g,收率90.4％，黄色固体)。LC-MS(ESI)m/z:143.2[M+H]+。To tert-butyl (2R)-4-(dimethylamino)-2-methylpiperidine-1-carboxylate (3.00 g, 12.3 mmol) was added a 4M HCl/dioxane solution (20 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then filtered, and the filter cake was washed with EA (50 mL) and dried under vacuum to afford the desired product (2.00 g, 90.4% yield, as a yellow solid). LC-MS (ESI) m/z: 143.2 [M+H] + .

步骤3：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

将(2R)-N,N,2-三甲基哌啶-4-胺盐酸盐(800mg,5.62mmol)和8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.97g,6.75mmol)溶于干燥的DMF(20mL)中，然后依次加入Cs2CO3(3.66g,11.2mmol)和RuPhos Pd G2(220mg,0.280mmol)。反应混合物在N2保护下130℃搅拌2hrs。冷却至室温，向反应混合物中加入水(100mL)和EA(50mL)稀释，用EA(50mL×2)萃取，合并有机相，用饱和NaCl水溶液洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(1.36g,收率53.2％，淡黄色固体)。LC-MS(ESI)m/z:455.3[M+H]+。(2R)-N,N,2-Trimethylpiperidin-4-amine hydrochloride (800 mg, 5.62 mmol) and 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.97 g, 6.75 mmol) were dissolved in dry DMF (20 mL), and then Cs 2 CO 3 (3.66 g, 11.2 mmol) and RuPhos Pd G 2 (220 mg, 0.280 mmol) were added in sequence. The reaction mixture was stirred at 130° C. for 2 hrs under N 2 protection. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and EA (50 mL). The mixture was extracted with EA (50 mL x 2). The combined organic phases were washed three times with saturated aqueous NaCl, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (1.36 g, 53.2% yield, light yellow solid). LC-MS (ESI) m/z: 455.3 [M+H] ⁺ .

步骤4：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 4: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺(1.36g,2.99mmol)溶于MeOH(10mL)中，加入4N HCl/二噁烷溶液(10mL)，反应混合物在N2保护下50℃搅拌16hrs。减压浓缩，残余物中加入饱和Na2CO3(100mL)，用DCM(100mL×2)萃取。合并有机相，用饱和Na2CO3(100mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(100％EA to 10％ MeOH/DCM)，得到目标化合物(1.02g,收率92.0％，黄色固体)。LC-MS(ESI)m/z:371.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine (1.36 g, 2.99 mmol) was dissolved in MeOH (10 mL), and 4N HCl/dioxane solution (10 mL) was added. The reaction mixture was stirred at 50°C under N2 protection for 16 hrs. The mixture was concentrated under reduced pressure, and saturated Na2CO3 (100 mL) was added to the residue, which was extracted with DCM (100 mL x 2). The combined organic phases were washed with saturated Na 2 CO 3 (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EA to 10% MeOH/DCM) to obtain the title compound (1.02 g, 92.0% yield, yellow solid). LC-MS (ESI) m/z: 371.2 [M+H] + .

步骤5：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 5: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺(1.02g,2.75mmol)和KOH(460mg,8.26mmol)溶解于DMF(20mL)中，再在2hrs内分批量缓慢加入I2(1.40g,5.51mmol)。N2保护下，反应液在25℃下搅拌1hr。加入饱和Na2SO3水溶液(50mL)，用EA(75mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)得到目标化合物(800mg,收率58.5％，黄色液体)。LC-MS(ESI)m/z:497.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine (1.02 g, 2.75 mmol) and KOH (460 mg, 8.26 mmol) were dissolved in DMF (20 mL). I₂ (1.40 g, 5.51 mmol) was added slowly in portions over 2 hr. Under N₂ protection, the reaction mixture was stirred at 25°C for 1 hr. Saturated aqueous Na₂SO₃ (50 mL) was added, and the mixture was extracted with EA (75 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to afford the title compound (800 mg, 58.5% yield, as a yellow liquid). LC-MS(ESI)m/z:497.2[M+H] + .

步骤6：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 6: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺(800mg,1.61mmol)的吡啶(10.0mL)溶液中加入1-(3,4,5,6-四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡唑(2.24g,8.05mmol)和醋酸铜(585mg,3.22mmol)，反应混合物在80℃下搅拌反应4hrs，冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA，0％～100％EA)得到目标化合物(650mg,收率62.3％，黄色固体)。LC-MS(ESI)m/z:647.3[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine (800 mg, 1.61 mmol) in pyridine (10.0 mL) was added 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.24 g, 8.05 mmol) and copper acetate (585 mg, 3.22 mmol) were stirred at 80°C for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0% to 100% EA) to obtain the title compound (650 mg, 62.3% yield, as a yellow solid). LC-MS (ESI) m/z: 647.3 [M+H] + .

步骤7：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 7: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

微波管中，将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺(550mg,0.851mmol)溶于DMF(10mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(798mg,2.55mmol)，鼓N2 3mins，反应混合物在微波下80℃下搅拌3hrs。冷却至室温，向反应混合物中加入水(50mL)，用EA(50mL×2)萃取，合并有机相，用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA，0％～100％EA)，得到目标化合物(90.0mg,收率17.9％，黄色固体)。LC-MS(ESI)m/z:589.4[M+H]+。In a microwave tube, (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine (550 mg, 0.851 mmol) was dissolved in DMF (10 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (798 mg, 2.55 mmol) was added. N2 was bubbled for 3 mins, and the reaction mixture was stirred at 80 °C under microwave for 3 hrs. After cooling to room temperature, water (50 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0% to 100% EA) to obtain the title compound (90.0 mg, 17.9% yield, as a yellow solid). LC-MS (ESI) m/z: 589.4 [M+H] + .

步骤8：(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺和(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺的合成
Step 8: Synthesis of (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine and (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine

向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,N,2-三甲基哌啶-4-胺(50.0mg,0.085mmol)的DCM(2mL)中，加入TFA(2mL)。反应混合物在25℃下搅拌16hrs，然后减压浓缩，残余物中加入DMF(2mL)，加入碳酸钾调节pH值至7，过滤，用Prep-HPLC分离纯化，再经SFC(Opti-Chiral IDB,250*21.2mm,5μm；流动相A：CO2，流动相B：0.1％NH3·H2O in MeOH；流速：40mL/min，B％：20-35％，柱温40℃)拆分，得到目标化合物P1(4.37mg,收率10.2％，淡黄色固体)。LC-MS(方法K)：RT＝0.99min，(ESI)m/z:505.3[M+H]+。SFC(方法N)RT＝3.01min。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.87(s,1H),6.80(d,J＝2.1Hz,1H),6.25(s,1H),4.57(s,2H),4.03–3.95(m,1H),3.70–3.63(m,2H),3.56(d,J＝10.7Hz,2H),3.31–3.20(m,2H),3.13–3.07(m,1H),2.21(s,6H),1.99–1.77(m,6H),1.73–1.67(m,1H),1.53–1.43(m,1H),0.94(d,J＝6.6Hz,3H)。得到目标化合物P2(10.1mg,收率23.7％，淡黄色固体)。LC-MS(方法K)：RT＝0.90min，(ESI)m/z:505.3[M+H]+。SFC(方法N)RT＝3.21min。1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.88(s,1H),6.79(s,1H),6.73(s,1H),4.61(d,J＝11.2Hz,2H),3.70–3.61(m,2H),3.60–3.55(m,2H),3.28–3.20(m,2H),2.62–2.54(m,1H),2.32–2.25(m,1H),2.21(s,6H),2.01–1.78(m,6H),1.56–1.46(m,1H),1.25–1.20(m,1H),0.94(d,J＝5.8Hz,3H)。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,N,2-trimethylpiperidin-4-amine (50.0 mg, 0.085 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at 25°C for 16 hours and then concentrated under reduced pressure. DMF (2 mL) was added to the residue, and the pH was adjusted to 7 with potassium carbonate. The product was filtered and purified by Prep-HPLC. Separation by SFC (Opti-Chiral IDB, 250 x 21.2 mm, 5 μm; mobile phase A: CO₂ , mobile phase B: 0.1% NH₃·H₂O in MeOH; flow rate: 40 mL/min, B%: 20-35%, column temperature 40°C) afforded the title compound P1 (4.37 mg, 10.2% yield, light yellow solid). LC-MS (Method K): RT = 0.99 min, (ESI) m/z: 505.3 [M+H] ⁺ . SFC (Method N): RT = 3.01 min. 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.87(s,1H),6.80(d,J＝2.1Hz,1H),6.25(s,1H),4.57(s,2H),4.03–3.95(m,1H),3.70–3.63(m,2H),3.56(d,J＝10.7Hz, 2H),3.31–3.20(m,2H),3.13–3.07(m,1H),2.21(s,6H),1.99–1.77(m,6H),1.73–1.67(m,1H),1.53–1.43(m,1H),0.94(d,J＝6.6Hz,3H). The target compound P2 (10.1 mg, 23.7% yield, light yellow solid) was obtained. LC-MS (Method K): RT = 0.90 min, (ESI) m/z: 505.3 [M+H] + . SFC (Method N) RT = 3.21 min. 1 H NMR (400MHz, DMSO-d 6 )δ13.02(s,1H),7.88(s,1H),6.79(s,1H),6.73(s,1H),4.61(d,J＝11.2Hz,2H),3.70–3.61(m,2H),3.60–3.55(m,2H),3.28–3.20(m,2 H),2.62–2.54(m,1H),2.32–2.25(m,1H),2.21(s,6H),2.01–1.78(m,6H),1.56–1.46(m,1H),1.25–1.20(m,1H),0.94(d,J＝5.8Hz,3H).

实施例226和实施例227：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-((1R,4R)-4-甲氧基环己基)-N-甲基 -1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺和6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8- 基)-N-((1S,4S)-4-甲氧基环己基)-N-甲基-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺
Example 226 and Example 227: 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((1R,4R)-4-methoxycyclohexyl)-N-methyl- 1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine and 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8- yl)-N-((1S,4S)-4-methoxycyclohexyl)-N-methyl-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

步骤1：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 1: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.47g,5.61mmol)和4-甲氧基环己烷-1-胺(870mg,6.73mmol)溶于干燥的DMF(20mL)，然后依次加入Cs2CO3(3.66g,11.2mmol)和Ruphos Pd G2(218mg,0.281mmol)。反应混合物在N2氛围下130℃搅拌2hrs，冷却至室温，向反应混合物中加入水(100mL)和EA(100mL)稀释，用EA(150mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1:1)，得到目标化合物(2.02g,收率81.5％，淡黄色固体)。LC-MS(ESI)m/z:442.3[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.47 g, 5.61 mmol) and 4-methoxycyclohexane-1-amine (870 mg, 6.73 mmol) were dissolved in dry DMF (20 mL), and then Cs 2 CO 3 (3.66 g, 11.2 mmol) and Ruphos Pd G 2 (218 mg, 0.281 mmol) were added in sequence. The reaction mixture was stirred at 130°C for 2 hours under a nitrogen atmosphere, cooled to room temperature, diluted with water (100 mL) and EA (100 mL), and extracted with EA (150 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( PE:EA = 1:1) to obtain the title compound (2.02 g, 81.5% yield, pale yellow solid). LC-MS (ESI) m/z: 442.3 [M+H] + .

步骤2：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 2: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-胺(2.00g,4.53mmol)的DMF(30mL)溶液中，加入叔丁醇钾(1.02g,9.05mmol)和CH3I(770mg,5.43mmol)，反应混合物在室温下搅拌2hrs。向反应混合物中加入水(150mL)和EA(50mL)稀释，用EA(100mL×2)萃取。合并有机相用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝7:3)，得到目标化合物(1.00g,收率48.4％，黄色固体)。LC-MS(ESI)m/z:456.3[M+H]+。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (2.00 g, 4.53 mmol) in DMF (30 mL) were added potassium tert-butoxide (1.02 g, 9.05 mmol) and CH₃I (770 mg, 5.43 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was diluted with water (150 mL) and EA (50 mL), and extracted with EA (100 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 7:3) to obtain the title compound (1.00 g, 48.4% yield, as a yellow solid). LC-MS(ESI)m/z:456.3[M+H] + .

步骤3：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-胺(1.12g,2.46mmol)的MeOH(20mL)溶液中，加入4N HCl/二噁烷溶液(10mL)，反应混合物在N2保护下50℃搅拌8hrs。减压浓缩，残余物中加入饱和Na2CO3(100mL)，用DCM(100mL×2)萃取，合并有机相用饱和Na2CO3(100mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(100％EA至10％MeOH/DCM)，得到目标化合物(750mg,收率82.1％，黄色固体)。LC-MS(ESI)m/z:372.2[M+H]+。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.12 g, 2.46 mmol) in MeOH (20 mL) was added 4N HCl/dioxane solution (10 mL), and the reaction mixture was stirred at 50 °C for 8 hrs under N2 protection. The mixture was concentrated under reduced pressure, and saturated Na₂CO₃ (100 mL) was added to the residue, followed by extraction with DCM (100 mL x 2 ). The combined organic phases were washed with saturated Na₂CO₃ (100 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EA to 10% MeOH/DCM) to obtain the title compound (750 mg, 82.1% yield, yellow solid). LC-MS (ESI) m/z: 372.2 [M+H] ⁺ .

步骤4：6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-(4-甲氧基环己基)-N-甲基-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 4: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-(4-methoxycyclohexyl)-N-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1H-吡唑并[3,4-b]吡啶-4-胺(750mg,2.02mmol)和KOH(283mg,5.05mmol)溶解于DMF(20mL)中，再在2hrs内分批量缓慢加入I2(1.02g,4.04mmol)。在N2氛围下置换三次，反应混合物在25℃下搅拌1hr。加入饱和Na2SO3水溶液(50mL)，用EA(75mL×2)萃取，合并有机相用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)，得到目标化合物(400mg,收率39.8％，黄色固体)。LC-MS(ESI)m/z:498.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine (750 mg, 2.02 mmol) and KOH (283 mg, 5.05 mmol) were dissolved in DMF (20 mL). I₂ (1.02 g, 4.04 mmol) was added slowly in portions over 2 hr. The atmosphere was replaced three times with N₂ , and the reaction mixture was stirred at 25° C for 1 hr. Saturated aqueous Na₂SO₃ (50 mL) was added, and the mixture was extracted with EA (75 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to obtain the title compound (400 mg, 39.8% yield, as a yellow solid). LC-MS(ESI)m/z:498.2[M+H] + .

步骤5：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-(4-甲氧基环己基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 5: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-(4-methoxycyclohexyl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-(4-甲氧基环己基)-N-甲基-1H-吡唑并[3,4-b]吡啶-4-胺(400mg,0.804mmol)的吡啶(10.0mL)溶液中加入1-(3,4,5,6-四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡唑(1.11g,4.02mmol)和醋酸铜(292mg,1.60mmol)，反应混合物在80℃下搅拌反应4hrs，冷却至室温，反应混合物减压浓缩，残余物经硅胶柱层析分离纯化(100％EA)，得到目标化合物(350mg,收率67.2％，黄色固体)。LC-MS(ESI)m/z:648.3[M+H]+。To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-(4-methoxycyclohexyl)-N-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine (400 mg, 0.804 mmol) in pyridine (10.0 mL) were added 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.11 g, 4.02 mmol) and copper acetate (292 mg, 1.60 mmol). The reaction mixture was stirred at 80°C for 4 hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EA) to give the title compound (350 mg, yield 67.2%) as a yellow solid. LC-MS(ESI)m/z:648.3[M+H] + .

步骤6：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡啶并[3,4-b]吡啶-4-胺的合成
Step 6: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrido[3,4-b]pyridin-4-amine

微波管中，将6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-N-(4-甲氧基环己基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-胺(250mg,0.386mmol)溶于DMF(4mL)，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(362mg,1.16mmol)，向微波管中鼓N23mins，反应混合物在微波下80℃下搅拌6hrs。冷却至室温，向反应混合物中加入水(20mL)，用EA(30mL×2)萃取。合并有机相用饱和食盐水(20mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)，得到目标化合物(50.0mg,收率21.9％，黄色液体)。LC-MS(ESI)m/z:590.4[M+H]+。In a microwave tube, 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-N-(4-methoxycyclohexyl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (250 mg, 0.386 mmol) was dissolved in DMF (4 mL). (1,10-Phenanthroline)(trifluoromethyl)copper(I) (95%) (362 mg, 1.16 mmol) was added. N₂ was bubbled through the microwave tube for 3 min. The reaction mixture was stirred at 80°C under microwave for 6 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 5), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (50.0 mg, 21.9% yield, yellow liquid). LC-MS (ESI) m/z: 590.4 [M+H] + .

步骤7：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-((1R,4R)-4-甲氧基环己基)-N-甲基-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺和6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-((1S，4S)-4-甲氧基环己基)-N-甲基-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-胺的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((1R,4R)-4-methoxycyclohexyl)-N-methyl-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine and 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((1S,4S)-4-methoxycyclohexyl)-N-methyl-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

向6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-N-(4-甲氧基环己基)-N-甲基-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡啶并[3,4-b]吡啶-4-胺(50.0mg,0.085mmol)的DCM(2mL)溶液中，加入TFA(2mL)。反应混合物在25℃下搅拌16hrs，然后减压浓缩，加入DMF(2mL)，加入无水K2CO3粉末调节pH值至7，过滤，滤液用Prep-HPLC(Triart C18,250*20.0mml.D.,S-5um,12nm；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；梯度：20-95％B,流速：17mL/min，检测波长220nm,254nm，柱温25℃)分离纯化，得到目标化合物P1(4.94mg,收率11.52％，白色固体)。LC-MS(方法C)：RT＝1.78min，(ESI)m/z:506.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.87(s,1H),6.80(d,J＝2.3Hz,1H),6.26(s,1H),4.57(s,2H),3.67(d,J＝10.7Hz,2H),3.57(d,J＝10.7Hz,2H),3.46–3.39(m,1H),3.21(s,3H),3.14–3.06(m,1H),2.75(s,3H),2.06–1.90(m,6H),1.70–1.57(m,4H),1.17–1.02(m,2H).；To a solution of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(4-methoxycyclohexyl)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrido[3,4-b]pyridin-4-amine (50.0 mg, 0.085 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at 25°C for 16 hours, then concentrated under reduced pressure. DMF (2 mL) was added, and the pH was adjusted to 7 by adding anhydrous K₂CO₃ powder. The mixture was filtered, and the filtrate was separated and purified by Prep-HPLC (Triart C18, 250*20.0 mm L·D . , S-5 μm, 12 nm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; gradient: 20-95% B, flow rate: 17 mL/min, detection wavelengths: 220 nm, 254 nm, column temperature: 25°C) to obtain the target compound P1 (4.94 mg, yield: 11.52%), as a white solid. LC-MS (Method C): RT = 1.78 min, (ESI) m/z: 506.3 [M+H] ⁺ . 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.87(s,1H),6.80(d,J＝2.3Hz,1H),6.26(s,1H),4.57(s,2H),3.67(d,J＝10.7Hz,2H),3.57(d,J＝10.7Hz,2H ),3.46–3.39(m,1H),3.21(s,3H),3.14–3.06(m,1H),2.75(s,3H),2.06–1.90(m,6H),1.70–1.57(m,4H),1.17–1.02(m,2H).;

和目标化合物P2(6.49mg,收率15.14％，白色固体)。LC-MS：(ESI)m/z:506.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),7.96–7.78(m,1H),6.84–6.73(m,1H),6.27(s,1H),4.57(s,2H),3.67(d,J＝10.7Hz,2H),3.57(d,J＝10.6Hz,2H),3.50–3.40(m,1H),3.36–3.33(m,1H),3.21(s,3H),2.75(s,3H),2.01–1.87(m,6H),1.86–1.74(m,2H),1.45–1.29(m,4H).and target compound P2 (6.49 mg, yield 15.14%, white solid). LC-MS: (ESI) m/z: 506.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.00(s,1H),7.96–7.78(m,1H),6.84–6.73(m,1H),6.27(s,1H),4.57(s,2H),3.67(d,J＝10.7Hz,2H),3.57(d,J＝10.6Hz,2 H),3.50–3.40(m,1H),3.36–3.33(m,1H),3.21(s,3H),2.75(s,3H),2.01–1.87(m,6H),1.86–1.74(m,2H),1.45–1.29(m,4H).

实施例228和实施例229：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲 基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈和(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8- 基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈
Example 228 and Example 229: (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-( trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile and (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8 -yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

步骤1：(2R)-4-氰基-2-甲基哌啶-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl (2R)-4-cyano-2-methylpiperidine-1-carboxylate

向(R)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(3.00g,14.1mmol)和2-对甲苯基乙腈(3.30g,16.9mmol)的DME(60mL)/EtOH(2mL)溶液中，0℃下缓慢加入叔丁醇钾(3.16g,28.1mmol)，反应混合物在N2保护下，室温搅拌16hrs，向反应混合物中加入H2O(60mL)，EA萃取(100mL×3)，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA＝4/1)得到目标化合物(2.55g,收率80.8％，白色固体)。LC-MS(ESI)m/z:125.2[M-100+H]+。1H NMR(400MHz,CDCl3)δ4.53–4.40(m,1H),4.07–3.93(m,1H),2.86–2.68(m,2H),2.04–1.97(m,1H),1.89–1.84(m,2H),1.69–1.58(m,1H),1.43(s,9H),1.11(d,J＝7.0Hz,3H).To a solution of (R)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (3.00 g, 14.1 mmol) and 2-p-tolylacetonitrile (3.30 g, 16.9 mmol) in DME (60 mL)/EtOH (2 mL) was slowly added potassium tert-butoxide (3.16 g, 28.1 mmol) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 16 hr. H₂O (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (100 mL × 3 ), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 4/1) to afford the title compound (2.55 g, 80.8% yield, as a white solid). LC-MS (ESI) m/z: 125.2 [M-100+H] ⁺ . 1 H NMR (400MHz, CDCl 3 )δ4.53–4.40(m,1H),4.07–3.93(m,1H),2.86–2.68(m,2H),2.04–1.97(m,1H ),1.89–1.84(m,2H),1.69–1.58(m,1H),1.43(s,9H),1.11(d,J=7.0Hz,3H).

步骤2：(2R)-2-甲基哌啶-4-腈的合成
Step 2: Synthesis of (2R)-2-methylpiperidine-4-carbonitrile

向(2R)-4-氰基-2-甲基哌啶-1-甲酸叔丁酯(2.55g,11.4mmol)的DCM(50mL)溶液中，加入HCl/二噁烷(20mL，4M)，反应混合物在室温下搅拌1hr，减压浓缩，得到目标化合物(1.41g,收率100％，棕色油状液体)。LC-MS(ESI)m/z:125.2[M+H]+。To a solution of tert-butyl (2R)-4-cyano-2-methylpiperidine-1-carboxylate (2.55 g, 11.4 mmol) in DCM (50 mL) was added HCl/dioxane (20 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain the title compound (1.41 g, 100% yield, brown oily liquid). LC-MS (ESI) m/z: 125.2 [M+H] + .

步骤3：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

将(2R)-2-甲基哌啶-4-腈(1.41g,11.4mmol)、8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(7.50g,17.1mmol)、RuPhos Pd G2(0.443g,0.570mmol)和Cs2CO3(7.43g,22.8mmol)依次加入到DMF(60mL)中，N2保护下加热至130℃反应3hrs，冷却至室温，加入水(100mL)，用EA(100mL×3)萃取，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化，得到目标产物(3.05g,收率61.4％，淡黄色固体)。LC-MS(ESI)m/z:437.3[M+H]+。(2R)-2-Methylpiperidine-4-carbonitrile (1.41 g, 11.4 mmol), 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (7.50 g, 17.1 mmol), RuPhos Pd G 2 (0.443 g, 0.570 mmol) and Cs 2 CO 3 (7.43 g, 22.8 mmol) were added to DMF (60 mL) in sequence. The mixture was heated to 130 °C under N 2 protection for 3 hrs. The mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with EA (100 mL×3) and anhydrous Na 2 SO 3 was added. 4. The residue was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product (3.05 g, yield 61.4%, light yellow solid). LC-MS (ESI) m/z: 437.3 [M+H] + .

步骤4：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 4: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈(3.05g,6.99mmol)的DCM(50mL)溶液中加入TFA(20mL)，反应混合物在室温下搅拌3hrs，减压浓缩，得到目标产物(2.46g,收率100％，淡黄色油状液体)。LC-MS(ESI)m/z:353.2[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile (3.05 g, 6.99 mmol) in DCM (50 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to afford the desired product (2.46 g, 100% yield, light yellow oily liquid). LC-MS (ESI) m/z: 353.2 [M+H] + .

步骤5：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 5: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈(2.46g,6.99mmol)和KOH(1.17g,20.9mmol)加入到DMF(60mL)中，室温下滴加I2(3.53g,13.9mmol)的DMF(20mL)溶液，滴加完毕，继续搅拌1hr，加入H2O(200mL)，用EA(150mL×3)萃取，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA＝1:1)，得到目标产物(1.95g,收率58.5％，黄色固体)。LC-MS(ESI)m/z:479.1[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile (2.46 g, 6.99 mmol) and KOH (1.17 g, 20.9 mmol) were added to DMF (60 mL), and a solution of I 2 (3.53 g, 13.9 mmol) in DMF (20 mL) was added dropwise at room temperature. After the addition was complete, stirring was continued for 1 hr, and H 2 O (200 mL) was added. The mixture was extracted with EA (150 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE/EA＝1:1) to obtain the target product (1.95 g, yield 58.5%, yellow solid). LC-MS(ESI)m/z:479.1[M+H] + .

步骤6：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 6: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈(1.95g,4.08mmol)、1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(5.67g,20.4mmol)和醋酸铜(1.47g,8.16mmol)加入到吡啶(30mL)中，反应混合物在空气氛围下，于80℃搅拌16hrs。冷却至室温，加入H2O(100mL)，用DCM(100mL×3)萃取，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(DCM/MeOH＝20/1)分离纯化，得到目标产物(850mg,收率33.2％，黄色固体)。LC-MS(ESI)m/z:629.2[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile (1.95 g, 4.08 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.67 g, 20.4 mmol) and copper acetate (1.47 g, 8.16 mmol) were added to pyridine (30 mL), and the reaction mixture was stirred at 80° C. under air atmosphere for 16 hrs. The mixture was cooled to room temperature, H 2 O (100 mL) was added, and the mixture was extracted with DCM (100 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain the desired product (850 mg, yield 33.2%, yellow solid). LC-MS (ESI) m/z: 629.2 [M+H] + .

步骤7：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 7: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈(800mg,1.27mmol)和(1,10-菲罗啉)(三氟甲基)铜(I)(792mg,2.55mmol)加入到DMF(8mL)中，N2置换三次，反应混合物于80℃下，微波反应6hrs，冷却至室温，加入H2O(20mL)，EA(20mLx3)萃取，无水Na2SO4干燥，减压浓缩，硅胶柱层析(MeOH/DCM＝1:20)分离纯化，得到目标产物(400mg,收率55.1％，黄色固体)。LC-MS(ESI)m/z:571.3[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile (800 mg, 1.27 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (792 mg, 2.55 mmol) were added to DMF (8 mL), and the atmosphere was replaced with N 2 three times. The reaction mixture was microwaved at 80° C. for 6 hrs, cooled to room temperature, added with H 2 O (20 mL), extracted with EA (20 mL×3), and dried over anhydrous Na 2 SO 4 was dried, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (MeOH/DCM=1:20) to obtain the desired product (400 mg, yield 55.1%, yellow solid). LC-MS (ESI) m/z: 571.3 [M+H] + .

步骤8：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈和(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈的合成
Step 8: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile and (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile

向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2-甲基哌啶-4-腈(400mg,0.701mmol)的DCM(20mL)溶液中加入TFA(4mL)，反应混合物在室温下搅拌16hrs。减压浓缩，残余物经Prep-HPLC(Triart C18,250×20.0mml.D.,S-5um,12nm，流动相A：H2O(0.1％FA)，流动相B:CH3CN，梯度：在2min，20％ B，在2-18min内20-95％ B，38min内保持至95％ B，最后停止；检测波长:254nm/220nm，流速：17mL/min，柱温25℃)纯化得到消旋体(120mg,收率34.0％，白色固体)，再经过SFC(Opti-Chiral IDB,250*21.2mm,5μm；流动相A：CO2，流动相B：0.1％NH3·H2O in MeOH；流速：40mL/min；梯度：在4min内15％ B至35％ B,20min内保持至35％B，最后在2min降至20％B；检测波长254nm,220nm，柱温40℃)拆分得到目标产物P1(41.77mg,收率12.3％，白色固体)，LC-MS(方法E)：RT＝1.645min，(ESI)m/z:487.3[M+H]+。SFC(方法N)RT＝2.891min。1H NMR(400MHz,CDCl3)δ7.80(d,J＝2.4Hz,1H),6.99(d,J＝2.2Hz,1H),6.30(s,1H),4.57(s,2H),3.93–3.79(m,2H),3.73–3.52(m,3H),3.31–3.20(m,1H),3.13–2.93(m,2H),2.22–2.04(m,6H),2.03–1.92(m,1H),1.88–1.76(m,1H),1.03(d,J＝6.2Hz,3H).；To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methylpiperidine-4-carbonitrile (400 mg, 0.701 mmol) in DCM (20 mL) was added TFA (4 mL) and the reaction mixture was stirred at room temperature for 16 hrs. The product was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Triart C18, 250×20.0 mml.D., S-5 μm, 12 nm; mobile phase A: H 2 O (0.1% FA), mobile phase B: CH 3 CN; gradient: 20% B in 2 min, 20-95% B in 2-18 min, hold at 95% B in 38 min, and then stop; detection wavelength: 254 nm/220 nm; flow rate: 17 mL/min; column temperature: 25°C) to give a racemate (120 mg, yield 34.0%, white solid). The product was then purified by SFC (Opti-Chiral IDB, 250*21.2 mm, 5 μm; mobile phase A: CO 2 , mobile phase B: 0.1% NH 3 ·H 2 O in MeOH; flow rate: 40 mL/min; gradient: 15% B to 35% B in 4 min. The target product P1 (41.77 mg, 12.3% yield, white solid) was obtained by separation using a 5-well column (HPLC) with 1% 4% B (maintained at 35% B over 20 minutes and finally reduced to 20% B over 2 minutes; detection wavelengths: 254 nm, 220 nm, column temperature: 40°C). LC-MS (Method E): RT = 1.645 min, (ESI) m/z: 487.3 [M+H] + . SFC (Method N): RT = 2.891 min. 1 H NMR (400MHz, CDCl 3 )δ7.80(d,J＝2.4Hz,1H),6.99(d,J＝2.2Hz,1H),6.30(s,1H),4.57(s,2H),3.93–3.79(m,2H),3.73–3.52(m,3H),3.3 1–3.20(m,1H),3.13–2.93(m,2H),2.22–2.04(m,6H),2.03–1.92(m,1H),1.88–1.76(m,1H),1.03(d,J＝6.2Hz,3H).;

和目标产物P2(10.01mg,收率2.94％，白色固体)。LC-MS(方法E)：RT＝1.642min，(ESI)m/z:487.2[M+H]+。SFC(方法N)RT＝3.111min。1H NMR(400MHz,CDCl3)δ7.82–7.69(m,1H),7.03–6.90(m,1H),6.28(s,1H),4.53(s,2H),3.95–3.77(m,2H),3.74–3.61(m,2H),3.46–3.32(m,1H),3.27–3.12(m,1H),2.74–2.53(m,2H),2.24–2.06(m,7H),1.89–1.74(m,1H),1.08(d,J＝6.2Hz,3H).The target product P2 (10.01 mg, 2.94% yield, white solid) was obtained. LC-MS (Method E): RT = 1.642 min, (ESI) m/z: 487.2 [M+H] + . SFC (Method N): RT = 3.111 min. 1 H NMR (400MHz, CDCl 3 )δ7.82–7.69(m,1H),7.03–6.90(m,1H),6.28(s,1H),4.53(s,2H),3.95–3.77(m,2H),3.74–3.61(m,2H),3.46– 3.32(m,1H),3.27–3.12(m,1H),2.74–2.53(m,2H),2.24–2.06(m,7H),1.89–1.74(m,1H),1.08(d,J＝6.2Hz,3H).

实施例230和实施例231：(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲 基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺和(2S，4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8- 基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺
Example 230 and Example 231: (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-( trifluoromethyl )-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide and (2S,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8 -yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

步骤1：2-氯-N,6-二甲基异烟酰胺的合成
Step 1: Synthesis of 2-chloro-N,6-dimethylisonicotinamide

将2-氯-6-甲基吡啶-4-羧酸(5.00g,29.1mmol)溶于DMF(50.0mL)中，依次加入Et3N(20.2mL,145mmol)、HATU(22.0g,57.8mmol)和甲胺盐酸盐(9.80g,145mmol)。反应混合物在室温下搅拌16hrs，加入H2O(100mL)，用EA(100mL×3)萃取，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(DCM：MeOH＝20:1)得到目标化合物(4.00g,收率74.3％，黄色油状物)。LC-MS(ESI)m/z:185.0[M+H]+。2-Chloro-6-methylpyridine-4-carboxylic acid (5.00 g, 29.1 mmol) was dissolved in DMF (50.0 mL). Et₃N (20.2 mL, 145 mmol), HATU (22.0 g, 57.8 mmol), and methylamine hydrochloride (9.80 g, 145 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hrs. H₂O (100 mL) was added and extracted with EA (100 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound (4.00 g, 74.3% yield, yellow oil). LC-MS (ESI) m/z: 185.0 [M+H] ⁺ .

步骤2：N,2-二甲基哌啶-4-甲酰胺的合成
Step 2: Synthesis of N,2-dimethylpiperidine-4-carboxamide

将2-氯-N,6-二甲基异烟酰胺(4.00g,21.7mmol)溶于MeOH(50.0mL)中，依次加入PtO2(490mg,2.16mmol)和HCl(0.500mL)，在H2氛围中置换三次，反应混合物在室温下搅拌16hrs。过滤，滤液减压浓缩后得到目标化合物(4.20g,收率124％，无色油状物)。LC-MS(ESI)m/z:157.1[M+H]+。2-Chloro-N,6-dimethylisonicotinamide (4.00 g, 21.7 mmol) was dissolved in MeOH (50.0 mL). PtO₂ (490 mg, 2.16 mmol) and HCl (0.500 mL) were added sequentially. The atmosphere was replaced three times with H₂ . The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.20 g, 124% yield, colorless oil). LC-MS (ESI) m/z: 157.1 [M+H] ⁺ .

步骤3：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 3: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

将N,2-二甲基哌啶-4-甲酰胺(1.40g,8.96mmol)和8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.00g,4.542mmol)溶于干燥的DMF(20.0mL)，然后依次加入Cs2CO3(4.30g,13.2mmol)和RuphosPd G2(348g,448mmol)。反应混合物在N2氛围下130℃搅拌2hrs。冷却至室温，向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。减压除去溶剂，残余物经硅胶柱层析分离纯化(DCM：MeOH＝15:1)得到目标产物(800mg,收率19.1％，黄色固体)。LC-MS(ESI)m/z:469.1[M+H]+。N,2-Dimethylpiperidine-4-carboxamide (1.40 g, 8.96 mmol) and 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.00 g, 4.542 mmol) were dissolved in dry DMF (20.0 mL). Cs₂CO₃ ( 4.30 g, 13.2 mmol) and RuphosPdG₂ ( 348 g, 448 mmol) were then added sequentially. The reaction mixture was stirred at 130°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and EA, and extracted with EA (100 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the desired product (800 mg, yield 19.1%, yellow solid). LC-MS (ESI) m/z: 469.1 [M+H] + .

步骤4：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 4: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

将1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺(800mg,1.71mmol)溶于MeOH(5.00mL)中，加入4N HCl/二噁烷(5.00mL)，于50℃反应16hrs。冷却至室温，加入饱和NaHCO3水溶液调节pH值至7，用EA(20.0mL×3)萃取，合并有机相，用饱和食盐水(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤，减压浓缩，得到目标化合物(600mg,收率91.4％，粗品，黄色固体)。LC-MS(ESI)m/z:385.2[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide (800 mg, 1.71 mmol) was dissolved in MeOH (5.00 mL), and 4N HCl/dioxane (5.00 mL) was added. The mixture was reacted at 50°C for 16 hr. After cooling to room temperature, the pH was adjusted to 7 by adding saturated aqueous NaHCO₃ . The mixture was extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL × 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the title compound (600 mg , 91.4% yield, crude product, as a yellow solid). LC-MS(ESI)m/z:385.2[M+H] + .

步骤5：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 5: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺(600mg,1.56mmol)的DMF(10.0mL)溶液中加入KOH(260mg,4.63mmol)粉末，然后分批加入I2(800mg,1.80mmol)，反应混合物在室温下搅拌1hr，加入水，用EA(40.0mL×3)萃取，合并有机相，用饱和NaCl溶液(20.0mL×3)洗涤，用无水Na2SO4干燥，过滤，减压浓缩，经硅胶柱(DCM/MeOH＝15/1)层析分离纯化，得到目标化合物(400mg,收率50.2％，黄色固体)。LC-MS(ESI)m/z:511.1[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide (600 mg, 1.56 mmol) in DMF (10.0 mL) was added KOH (260 mg, 4.63 mmol) powder, and then I (800 mg, 1.80 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with EA (40.0 mL×3). The combined organic phases were washed with saturated NaCl solution (20.0 mL×3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (DCM/MeOH=15/1) to give the title compound (400 mg, yield 50.2%, yellow solid). LC-MS(ESI)m/z:511.1[M+H] + .

步骤6：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 6: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺(400mg,0.784mmol)的吡啶(10.0mL)溶液中加入1-(3,4,5,6-四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡唑(1.20g,4.31mmol)和醋酸铜(280mg,1.55mmol)，反应混合物在80℃搅拌反应16hrs，冷却至室温，反应混合物减压浓缩，残余物通过硅胶柱层析(DCM/EA＝15/1)分离纯化，得到目标化合物(200mg,收率38.6％，黄色固体)。LC-MS(ESI)m/z:611.3[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide (400 mg, 0.784 mmol) in pyridine (10.0 mL) were added 1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.20 g, 4.31 mmol) and copper acetate (280 mg, 1.55 mmol). The reaction mixture was stirred at 80° C. for 16 hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (DCM/EA=15/1) to give the title compound (200 mg, yield 38.6%) as a yellow solid. LC-MS(ESI)m/z:611.3[M+H] + .

步骤7：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 7: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

在N2保护下，在室温下，向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺(200mg,0.303mmol)的DMF(3.00mL)溶液加入(1,10-菲罗啉)(三氟甲基)铜(I)(284mg,0.910mmol)。反应混合物在微波中80℃下搅拌3hrs。反应混合物冷却到室温，加入H2O，用EA(10.0mL×3)萃取，合并有机相，用Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析(洗脱剂：0％-3％ MeOH/DCM)分离纯化，得到目标产物(50.0mg,27.4％，棕色固体)。LC-MS(ESI)m/z:615.0[M+H]+。Under N protection, to a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide (200 mg, 0.303 mmol) in DMF (3.00 mL) was added (1,10-phenanthroline)(trifluoromethyl)copper(I) (284 mg, 0.910 mmol) at room temperature. The reaction mixture was stirred at 80° C. in a microwave for 3 hrs. The reaction mixture was cooled to room temperature, H₂O was added, and the mixture was extracted with EA (10.0 mL x 3 ) . The organic phases were combined, dried over Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: 0%-3% MeOH/DCM) to obtain the desired product (50.0 mg, 27.4%, brown solid). LC-MS (ESI) m/z: 615.0 [M+H] ⁺ .

步骤8：(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺和(2R,4S)-1-(6-(-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺的合成
Step 8: Synthesis of (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide and (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide

在室温下，向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N,2-二甲基哌啶-4-甲酰胺(50.0mg,0.0830mmol)的DCM(3.00mL)溶液中滴加TFA(3.00mL)。然后反应混合物在室温下搅拌16hrs。加入H2O，用EA(10.0mL×3)萃取，合并有机相，用Na2SO4干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(Triart C18,250*20.0mml.D.,S-5um,12nm，流动相A：H2O(10mmol NH4HCO3)，流动相B:CH3CN，梯度：在2min，17-20％ B，在2-6min内20-60％ B，在6-23min内60-95％ B，38min内保持至95％ B，最后停止；检测波长:254nm/220nm，流速：17mL/min，柱温25℃)纯化，得到消旋体(8.00mg,收率18.52％，白色固体的)，用SFC拆分(Opti-Chiral IDB,250*21.2mm,5μm；流动相A：CO2，流动相B：0.1％NH3·H2O in MeOH；流速：40mL/min；梯度：20-40％B，柱温40℃)得到目标化合物P1(3.67mg,收率8.53％，白色固体)，LC-MS(方法C)：RT＝1.31min，(ESI)m/z:519.3[M+H]+。SFC(方法M)RT＝1.512min。1H NMR(400MHz,DMSO-d6)δ7.66(s,1H),6.26(s,1H),5.52(d,J＝4.6Hz,1H),4.47(s,2H),3.83–3.75(m,2H),3.61(d,J＝10.9Hz,2H),3.37–3.31(m,1H),3.04(s,1H),2.80(d,J＝4.7Hz,3H),2.51–2.45(m,1H),2.30–2.24(m,1H),2.11–2.06(m,2H),2.02(d,J＝12.3Hz,3H),1.87–1.80(m,2H),1.58–1.54(m,1H),0.98(d,J＝5.9Hz,3H).；To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N,2-dimethylpiperidine-4-carboxamide (50.0 mg, 0.0830 mmol) in DCM (3.00 mL) was added TFA (3.00 mL) dropwise at room temperature. The reaction mixture was then stirred at room temperature for 16 hrs. H2O was added, extracted with EA (10.0 mL×3), the organic phases were combined, dried over Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC ( Triart C18, 250*20.0 mml.D., S-5 μm, 12 nm, mobile phase A: H2O (10 mmol NH4HCO3 ), mobile phase B: CH3CN , gradient: 17-20% B in 2 min, 20-60% B in 2-6 min, 60-95% B in 6-23 min, maintained at 95% B in 38 min, and finally stopped; detection wavelength: 254 nm/220 nm, flow rate: 17 mL/min, column temperature 25°C) to give a racemate (8.00 mg, yield 18.52%, white solid), which was separated by SFC (Opti-Chiral IDB, 250*21.2mm, 5μm; mobile phase A: CO 2 , mobile phase B: 0.1% NH 3 ·H 2 O in MeOH; flow rate: 40mL/min; gradient: 20-40% B, column temperature 40°C) to obtain the target compound P1 (3.67mg, yield 8.53%, white solid). LC-MS (Method C): RT=1.31min, (ESI) m/z: 519.3[M+H] + . SFC (Method M) RT=1.512min. 1H NMR (400MHz, DMSO-d 6 )δ7.66(s,1H),6.26(s,1H),5.52(d,J＝4.6Hz,1H),4.47(s,2H),3.83–3.75( m,2H),3.61(d,J＝10.9Hz,2H),3.37–3.31(m,1H),3.04(s,1H),2.80(d,J＝4. 7Hz,3H),2.51–2.45(m,1H),2.30–2.24(m,1H),2.11–2.06(m,2H),2.02(d,J ＝12.3Hz,3H),1.87–1.80(m,2H),1.58–1.54(m,1H),0.98(d,J＝5.9Hz,3H).;

和P2(3.82mg,收率8.88％，白色固体)。LC-MS(方法C)：RT＝1.30min，(ESI)m/z:519.3[M+H]+。SFC(方法M)RT＝1.856min 1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),6.26(s,1H),5.53(d,J＝4.4Hz,1H),4.47(s,2H),3.83–3.75(m,2H),3.61(d,J＝10.9Hz,2H),3.37–3.31(m,1H),3.04(s,1H),2.79(d,J＝4.5Hz,3H),2.52–2.45(m,1H),2.31–2.24(m,1H),2.15–2.08(m,2H),2.01(d,J＝12.4Hz,3H),1.88–1.81(m,2H),1.55(d,J＝10.9Hz,1H),0.99(d,J＝5.9Hz,3H).and P2 (3.82 mg, yield 8.88%, white solid). LC-MS (Method C): RT = 1.30 min, (ESI) m/z: 519.3 [M+H] + . SFC (Method M) RT = 1.856 min 1 H NMR (400 MHz, DMSO-d 6 )δ7.69(s,1H),6.26(s,1H),5.53(d,J＝4.4Hz,1H),4.47(s,2H),3.83–3.75( m,2H),3.61(d,J＝10.9Hz,2H),3.37–3.31(m,1H),3.04(s,1H),2.79(d,J＝4.5 Hz,3H),2.52–2.45(m,1H),2.31–2.24(m,1H),2.15–2.08(m,2H),2.01(d,J＝1 2.4Hz,3H),1.88–1.81(m,2H),1.55(d,J＝10.9Hz,1H),0.99(d,J＝5.9Hz,3H).

实施例232和实施例233：6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-((3R)-3-甲基四氢-2H-吡喃-4-基)-1-(1H- 吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈和6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-4-((3S)-3-甲基四氢-2H-吡 喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-腈
Example 232 and Example 233: 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((3R)-3-methyltetrahydro-2H-pyran-4-yl)-1-(1H -pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile and 6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((3S)-3-methyltetrahydro-2H - pyran -4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

步骤1：4-甲基-N’-(3-甲基四氢-4H-吡喃-4-亚基)苯磺酰肼的合成
Step 1: Synthesis of 4-methyl-N'-(3-methyltetrahydro-4H-pyran-4-ylidene)benzenesulfonylhydrazide

将对甲基苯磺酰肼(1.00g,8.76mmol)溶于干燥的MeOH(40mL)中，然后加入3-甲基四氢-4H-吡喃-4-酮(1.63g,8.76mmol)。反应混合物在N2保护下室温搅拌16hrs。向反应混合物中加入水和EA稀释，用EA(30mL×3)萃取，合并有机相用，饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝5：1)，得到目标化合物(2.0g,收率80.97％，白色固体)。LC-MS(ESI)m/z:283.1[M+H]+。Dissolve p-Toluenesulfonylhydrazide (1.00 g, 8.76 mmol) in dry MeOH (40 mL), then add 3-methyltetrahydro-4H-pyran-4-one (1.63 g, 8.76 mmol). The reaction mixture was stirred at room temperature for 16 hours under N₂ protection. Dilute the reaction mixture with water and EA, then extract with EA (30 mL x 3). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound (2.0 g, 80.97% yield, as a white solid). LC-MS (ESI) m/z: 283.1 [M+H] ⁺ .

步骤2：8-(4-(3-甲基-3,6-二氢-2H-吡喃-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(3-methyl-3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(2.34g,5.31mmol)和4-甲基-N’-(3-甲基四氢-4H-吡喃-4-亚基)苯磺酰肼(1.50g,5.31mmol)溶于1,4-二氧六环(25.0mL)中，然后依次加入叔丁基锂(1.06g,13.3mmol)和Pd(dppf)Cl2(190mg,0.26mmol)。反应混合物在N2保护下110℃搅拌16hrs。冷却至室温，向反应混合物中加入水和EA稀释，用EA(100mL×3)萃取。合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。减压除去溶剂，得到目标化合物(粗品，580mg,收率26.6％，黄色油状物)。LC-MS(ESI)m/z:411.4[M+H]+。8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.34 g, 5.31 mmol) and 4-methyl-N'-(3-methyltetrahydro-4H-pyran-4-ylidene)benzenesulfonylhydrazide (1.50 g, 5.31 mmol) were dissolved in 1,4-dioxane (25.0 mL). Tert-butyl lithium (1.06 g, 13.3 mmol) and Pd(dppf) Cl₂ (190 mg, 0.26 mmol) were then added sequentially. The reaction mixture was stirred at 110°C under N₂ protection for 16 hr. After cooling to room temperature, the reaction mixture was diluted with water and EA, and extracted with EA (100 mL x 3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous Na 2 SO 4 , and filtered. The solvent was removed under reduced pressure to obtain the target compound (crude product, 580 mg, yield 26.6%, yellow oil). LC-MS (ESI) m/z: 411.4 [M+H] + .

步骤3：8-(4-(3-甲基四氢-2H-吡喃-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3-甲基-3,6-二氢-2H-吡喃-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(400.00mg,0.97mmol)溶于干燥的MeOH(10mL)，然后加入Pd/C(518.46mg,4.87mmol，10％wt)。在H2氛围下置换三次，然后混合物在H2氛围下27℃搅拌2hrs，过滤，减压除去溶剂，得到目标化合物(200mg,收率49.76％，白色油状液体)。LC-MS(ESI)m/z:413.12[M+H]+。8-(4-(3-methyl-3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400.00 mg, 0.97 mmol) was dissolved in dry MeOH (10 mL), followed by the addition of Pd/C (518.46 mg, 4.87 mmol, 10% wt). The mixture was then purged three times under a H₂ atmosphere, stirred at 27°C under a H₂ atmosphere for 2 hr, filtered, and the solvent removed under reduced pressure to yield the title compound (200 mg, 49.76% yield, white oily liquid). LC-MS (ESI) m/z: 413.12 [M+H] ⁺ .

步骤4：8-(4-(3-甲基四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3-甲基四氢-2H-吡喃-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(200mg,0.48mmol)溶于MeOH(10mL)中，加入4N HCl/二噁烷溶液(5mL)，反应混合物在N2保护下50℃搅拌16hrs。冷却至室温，减压除去溶剂，残余物中加入饱和NaHCO3水溶液，用DCM(100mL×2)萃取，合并有机相，用饱和NaHCO3(100mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(150mg,收率88.24％，黄色固体)，直接用于下一步。LC-MS(ESI)m/z:329.1[M+H]+。8-(4-(3-Methyltetrahydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (200 mg, 0.48 mmol) was dissolved in MeOH (10 mL), and 4N HCl/dioxane solution (5 mL) was added. The reaction mixture was stirred at 50°C under N₂ protection for 16 hr. After cooling to room temperature, the solvent was removed under reduced pressure, and saturated aqueous NaHCO₃ was added to the residue, which was extracted with DCM (100 mL × 2). The combined organic phases were washed with saturated NaHCO₃ (100 mL × 2) , dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (150 mg, 88.24% yield, yellow solid), which was used directly in the next step. LC-MS(ESI)m/z:329.1[M+H] + .

步骤5：8-(3-碘-4-(3-甲基四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(3-iodo-4-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-(3-甲基四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(150mg,0.45mmol)和KOH(51.25mg,0.91mmol)溶于DMF(5mL)中，再分批量缓慢加入I2(173.88mg,0.68mmol)。反应混合物在N2保护下25℃下搅拌1hrs。加入饱和Na2SO3水溶液淬灭反应，用EA(100mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1:4)得到目标化合物(150mg,收率72.29％，黄色固体)。LC-MS(ESI)m/z:455.31[M+H]+。8-(4-(3-Methyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (150 mg, 0.45 mmol) and KOH (51.25 mg, 0.91 mmol) were dissolved in DMF (5 mL), and I₂ (173.88 mg, 0.68 mmol) was slowly added portionwise. The reaction mixture was stirred at 25°C for 1 hr under N₂ protection. The reaction was quenched by addition of saturated aqueous Na₂SO₃ solution and extracted with EA (100 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to afford the title compound (150 mg, 72.29% yield, as a yellow solid). LC-MS(ESI)m/z:455.31[M+H] + .

步骤6：8-(3-碘-4-(3-甲基四氢-2H-吡喃-4-基)-1(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷
Step 6: 8-(3-iodo-4-(3-methyltetrahydro-2H-pyran-4-yl)-1(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-(3-甲基四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(150mg,0.33mmol)、1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(918.40mg,3.30mmol)、醋酸铜(197.76mg,0.99mmol)依次加入到吡啶(10mL)中。反应混合物在空气氛围下80℃搅拌16hrs。向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相用饱和食盐水(20mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA，0～15％EA)，得到目标化合物(150mg,收率75.16％，黄色固体)。LC-MS(ESI)m/z:605.51[M+H]+。8-(3-iodo-4-(3-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (150 mg, 0.33 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (918.40 mg, 3.30 mmol), and copper acetate (197.76 mg, 0.99 mmol) were added sequentially to pyridine (10 mL). The reaction mixture was stirred at 80°C under air atmosphere for 16 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (60 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0-15% EA) to obtain the title compound (150 mg, 75.16% yield, yellow solid). LC-MS (ESI) m/z: 605.51 [M+H] + .

步骤7：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基四氢-2H-吡喃-4-基)-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
Step 7: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methyltetrahydro-2H-pyran-4-yl)-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将8-(3-碘-4-(3-甲基四氢-2H-吡喃-4-基)-1(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(30mg,0.05mmol)、锌粉(28.35mg,0.15mmol)、氰化锌(17.48mg,0.15mmol)、Pd2(dba)3(9.09mg,0.01mmol)、Pd(dppf)Cl2(3.63mg,0.005mmol)依次加入到DMA(5mL)中。反应混合物在N2保护下100℃搅拌1hr。冷却至室温，向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相，用饱和食盐水(20mL×5)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩得到粗产品(20mg,收率80.02％，黄色油状液体)，直接用于下一步。LC-MS(ESI)m/z:504.71[M+H]+。8-(3-iodo-4-(3-methyltetrahydro-2H-pyran-4-yl)-1(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (30 mg, 0.05 mmol), zinc powder (28.35 mg, 0.15 mmol), zinc cyanide (17.48 mg, 0.15 mmol), Pd2 (dba) 3 (9.09 mg, 0.01 mmol), and Pd(dppf) Cl2 (3.63 mg, 0.005 mmol) were added sequentially to DMA (5 mL). The reaction mixture was stirred at 100°C for 1 hr under N2 protection. After cooling to room temperature, water (60 mL) was added to the reaction mixture, which was then extracted with EA (60 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 5), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to give the crude product (20 mg, 80.02% yield, yellow oily liquid), which was used directly in the next step. LC-MS (ESI) m/z: 504.71 [M+H] + .

步骤8：6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
Step 8: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

将6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基四氢-2H-吡喃-4-基)-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈(20mg,0.04mmol)溶于DCM(5mL)中，加入TFA(5mL)。反应混合物在25℃下搅拌16hrs。反应混合物减压浓缩，残留物中加入饱和Na2CO3水溶液(50mL)，用DCM(50mL×2)萃取，合并有机相，用饱和Na2CO3水溶液(50mL×2)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，再经Prep-HPLC(柱：Triart c18250*20.0mm.d,S-5um，12nm；流动相A：10mmolNH4CO3/水，流动相B：CH3CN；梯度：48-73％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(8mg,收率48.33％，白色固体)。LC-MS(ESI)m/z:420.2[M+H]+。6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methyltetrahydro-2H-pyran-4-yl)-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (20 mg, 0.04 mmol) was dissolved in DCM (5 mL), and TFA (5 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous Na₂CO₃ ( 50 mL) was added to the residue. The mixture was extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated aqueous Na₂CO₃ (50 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 75% EA), followed by Prep-HPLC (column: Triart c18250*20.0 mm.d, S-5 μm, 12 nm; mobile phase A: 10 mmol NH 4 CO 3 /water, mobile phase B: CH 3 CN; gradient: 48-73% B, detection wavelength at 214 nm, flow rate: 20 mL/min, column temperature at 25°C) to obtain the title compound (8 mg, 48.33% yield, white solid). LC-MS (ESI) m/z: 420.2 [M+H] + .

步骤9：6-(-3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((3R)3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈；和6-(-3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-((3S)3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
Step 9: Synthesis of 6-(-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((3R)3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile; and 6-(-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-((3S)3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

6-(3-氧杂-8-氮杂双环[3.2.1]辛-8-基)-4-(3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-3-甲腈(8mg,0.19mmol)经过手性拆分SFC(column：Opti-chiral A1-3 100*4.6mm,3um，流动相A:Supercritical CO2；流动相B：MeOH，流速：40mL/min)，得到目标化合物P1(3mg,收率37.50％，白色固体)，LC-MS(方法C)：RT＝1.49min，(ESI)m/z:420.2[M+H]+。SFC(方法O)RT＝2.967min。1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.04(s,1H),6.33(s,1H),4.55(s,2H),4.14–4.06(m,1H),3.92–3.69(m,6H),3.68–3.54(m,3H),2.29–2.20(m,2H),2.12(d,J＝4.9Hz,2H),2.08–2.03(m,2H),0.81(s,3H).；和目标化合物P2(2.5mg,收率31.25％，白色固体)。LC-MS(方法C)：RT＝1.50min，(ESI)m/z:420.2[M+H]+。SFC(方法O)RT＝3.313min。1H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.02(s,1H),6.33(s,1H),4.55(s,2H),4.15–4.06(m,1H),3.94–3.70(m,6H),3.69–3.53(m,3H),2.32–2.20(m,2H),2.16–2.11(m,2H),2.06–2.02(m,2H),0.82(d,J＝7.0Hz,3H).Chiral separation of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (8 mg, 0.19 mmol) by SFC (column: Opti-chiral A1-3 100*4.6 mm, 3 μm, mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH, flow rate: 40 mL/min) afforded the title compound P1 (3 mg, 37.50% yield, white solid). LC-MS (Method C): RT = 1.49 min, (ESI) m/z: 420.2 [M+H] + . SFC (Method O) RT = 2.967 min. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.04 (s, 1H), 6.33 (s, 1H), 4.55 (s, 2H), 4.14–4.06 (m, 1H), 3.92–3.69 (m, 6H), 3.68–3.54 (m, 3H), 2.29–2.20 (m, 2H), 2.12 (d, J = 4.9 Hz, 2H), 2.08–2.03 (m, 2H), 0.81 (s, 3H); and the target compound P2 (2.5 mg, yield 31.25%), white solid. LC-MS (Method C): RT = 1.50 min, (ESI) m/z: 420.2 [M+H] + . SFC (Method O) RT = 3.313 min. 1 H NMR(400MHz,Chloroform-d)δ7.83(s,1H),7.02(s,1H),6.33(s,1H),4.55(s,2H),4.15–4.06(m,1H),3.94–3. 70(m,6H),3.69–3.53(m,3H),2.32–2.20(m,2H),2.16–2.11(m,2H),2.06–2.02(m,2H),0.82(d,J＝7.0Hz,3H).

实施例234和实施例235：8-(4-((3R)-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并 [3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷和8-(4-((3S)-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3- 基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 234 and Example 235: 8-(4-((3R)-3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((3S)-3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3- yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-(-3-甲基四氢-2H-吡喃-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在微波管中，将8-(3-碘-4-(3-甲基四氢-2H-吡喃-4-基)-1(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(100mg,0.17mmol)溶于DMF(5mL)，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(152mg,0.5mmol)，向微波管中鼓N23mins，反应液在微波下80℃下搅拌6hrs。冷却至室温，向反应混合物中加入水(20mL)，用EA(40mL×2)萃取，合并有机相，用水(80mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向硅胶柱层析分离纯化(H2O：CH3CN，90％CH3CN)，得到目标化合物(25mg,收率27.65％，黄色固体)。LC-MS(ESI)m/z:547.2[M+H]+。In a microwave tube, 8-(3-iodo-4-(3-methyltetrahydro-2H-pyran-4-yl)-1(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (100 mg, 0.17 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (152 mg, 0.5 mmol) was added. N2 was bubbled into the microwave tube for 3 mins, and the reaction solution was stirred at 80°C under microwave for 6 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (40 mL × 2). The combined organic phases were washed with water (80 mL × 5), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H 2 O:CH 3 CN, 90% CH 3 CN) to obtain the title compound (25 mg, 27.65% yield, yellow solid). LC-MS (ESI) m/z: 547.2 [M+H] + .

步骤2：8-(4-(-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(-3-甲基四氢-2H-吡喃-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(25mg,0.05mmol)的DCM(5mL)溶液中，加入TFA(5mL)。反应混合物在25℃下搅拌16hrs，减压浓缩，残留物中加入饱和Na2CO3(50mL)水溶液，用DCM(50mL×2)萃取，合并有机相，用饱和Na2CO3(50mL×2)水溶液洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，再经Prep-HPLC(柱：Triart c18250*20.0mm.d,S-5um，12nm；流动相A：10mmolNH4CO3/水，流动相B：CH3CN；梯度：48-73％B，检测波长214nm，流速：20mL/min，柱温25℃)分离纯化，得到目标化合物(8mg,收率38.09％，白色固体)。LC-MS(ESI)m/z:463.4[M+H]+。To a solution of 8-(4-(3-methyltetrahydro-2H-pyran-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (25 mg, 0.05 mmol) in DCM (5 mL) was added TFA ( 5 mL). The reaction mixture was stirred at 25°C for 16 hrs and concentrated under reduced pressure. Saturated aqueous Na₂CO₃ (50 mL) was added to the residue, and the mixture was extracted with DCM (50 mL × 2). The combined organic phases were washed with saturated aqueous Na₂CO₃ (50 mL × 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA, 75% EA), followed by Prep-HPLC (column: Triart c18250*20.0 mm.d, S-5 μm, 12 nm; mobile phase A: 10 mmol NH 4 CO 3 /water, mobile phase B: CH 3 CN; gradient: 48-73% B, detection wavelength at 214 nm, flow rate: 20 mL/min, column temperature at 25°C) to obtain the title compound (8 mg, yield 38.09%), as a white solid. LC-MS (ESI) m/z: 463.4 [M+H] + .

步骤3：8-(4-((3S)-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷和8-(4-((3R)-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 3: Synthesis of 8-(4-((3S)-3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((3R)-3-methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

8-(4-(-3-甲基四氢-2H-吡喃-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(8mg,0.017mmol)经过SFC(column：Opti-chiral IDB-3 100*4.6mm,3um，流动相A：Supercritical CO2；流动相B:MeOH，流速：40mL/min)拆分，得到目标化合物P1(2.3mg,收率28.75％，白色固体)，LC-MS(方法C)：RT＝1.49min，(ESI)m/z:463.4[M+H]+。SFC(方法O)RT＝2.967min。1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.90(s,1H),6.31(s,1H),4.50(s,2H),4.15–4.03(m,1H),3.81–3.75(m,3H),3.72–3.67(m,1H),3.64–3.59(m,3H),3.55–3.47(m,2H),2.31–2.17(m,1H),2.14–2.06(m,2H),2.07–1.96(m,3H),0.85(d,J＝7.1Hz,3H).；8-(4-(3-Methyltetrahydro-2H-pyran-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (8 mg, 0.017 mmol) was separated by SFC (column: Opti-chiral IDB-3 100*4.6 mm, 3 μm, mobile phase A: Supercritical CO 2 ; mobile phase B: MeOH, flow rate: 40 mL/min) to afford the title compound P1 (2.3 mg, yield 28.75%, white solid). LC-MS (Method C): RT = 1.49 min, (ESI) m/z: 463.4 [M+H] + . SFC (Method O) RT = 2.967 min. 1 H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.90(s,1H),6.31(s,1H),4.50(s,2H),4.15–4.03(m,1H),3.81–3.75(m,3H),3.72–3. 67(m,1H),3.64–3.59(m,3H),3.55–3.47(m,2H),2.31–2.17(m,1H),2.14–2.06(m,2H),2.07–1.96(m,3H),0.85(d,J＝7.1Hz,3H).;

和目标化合物P2(3.3mg,收率41.25％，白色固体)。LC-MS(方法C)：RT＝1.50min，(ESI)m/z:463.4[M+H]+。SFC(方法O)RT＝3.31min。1H NMR(400MHz,Chloroform-d)δ7.70(s,1H),6.93(s,1H),6.30(s,1H),4.50(s,2H),4.17–4.02(m,1H),3.84–3.74(m,3H),3.71–3.66(m,1H),3.64–3.58(m,3H),3.53–3.44(m,2H),2.30–2.16(m,1H),2.15–2.07(m,2H),2.05–1.96(m,3H),0.84(d,J＝7.1Hz,3H).The target compound P2 (3.3 mg, yield 41.25%, white solid) was obtained. LC-MS (Method C): RT = 1.50 min, (ESI) m/z: 463.4 [M+H] + . SFC (Method O) RT = 3.31 min. 1 H NMR(400MHz,Chloroform-d)δ7.70(s,1H),6.93(s,1H),6.30(s,1H),4.50(s,2H),4.17–4.02(m,1H),3.84–3.74(m,3H),3.71–3. 66(m,1H),3.64–3.58(m,3H),3.53–3.44(m,2H),2.30–2.16(m,1H),2.15–2.07(m,2H),2.05–1.96(m,3H),0.84(d,J＝7.1Hz,3H).

实施例236：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡 啶-4-基)-3-甲基硫代吗啉1,1-二氧化物
Example 236: 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin -4-yl)-3-methylthiomorpholine 1,1-dioxide

步骤1：3-甲基硫代吗啉的合成
Step 1: Synthesis of 3-methylthiomorpholine

在0℃下，将KOH(24.7g,440mmol)溶于MeOH(400mL)中，分批加入2-氨基乙烷-1-硫醇盐酸盐(20.0g,176mmol)，然后缓慢加入1-氯-2-丙酮(17.9g,193mmol)的甲醇(100mL)溶液。滴加完毕，反应混合物在0℃下搅拌90mins后，加入8NHCl/MeOH溶液(75mL)酸化并搅拌1hr，然后分批加入NaBH4(13.3g,0.35mol)，反应混合物继续搅拌30mins，用4NHCl淬灭反应，减压浓缩，残留物用DCM(50mL×3)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩得到目标产物(3.40g,收率16.5％，黄色液体)，直接用于下一步。KOH (24.7 g, 440 mmol) was dissolved in MeOH (400 mL) at 0°C, and 2-aminoethane-1-thiol hydrochloride (20.0 g, 176 mmol) was added portionwise. Then, a solution of 1-chloro-2-propanone (17.9 g, 193 mmol) in methanol (100 mL) was slowly added. After the addition was complete, the reaction mixture was stirred at 0°C for 90 min. Then, 8N HCl/MeOH solution (75 mL) was added to acidify the mixture and stirred for 1 hr. NaBH₄ (13.3 g, 0.35 mol) was then added portionwise. The reaction mixture was stirred for an additional 30 min. The reaction was quenched with 4N HCl and concentrated under reduced pressure. The residue was extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the desired product (3.40 g, 16.5% yield, yellow liquid), which was used directly in the next step.

步骤2：3-甲硫基吗啉-4-羧酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 3-methylthiomorpholine-4-carboxylate

将3-甲基硫代吗啉(3.40g,29.0mmol)溶于MeOH(20mL)中，加入Et3N(8mL)、二碳酸二叔丁酯(6.96g,31.9mmol)，反应混合物在25℃下搅拌过夜。减压除去溶剂，加入饱和NH4Cl溶液(50mL)，用DCM(100mL×2)萃取，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，20％EA)得到目标化合物(3.50g,收率55.5％，无色液体)。3-Methylthiomorpholine (3.40 g, 29.0 mmol) was dissolved in MeOH (20 mL), and Et 3 N (8 mL) and di-tert-butyl dicarbonate (6.96 g, 31.9 mmol) were added. The reaction mixture was stirred at 25°C overnight. The solvent was removed under reduced pressure, and saturated NH 4 Cl solution (50 mL) was added. The mixture was extracted with DCM (100 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 20% EA) to obtain the title compound (3.50 g, yield 55.5%, colorless liquid).

步骤3：3-甲硫基吗啉-4-羧酸叔丁酯1,1-二氧化物的合成
Step 3: Synthesis of tert-butyl 3-methylthiomorpholine-4-carboxylate 1,1-dioxide

向3-甲硫基吗啉-4-羧酸叔丁酯(3.20g,14.7mmol)的DCM(60mL)溶液中，加入间氯过氧苯甲酸(10.1g,58.8mmol)，反应混合物在25℃下搅拌2hrs。加入饱和Na2S2O3水溶液(50mL)，用DCM(100mL×2)萃取，合并有机相，用饱和Na2S2O3水溶液(100mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到目标化合物(2.76g,收率75.1％，白色固体)。To a solution of tert-butyl 3-methylthiomorpholine-4-carboxylate (3.20 g, 14.7 mmol) in DCM (60 mL) was added m - chloroperbenzoic acid (10.1 g, 58.8 mmol). The reaction mixture was stirred at 25 °C for 2 hours. Saturated aqueous Na₂S₂O₃ (50 mL) was added, and the mixture was extracted with DCM (100 mL x 2) . The combined organic phases were washed with saturated aqueous Na₂S₂O₃ (100 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (2.76 g, 75.1% yield, as a white solid).

步骤4：3-甲基硫代吗啉1,1-二氧化物的合成
Step 4: Synthesis of 3-methylthiomorpholine 1,1-dioxide

向3-甲硫基吗啉-4-羧酸叔丁酯1,1-二氧化物(2.76g,11.1mmol)的DCM(20mL)溶液中，加入TFA(10mL)，反应混合物在25℃下搅拌8hrs，然后减压浓缩得到目标化合物(1.48g,收率89.6％，淡黄色固体)。To a solution of tert-butyl 3-methylthiomorpholine-4-carboxylate 1,1-dioxide (2.76 g, 11.1 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at 25°C for 8 hrs and then concentrated under reduced pressure to give the title compound (1.48 g, yield 89.6%, light yellow solid).

步骤5：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉-1,1-二氧化物的合成
Step 5: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine-1,1-dioxide

将3-甲基硫代吗啉1,1-二氧化物(1.40g,9.38mmol)和8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(4.96g,11.2mmol)溶于干燥的DMF(30mL)，再依次加入Cs2CO3(6.11g,18.7mmol)和RuPhos Pd G2(0.360g,0.469mmol)。反应混合物在N2保护下130℃搅拌2hrs，冷却至室温，向反应混合物中加入水(100mL)和EA(50mL)稀释，用EA(50mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。减压除去溶剂，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(750mg,收率17.3％，黄色固体)。LC-MS(ESI)m/z:462.2[M+H]+。3-Methylthiomorpholine 1,1-dioxide (1.40 g, 9.38 mmol) and 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (4.96 g, 11.2 mmol) were dissolved in dry DMF (30 mL). Cs 2 CO 3 (6.11 g, 18.7 mmol) and RuPhos Pd G 2 (0.360 g, 0.469 mmol) were then added sequentially. The reaction mixture was stirred at 130°C for 2 hrs under N 2 protection, cooled to room temperature, diluted with water (100 mL) and EA (50 mL), and extracted with EA (50 mL x 2). The organic phases were combined, washed three times with saturated brine, dried over anhydrous Na 2 SO 4 , and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (750 mg, yield 17.3%, yellow solid). LC-MS (ESI) m/z: 462.2 [M+H] + .

步骤6：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲硫基吗啉1,1-二氧化物的合成
Step 6: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide

向4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉-1,1-二氧化物(750mg,1.62mmol)的MeOH(20mL)溶液中，加入4NHCl/二噁烷(10mL)，反应混合物在N2保护下50℃搅拌4hrs。减压除去溶剂，残余物中加入饱和Na2CO3(100mL)水溶液淬灭，用DCM(100mL×2)萃取，合并有机相，用饱和Na2CO3水溶液(100mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩得到目标化合物(500mg,收率81.5％，黄色固体)。LC-MS(ESI)m/z:378.1[M+H]+。To a solution of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine-1,1-dioxide (750 mg, 1.62 mmol) in MeOH (20 mL) was added 4N HCl/dioxane (10 mL). The reaction mixture was stirred at 50°C under N₂ protection for 4 hrs. The solvent was removed under reduced pressure, and the residue was quenched with saturated aqueous Na₂CO₃ (100 mL) and extracted with DCM (100 mL x 2). The combined organic phases were washed with saturated aqueous Na₂CO₃ (100 mL), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the title compound (500 mg, 81.5% yield, as a yellow solid). LC-MS(ESI)m/z:378.1[M+H] + .

步骤7：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲硫基吗啉1,1-二氧化物的合成
Step 7: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide

将4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲硫基吗啉1,1-二氧化物(500mg,1.32mmol)和KOH(223mg,3.97mmol)溶解于DMF(20mL)中，再在1hr内分批量缓慢加入I2(672mg,2.65mmol)。在N2保护下，反应液在25℃下搅拌3hrs。加入饱和Na2SO3水溶液(50mL)，用EA(75mL×2)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)得到目标化合物(600mg,收率89.9％，黄色油状液体)。LC-MS(ESI)m/z:504.1[M+H]+。4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide (500 mg, 1.32 mmol) and KOH (223 mg, 3.97 mmol) were dissolved in DMF (20 mL). I 2 (672 mg, 2.65 mmol) was then slowly added portionwise over 1 hr. Under N 2 protection, the reaction solution was stirred at 25°C for 3 hrs. Saturated aqueous Na₂SO₃ (50 mL) was added, and the mixture was extracted with EA (75 mL × 2). The combined organic phases were washed twice with saturated brine (100 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to obtain the title compound (600 mg, 89.9% yield, yellow oily liquid). LC-MS (ESI) m/z: 504.1 [M+H] + .

步骤8：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉-1,1-二氧化物的合成
Step 8: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine-1,1-dioxide

向4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲硫基吗啉1,1-二氧化物(600mg,1.19mmol)的吡啶(10.0mL)溶液中加入1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(1.65g,5.96mmol)和醋酸铜(0.433g,2.38mmol)，反应混合物在80℃下搅拌反应过夜，冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(PE/EA，0％～100％EA)得到目标化合物(700mg,收率89.8％，黄色固体)。LC-MS(ESI)m/z:654.2[M+H]+。To a solution of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide (600 mg, 1.19 mmol) in pyridine (10.0 mL) were added 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.65 g, 5.96 mmol) and cupric acetate (0.433 g, 2.38 mmol). The reaction mixture was stirred at 80°C overnight, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0% to 100% EA) to give the title compound (700 mg, yield 89.8%) as a yellow solid. LC-MS(ESI)m/z:654.2[M+H] + .

步骤9：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉1,1-二氧化物的合成
Step 9: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide

微波管中，将4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉-1,1-二氧化物(250mg,0.380mmol)溶于DMF(5mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(358mg,1.15mmol)，向微波管中鼓N2 3mins，反应混合物在微波下80℃下搅拌3hrs。冷却至室温，向反应混合物中加入水(20mL)，用EA(30mL×2)萃取，合并有机相，用饱和食盐水(20mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向柱层析分离纯化(H2O：CH3CN，90％CH3CN)得到目标化合物(50.0mg,收率21.9％，黄色固体)。LC-MS(方法A)：RT＝1.76min，(ESI)m/z:596.2[M+H]+。In a microwave tube, 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine-1,1-dioxide (250 mg, 0.380 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (358 mg, 1.15 mmol) was added. N2 was bubbled into the microwave tube for 3 mins, and the reaction mixture was stirred at 80°C under microwave for 3 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 5 ), dried over anhydrous Na₂SO₄ , and concentrated under reduced pressure. The residue was separated and purified by reverse-phase column chromatography ( H₂O : CH₃CN , 90% CH₃CN ) to afford the title compound (50.0 mg, 21.9% yield, yellow solid). LC-MS (Method A): RT = 1.76 min, (ESI) m/z: 596.2 [M+H] ⁺ .

步骤10：4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉1,1-二氧化物的合成
Step 10: Synthesis of 4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide

将4-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基硫代吗啉1,1-二氧化物(50.0mg,0.080mmol)溶于DCM(2mL)中，加入TFA(2mL)。反应混合物在25℃下搅拌16hrs，然后减压浓缩，加入DMF(2mL)，加入无水K2CO3调节pH值至7，过滤，然后用Prep-HPLC(YMC-Triart C18,250*20.0mml.D.,S-5um,12nm；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；流速：17mL/min，检测波长220nm,254nm，柱温25℃。)分离纯化，得到目标化合物(7.10mg,收率16.5％，白色固体)。LC-MS(方法C)：RT＝1.78min，(ESI)m/z:506.3[M+H]+。1H NMR(400MHz,CDCl3)δ7.75(s,1H),6.97(s,1H),6.37(s,1H),4.55(d,J＝11.1Hz,2H),3.91–3.81(m,3H),3.70(d,J＝11.0Hz,2H),3.61–3.54(m,1H),3.51–3.29(m,3H),3.23–3.17(m,1H),3.11–3.07(m,1H),2.25–2.15(m,2H),2.13–2.05(m,2H),1.15(d,J＝6.3Hz,3H).4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylthiomorpholine 1,1-dioxide (50.0 mg, 0.080 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at 25°C for 16 hours, then concentrated under reduced pressure. DMF (2 mL) was added, and the pH was adjusted to 7 with anhydrous K₂CO₃ . The mixture was filtered and then purified using Prep-HPLC (YMC-Triart C18, 250*20.0 mm L.D., S-5 μm, 12 nm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; flow rate: 17 mL/min, detection wavelengths: 220 nm, 254 nm, column temperature: 25°C) to obtain the title compound (7.10 mg, 16.5% yield, white solid). LC-MS (Method C): RT = 1.78 min, (ESI) m/z: 506.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.75(s,1H),6.97(s,1H),6.37(s,1H),4.55(d,J＝11.1Hz,2H),3.91–3.81(m,3H),3.70(d,J＝11.0Hz,2H),3.61–3.54(m, 1H),3.51–3.29(m,3H),3.23–3.17(m,1H),3.11–3.07(m,1H),2.25–2.15(m,2H),2.13–2.05(m,2H),1.15(d,J＝6.3Hz,3H).

实施例237和实施例238：8-(4-((R)-1-吗啉代乙基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6- 基)-3-氧杂-8-氮杂二环[3.2.1]辛烷和8-(4-((S)-1-吗啉代乙基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并 [3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 237 and Example 238: 8-(4-((R)-1-morpholinoethyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)-3-oxa-8-azabicyclo[3.2.1]octane and 8-(4-((S)-1-morpholinoethyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：8-(4-(1-吗啉代乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 1: Synthesis of 8-(4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

微波管中，将8-(3-碘-4-(1-吗啉代乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(350mg,0.560mmol)溶于DMF(5mL)，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(530mg,1.69mmol)，向微波管中鼓N23mins，反应混合物在微波下100℃下搅拌3hrs。冷却至室温，向反应混合物中加入水(50mL)，用EA(50mL×2)萃取，合并有机相，用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析(PE/EA，0％～100％EA)纯化得到目标化合物(127mg,收率40.0％，黄色液体)。LC-MS(ESI)m/z:562.3[M+H]+。In a microwave tube, 8-(3-iodo-4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (350 mg, 0.560 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (530 mg, 1.69 mmol) was added. N2 was bubbled into the microwave tube for 3 mins, and the reaction mixture was stirred at 100°C under microwave for 3 hrs. After cooling to room temperature, water (50 mL) was added to the reaction mixture, which was then extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0%-100% EA) to obtain the title compound (127 mg, 40.0% yield, yellow liquid). LC-MS (ESI) m/z: 562.3 [M+H] + .

步骤2：8-(4-(1-吗啉代乙基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 2: Synthesis of 8-(4-(1-morpholinoethyl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-(1-吗啉代乙基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(127mg,0.23mmol)的DCM(3mL)溶液中，加入TFA(3mL)，反应混合物在25℃下搅拌16hrs。然后加入饱和NaHCO3水溶液，调节pH值至7，有机层分离并浓缩，残余物用Prep-HPLC(YMC-Triart C18,250*20.0mml.D.,S-5um,12nm；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；流速：17mL/min，检测波长220nm/254nm，柱温25℃)分离纯化，再用SFC(Opti-Chiral IDB,250*21.2mm,5μm；流动相A：CO2，流动相B：0.1％NH3·H2O in MeOH；流速：40mL/min；检测波长254nm,220nm，柱温40℃)拆分，得到目标化合物P1(12.49mg,收率11.6％，白色固体)。LC-MS(方法C)：RT＝0.96min，(ESI)m/z:478.2[M+H]+，SFC(方法N)RT＝4.40min。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),7.90(d,J＝1.9Hz,1H),7.13(s,1H),6.80(d,J＝2.3Hz,1H),4.59(s,2H),3.92–3.57(m,10H),2.82–2.55(m,3H),2.07–1.92(m,4H),1.69–1.27(m,3H)；To a solution of 8-(4-(1-morpholinoethyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (127 mg, 0.23 mmol) in DCM (3 mL) was added TFA (3 mL) and the reaction mixture was stirred at 25 °C for 16 hrs. Saturated aqueous NaHCO₃ was then added to adjust the pH to 7. The organic layer was separated and concentrated, and the residue was separated and purified by Prep-HPLC (YMC-Triart C18, 250*20.0 mml.D., S-5 μm, 12 nm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; flow rate: 17 mL/min, detection wavelengths: 220 nm/254 nm, column temperature: 25°C), and then separated by SFC (Opti-Chiral IDB, 250*21.2 mm, 5 μm; mobile phase A: CO₂ , mobile phase B: 0.1% NH₃·H₂O in MeOH; flow rate: 40 mL/min; detection wavelengths: 254 nm, 220 nm, column temperature: 40°C) to obtain the target compound P1 (12.49 mg, yield: 11.6%, white solid). LC-MS (Method C): RT = 0.96 min, (ESI) m/z: 478.2 [M+H] + , SFC (Method N) RT = 4.40 min. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.08 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.13 (s, 1H), 6.80 (d, J = 2.3 Hz, 1H), 4.59 (s, 2H), 3.92–3.57 (m, 10H), 2.82–2.55 (m, 3H), 2.07–1.92 (m, 4H), 1.69–1.27 (m, 3H);

和目标化合物P2(12.65mg,收率11.7％，白色固体)。LC-MS(方法C)：RT＝0.95min，(ESI)m/z:478.2[M+H]+，SFC(方法N)RT＝4.85min。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),7.90(d,J＝1.9Hz,1H),7.13(s,1H),6.80(d,J＝2.3Hz,1H),4.59(s,2H),3.92–3.57(m,10H),2.82–2.55(m,3H),2.07–1.92(m,4H),1.69–1.27(m,3H).The target compound P2 (12.65 mg, 11.7% yield) was obtained as a white solid. LC-MS (Method C): RT = 0.95 min, (ESI) m/z: 478.2 [M+H] + , SFC (Method N) RT = 4.85 min. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.08 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.13 (s, 1H), 6.80 (d, J = 2.3 Hz, 1H), 4.59 (s, 2H), 3.92–3.57 (m, 10H), 2.82–2.55 (m, 3H), 2.07–1.92 (m, 4H), 1.69–1.27 (m, 3H).

实施例239和实施例240：(R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H- 吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺和(S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8- 基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺
Example 239 and Example 240: (R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H -pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine and (S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine

步骤1：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 1: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethane-1-amine

将1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)甲磺酸乙酯(900mg,2.06mmol)、2-甲氧基-N-甲基乙烷-1-胺(275.65mg,3.09mmol)溶于干燥的NMP(10mL)，然后加入KI(684.49mg,4.12mmol)、Et3N(417.25mg,4.12mmol)。反应混合物在N2保护下室温搅拌2hrs。然后向反应混合物中加入水和EA稀释，用EA(100mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA＝5：1)得到目标化合物(800mg,收率90.33％，白色固体)。LC-MS(ESI)m/z:430.20[M+H]+。Ethyl 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)methanesulfonate (900 mg, 2.06 mmol) and 2-methoxy-N-methylethan-1-amine (275.65 mg, 3.09 mmol) were dissolved in dry NMP (10 mL), followed by the addition of KI (684.49 mg, 4.12 mmol) and Et₃N (417.25 mg, 4.12 mmol). The reaction mixture was stirred at room temperature under N₂ protection for 2 hrs. The reaction mixture was then diluted with water and EA, extracted with EA (100 mL x 2), and the combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , and filtered. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA=5:1) to obtain the title compound (800 mg, yield 90.33%, white solid). LC-MS (ESI) m/z: 430.20 [M+H] + .

步骤2：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 2: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethane-1-amine

向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(800mg,1.86mmol)的MeOH(10mL)溶液中，加入浓盐酸(4M；HCl:679.01mg,18.62mmol)，然后反应混合物在N2保护下50℃搅拌16hrs。减压浓缩，残余物中加入饱和NaHCO3水溶液中和，用DCM(100mL×2)萃取，合并有机相，用饱和NaHCO3(100mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩得到粗产品(300mg,收率46.63％，黄色固体)，直接用于下一步。LC-MS(ESI)m/z:346.1[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (800 mg, 1.86 mmol) in MeOH (10 mL) was added concentrated hydrochloric acid (4 M; HCl: 679.01 mg, 18.62 mmol), and the reaction mixture was stirred at 50° C. for 16 hrs under N protection. The mixture was concentrated under reduced pressure, and saturated aqueous NaHCO₃ was added to the residue for neutralization. The mixture was extracted with DCM (100 mL × 2). The combined organic phases were washed with saturated NaHCO₃ (100 mL × 2), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure to give the crude product (300 mg, 46.63% yield, yellow solid), which was used directly in the next step. LC-MS (ESI) m/z: 346.1 [M+H] ⁺ .

步骤3：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 3: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethane-1-amine

将1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(300mg,0.87mmol)和KOH(48.73mg,0.87mmol)溶解于DMF(5mL)中，再分批量缓慢加入I2(330.63mg,1.30mmol)。在N2保护下，反应混合物在25℃下搅拌1hr。加入饱和Na2SO3水溶液，用EA(100mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA＝1:4)得到目标化合物(300mg,收率73.29％，黄色固体)。LC-MS(ESI)m/z:472.34[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (300 mg, 0.87 mmol) and KOH (48.73 mg, 0.87 mmol) were dissolved in DMF (5 mL), and I₂ (330.63 mg, 1.30 mmol) was slowly added portionwise. Under N₂ protection, the reaction mixture was stirred at 25°C for 1 hr. Saturated aqueous Na₂SO₃ was added, and the mixture was extracted with EA (100 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (300 mg, 73.29% yield, as a yellow solid). LC-MS(ESI)m/z:472.34[M+H] + .

步骤4：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 4: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethane-1-amine

将1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(300mg,0.64mmol)、1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(1.77g,6.36mmol)、醋酸铜(254.15mg,1.27mmol)依次加入到吡啶(10mL)中。反应液在空气氛围下80℃搅拌16hrs。向反应混合物中加入水(60mL)，用EA(60mL×2)萃取，合并有机相，用饱和食盐水(20mL×5)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，100％EA)，得到目标化合物(250mg,收率63.20％，黄色固体)。LC-MS(ESI)m/z:622.50[M+H]+。1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (300 mg, 0.64 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.77 g, 6.36 mmol), and copper acetate (254.15 mg, 1.27 mmol) were added sequentially to pyridine (10 mL). The reaction mixture was stirred at 80°C under air for 16 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (60 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 5), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 100% EA) to obtain the title compound (250 mg, 63.20% yield, yellow solid). LC-MS (ESI) m/z: 622.50 [M+H] + .

步骤5：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 5: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine

微波管中，将1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(250mg,0.40mmol)溶于DMF(5mL)，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(125.80mg,0.4mmol)，向微波管中鼓N23mins，反应混合物在微波下80℃下搅拌6hrs。冷却至室温，向反应混合物中加入水(20mL)，用EA(40mL×2)萃取，合并有机相，用水(80mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向硅胶柱层析分离纯化(H2O：CH3CN，90％CH3CN)，得到目标化合物(100mg,收率44.11％，黄色固体)。LC-MS(ESI)m/z:564.20[M+H]+。In a microwave tube, 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (250 mg, 0.40 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (125.80 mg, 0.4 mmol) was added. N2 was bubbled into the microwave tube for 3 mins, and the reaction mixture was stirred at 80°C under microwave for 6 hrs. After cooling to room temperature, water (20 mL) was added to the reaction mixture, which was then extracted with EA (40 mL × 2). The combined organic phases were washed with water (80 mL × 5), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H 2 O:CH 3 CN, 90% CH 3 CN) to obtain the title compound (100 mg, 44.11% yield, yellow solid). LC-MS (ESI) m/z: 564.20 [M+H] + .

步骤6：1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺的合成
Step 6: Synthesis of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine

向1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(100mg,0.05mmol)的DCM(5mL)溶液中，加入TFA(5mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残余物中加入饱和Na2CO3(50mL)水溶液，用DCM(50mL×2)萃取，合并有机相，用饱和Na2CO3(50mL×2)水溶液洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，再经Prep-HPLC(柱：Triart c18250*20.0mm.d,S-5um，12nm；流动相A：10mmolNH4HCO3/水，流动相B：CH3CN；梯度：0-95％B，检测波长214nm，流速：17mL/min，柱温25℃)分离纯化，得到目标化合物(50mg,收率38.09％，白色固体)。LC-MS(ESI)m/z:480.51[M+H]+。To a solution of 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (100 mg, 0.05 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and saturated aqueous Na₂CO₃ (50 mL) was added to the residue, followed by extraction with DCM (50 mL x 2). The combined organic phases were washed with saturated aqueous Na₂CO₃ (50 mL x 2), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA, 75% EA), followed by Prep-HPLC (column: Triart c18250*20.0 mm.d, S-5 μm, 12 nm; mobile phase A: 10 mmol NH 4 HCO 3 /water, mobile phase B: CH 3 CN; gradient: 0-95% B, detection wavelength at 214 nm, flow rate: 17 mL/min, column temperature at 25°C) to obtain the title compound (50 mg, yield 38.09%), as a white solid. LC-MS (ESI) m/z: 480.51 [M+H] + .

步骤7：(R)-1-(6-(3-氧杂-8-氮杂[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺和(S)-1-(6-(3-氧杂-8-氮杂[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺
Step 7: (R)-1-(6-(3-oxa-8-aza[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine and (S)-1-(6-(3-oxa-8-aza[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine

1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-N-(2-甲氧基乙基)-N-甲基乙烷-1-胺(50mg,0.017mmol)经过SFC拆分(Opti-chiral A1-3100*4.6mm,3um，流动相A：Supercritical CO2；流动相B：0.5％氨水/甲醇，流速：40mL/min，柱温：25℃)，得到目标化合物P1(14.43mg,收率28.86％，白色固体)，LC-MS(方法C)：RT＝1.49min，(ESI)m/z:480.51[M+H]+。SFC(方法P)：RT＝2.967min。1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),7.90(s,1H),7.07(s,1H),6.80(s,1H),4.57(s,2H),3.87–3.76(m,1H),3.72–3.53(m,5H),3.41(s,1H),3.18(s,3H),2.70–2.54(m,1H),2.40–2.31(m,1H),2.29(s,3H),2.05–1.91(m,4H),1.32(d,J＝4.9Hz,3H)；1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-N-(2-methoxyethyl)-N-methylethan-1-amine (50 mg, 0.017 mmol) was separated by SFC (Opti-chiral A1-3100*4.6 mm, 3 um, mobile phase A: Supercritical CO 2 ; mobile phase B: 0.5% ammonia/methanol, flow rate: 40 mL/min, column temperature: 25°C) to give the title compound P1 (14.43 mg, yield 28.86%, white solid). LC-MS (Method C): RT = 1.49 min, (ESI) m/z: 480.51 [M+H] + . SFC (Method P): RT=2.967min. 1 H NMR (400MHz, DMSO-d 6 )δ13.05(s,1H),7.90(s,1H),7.07(s,1H),6.80(s,1H),4.57(s,2H),3.87–3.76(m,1H),3.72–3.53(m,5H),3.41( s,1H),3.18(s,3H),2.70–2.54(m,1H),2.40–2.31(m,1H),2.29(s,3H),2.05–1.91(m,4H),1.32(d,J＝4.9Hz,3H);

和目标化合物P2(13.15mg,收率26.30％，白色固体)。LC-MS(方法C)：RT＝1.50min，(ESI)m/z:480.51[M+H]+。SFC(方法P)：RT＝3.31min。1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),7.90(s,1H),7.07(s,1H),6.81(s,1H),4.57(s,2H),3.93–3.79(m,1H),3.70–3.58(m,5H),3.44–3.38(m,1H),3.18(s,3H),2.72–2.56(m,1H),2.39–2.30(m,1H),2.29(s,3H),2.05–1.92(m,4H),1.32(d,J＝6.0Hz,3H).The target compound P2 (13.15 mg, yield 26.30%, white solid) was obtained. LC-MS (Method C): RT = 1.50 min, (ESI) m/z: 480.51 [M+H] + . SFC (Method P): RT = 3.31 min. 1 H NMR (400MHz, DMSO-d 6 )δ13.05(s,1H),7.90(s,1H),7.07(s,1H),6.81(s,1H),4.57(s,2H),3.93–3.79(m,1H),3.70–3.58(m,5H),3.44–3. 38(m,1H),3.18(s,3H),2.72–2.56(m,1H),2.39–2.30(m,1H),2.29(s,3H),2.05–1.92(m,4H),1.32(d,J＝6.0Hz,3H).

实施例241：(2R,4R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并 [3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇
Example 241: (2R,4R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo [3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

步骤1：(2R,4S)-4-乙基-4-羟基-2-甲基哌啶-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl (2R,4S)-4-ethyl-4-hydroxy-2-methylpiperidine-1-carboxylate

N2保护下，在-78℃下向(R)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(3.00g,14.1mmol)的THF(40mL)溶液中滴加乙基溴化镁(23mL，1mol/L)，反应混合物在0℃下搅拌8hrs。加入饱和NH4Cl水溶液(100mL)，然后用EA(50mL×3)萃取，合并有机相，用无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析(PE：EA＝4:1)分离纯化(PE：EA，20％ EA)得到目标化合物(2.1g,收率61.35％，黄色液体)。Under N₂ protection, ethylmagnesium bromide (23 mL, 1 mol/L) was added dropwise to a solution of (R)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (3.00 g, 14.1 mmol) in THF (40 mL) at -78°C. The reaction mixture was stirred at 0°C for 8 hrs. Saturated aqueous NH₄Cl solution (100 mL) was added, followed by extraction with EA (50 mL x 3) . The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA = 4:1) (PE:EA, 20% EA) to obtain the title compound (2.1 g, 61.35% yield, yellow liquid).

步骤2：(2R,4S)-4-乙基-2-甲基哌啶-4-醇的合成
Step 2: Synthesis of (2R,4S)-4-ethyl-2-methylpiperidin-4-ol

向(2R,4S)-4-乙基-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(2.60g,4.80mmol)中加入4N HCl/二噁烷(10mL)。反应混合物在25℃下搅拌3hrs，过滤，滤饼用EA(50mL)洗涤，然后真空干燥得到目标化合物(1.20g,收率97.1％，白色固体)。To tert-butyl (2R,4S)-4-ethyl-4-hydroxy-2-methylpiperidine-1-carboxylate (2.60 g, 4.80 mmol) was added 4N HCl/dioxane (10 mL). The reaction mixture was stirred at 25°C for 3 hrs, filtered, and the filter cake was washed with EA (50 mL) and dried under vacuum to afford the title compound (1.20 g, 97.1% yield, as a white solid).

步骤3：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 3: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

将(2R,4S)-4-乙基-2-甲基哌啶-4-醇(1.00g,6.98mmol)和8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(3.07g,6.98mmol)溶于干燥的DMF(20mL)，然后依次加入Cs2CO3(4.55g,13.9mmol)和RuPhos Pd G2(270mg,0.350mmol)。反应混合物在N2保护下130℃搅拌2hrs。冷却至室温，向反应混合物中加入水(100mL)和EA(50mL)稀释，用EA(50mL×2)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，50％EA)得到目标化合物(1.50g,收率47.2％，淡黄色固体)。LC-MS(ESI)m/z:456.3[M+H]+。(2R,4S)-4-ethyl-2-methylpiperidin-4-ol (1.00 g, 6.98 mmol) and 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (3.07 g, 6.98 mmol) were dissolved in dry DMF (20 mL), and then Cs 2 CO 3 (4.55 g, 13.9 mmol) and RuPhos Pd G 2 (270 mg, 0.350 mmol) were added in sequence. The reaction mixture was stirred at 130° C. for 2 hrs under N 2 protection. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and EA (50 mL). The mixture was extracted with EA (50 mL x 2). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 50% EA) to obtain the title compound (1.50 g, 47.2% yield, light yellow solid). LC-MS (ESI) m/z: 456.3 [M+H] ⁺ .

步骤4：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 4: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

向(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇(1.50g,3.29mmol)的MeOH(10mL)溶液中，加入4N HCl/二噁烷(10mL)，反应混合物在N2保护下50℃搅拌16hrs，冷却至室温，减压浓缩，残余物中加入饱和Na2CO3(100mL)水溶液，用DCM(100mL×2)萃取，合并有机相，用饱和Na2CO3(100mL)水溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(100％EA to 10％ MeOH/DCM)，得到目标化合物(1.00g,收率81.7％，黄色固体)。LC-MS(ESI)m/z:372.4[M+H]+。To a solution of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol (1.50 g, 3.29 mmol) in MeOH (10 mL) was added 4N HCl/dioxane (10 mL). The reaction mixture was stirred at 50°C for 16 hrs under N2 protection, cooled to room temperature, and concentrated under reduced pressure. Saturated aqueous Na2CO3 (100 mL) was added to the residue, and the mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with saturated aqueous Na2CO3 (100 mL), dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EA to 10% The title compound (1.00 g, yield 81.7%, yellow solid) was obtained by addition of MeOH/DCM. LC-MS (ESI) m/z: 372.4 [M+H] + .

步骤5：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 5: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

将(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇(1.00g,2.69mmol)和KOH(380mg,6.73mmol)溶解于DMF(20mL)中，再在2hrs分批量缓慢加入I2(1.37g,5.38mmol)。在N2保护下，反应液在25℃下搅拌1hr。加入饱和Na2SO3水溶液(50mL)，用EA(75mL×2)萃取，合并有机相，用水洗涤两次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，80％EA)得到目标化合物(500mg,收率37.3％，黄色液体)。LC-MS(ESI)m/z:498.2[M+H]+。(2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol (1.00 g, 2.69 mmol) and KOH (380 mg, 6.73 mmol) were dissolved in DMF (20 mL). I₂ (1.37 g, 5.38 mmol) was added slowly in portions over 2 hr. Under N₂ protection, the reaction solution was stirred at 25°C for 1 hr. Saturated aqueous Na₂SO₃ (50 mL) was added, and the mixture was extracted with EA (75 mL x 2). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 80% EA) to afford the title compound (500 mg, 37.3% yield, as a yellow liquid). LC-MS(ESI)m/z:498.2[M+H] + .

步骤6：((2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 6: Synthesis of ((2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

向(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇(500mg,1.01mmol)的吡啶(10.0mL)溶液中加入1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(1.40g,5.03mmol)和醋酸铜(365mg,2.01mmol)，反应混合物在80℃下搅拌反应4hrs，冷却至室温，反应混合物减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，100％EA)得到目标化合物(500mg,收率76.8％，黄色固体)。LC-MS(ESI)m/z:648.3[M+H]+。To a solution of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol (500 mg, 1.01 mmol) in pyridine (10.0 mL) was added 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-1H-pyrazole (1.40 g, 5.03 mmol) and copper acetate (365 mg, 2.01 mmol) were stirred at 80°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 100% EA) to obtain the title compound (500 mg, 76.8% yield, as a yellow solid). LC-MS (ESI) m/z: 648.3 [M+H] + .

步骤7：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 7: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

微波管中，将(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇(400mg,0.620mmol)溶于DMF(10mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(579mg,1.85mmol)，鼓N2 3mins，反应混合物在微波下80℃下搅拌3hrs，冷却至室温，向反应混合物中加入水(50mL)，用EA(50mL×2)萃取，合并有机相，用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，100％EA)，得到目标化合物(200mg,收率54.9％，黄色液体)。LC-MS(ESI)m/z:590.3[M+H]+。In a microwave tube, (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol (400 mg, 0.620 mmol) was dissolved in DMF (10 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (579 mg, 1.85 mmol) was added. N2 was blown for 3 mins. The reaction mixture was stirred at 80°C under microwave for 3 hrs, cooled to room temperature, and water (50 mL) was added to the reaction mixture. The mixture was extracted with EA (50 mL×2). The organic phases were combined and washed with saturated brine (50 mL×3). Anhydrous Na2SO 4 was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 100% EA) to obtain the title compound (200 mg, yield 54.9%, yellow liquid). LC-MS (ESI) m/z: 590.3 [M+H] + .

步骤8：(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇的合成
Step 8: Synthesis of (2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol

将(2R,4S)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-4-乙基-2-甲基哌啶-4-醇(200mg,0.340mmol)溶于DCM(5mL)中，加入三氟乙酸(3mL)，混合物在25℃下搅拌16hrs。然后加入饱和NaHCO3水溶液，调节pH值至7，有机层分离并浓缩，残余物用Prep-HPLC(：YMC-Triart C18,250*20.0mml.D.,S-5um,12nm；流动相A：水/0.1％ TFA,流动相B:ACN/0.1％TFA；检测波长220nm,254nm，流速：17mL/min，柱温25℃)分离纯化，得到目标化合物P1(63.2mg,收率36.8％，白色固体)。LC-MS(方法C)：RT＝1.63min，(ESI)m/z:506.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),7.93–7.77(m,1H),6.86–6.72(m,1H),6.60(s,1H),4.72–4.56(m,2H),4.21(s,1H),3.71–3.62(m,2H),3.62–3.51(m,3H),3.27–3.19(m,1H),2.76–2.66(m,1H),2.02–1.87(m,4H),1.80–1.65(m,2H),1.63–1.52(m,3H),1.49–1.42(m,1H),0.95(d,J＝6.2Hz,3H),0.88(t,J＝7.4Hz,3H).(2R,4S)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-ethyl-2-methylpiperidin-4-ol (200 mg, 0.340 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at 25 °C for 16 hrs. Saturated aqueous NaHCO₃ was then added, and the pH was adjusted to 7. The organic layer was separated and concentrated, and the residue was purified by Prep-HPLC (YMC-Triart C18, 250*20.0 mm L.D., S-5 μm, 12 nm; mobile phase A: water/0.1% TFA, mobile phase B: ACN/0.1% TFA; detection wavelengths 220 nm, 254 nm, flow rate: 17 mL/min, column temperature 25°C) to obtain the target compound P1 (63.2 mg, 36.8% yield, white solid). LC-MS (Method C): RT = 1.63 min, (ESI) m/z: 506.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ13.00(s,1H),7.93–7.77(m,1H),6.86–6.72(m,1H),6.60(s,1H),4.72– 4.56(m,2H),4.21(s,1H),3.71–3.62(m,2H),3.62–3.51(m,3H),3.27–3.19 (m,1H),2.76–2.66(m,1H),2.02–1.87(m,4H),1.80–1.65(m,2H),1.63–1. 52(m,3H),1.49–1.42(m,1H),0.95(d,J＝6.2Hz,3H),0.88(t,J＝7.4Hz,3H).

实施例242：8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b] 吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 242: 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(R)-3-(苄胺)正丁醇的合成
Step 1: Synthesis of (R)-3-(benzylamino)-n-butanol

向(R)-3-氨基正丁醇(10g,112.19mmol)的MeOH(100mL)溶液，加入苯甲醛(17.86g,168.28mmol)和NaBH4(8.49g,224.37mmol)，反应混合物在室温搅拌2hrs。减压除去溶剂，得到目标产物(19g,收率94.5％，黄色油状物)，直接用于下一步。LC-MS(ESI)m/z:180.1[M+H]+。To a solution of (R)-3-aminobutanol (10 g, 112.19 mmol) in MeOH (100 mL) were added benzaldehyde (17.86 g, 168.28 mmol) and NaBH₄ (8.49 g, 224.37 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the desired product (19 g, 94.5% yield, yellow oil), which was used directly in the next step. LC-MS (ESI) m/z: 180.1 [M+H] ⁺ .

步骤2：(R)-N-苄基-2-氯-N-(4-羟基丁-2-基)乙酰胺的合成
Step 2: Synthesis of (R)-N-benzyl-2-chloro-N-(4-hydroxybutan-2-yl)acetamide

向(R)-3-(苄胺)正丁醇(19g,105.99mmol)的DCM(10mL)溶液中，加入氯乙酰氯(10.11mL，127.19mmol)和Et3N(29.46mL，211.98mmol)，反应混合物在室温下搅拌2hrs。向反应混合物中加入水和EA稀释，用EA(100mL×3)萃取，合并有机相，用饱和食盐水洗涤三次，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA,0％～10％EA)，得到目标化合物(10g,收率36.89％，白色固体)LC-MS(ESI)m/z:256.2[M+H]+。To a solution of (R)-3-(benzylamino)-n-butanol (19 g, 105.99 mmol) in DCM (10 mL) were added chloroacetyl chloride (10.11 mL, 127.19 mmol) and Et₃N (29.46 mL, 211.98 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and EA, then extracted with EA (100 mL x 3). The combined organic phases were washed three times with saturated brine, dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 0%-10% EA) to obtain the title compound (10 g, 36.89% yield, as a white solid). LC-MS (ESI) m/z: 256.2 [M+H] ⁺ .

步骤3：(R)-4-苯基-5-甲基-1,4-氧杂氮杂环庚烷-3-酮的合成
Step 3: Synthesis of (R)-4-phenyl-5-methyl-1,4-oxazepan-3-one

将(R)-N-苄基-2-氯-N-(4-羟基丁-2-基)乙酰胺(19g,74.29mmol)溶于THF(200mL)中，加入NaH(3.57g,148.59mmol)，反应混合物在N2保护下27℃搅拌2hrs。减压除去溶剂，残余物中加入饱和NH4Cl溶液，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL×3)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA,0％～30％EA)，得到目标化合物(11g,收率67.52％，黄色固体)。LC-MS(ESI)m/z:220.1[M+H]+。(R)-N-Benzyl-2-chloro-N-(4-hydroxybutan-2-yl)acetamide (19 g, 74.29 mmol) was dissolved in THF (200 mL), and NaH (3.57 g, 148.59 mmol) was added. The reaction mixture was stirred at 27°C under N₂ protection for 2 hr. The solvent was removed under reduced pressure, and saturated NH₄Cl solution was added to the residue. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 0% to 30% EA) to obtain the title compound (11 g, 67.52% yield, as a yellow solid). LC-MS (ESI) m/z: 220.1 [M+H] ⁺ .

步骤4：(R)-4-苯基-5-甲基-1,4-氧杂氮杂环庚烷的合成
Step 4: Synthesis of (R)-4-phenyl-5-methyl-1,4-oxazepane

0℃下，向(R)-4-苯基-5-甲基-1,4-氧杂氮杂环庚烷-3-酮(3g,13.68mmol)的THF(20mL)溶液中加入四氢呋喃硼烷溶液(27.5mL，27.36mmol,1M)，反应混合物在N2保护下27℃搅拌3hrs。减压除去溶剂，残余物中加入饱和NH4Cl水溶液，用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(DCM:MeOH,0％～5％MeOH)，得到目标化合物(2.2g,收率78.33％，白色油状液体)。To a solution of (R)-4-phenyl-5-methyl-1,4-oxazepan-3-one (3 g, 13.68 mmol) in THF (20 mL) was added tetrahydrofuran borane solution (27.5 mL, 27.36 mmol, 1 M) at 0°C. The reaction mixture was stirred at 27°C for 3 hr under N₂ protection. The solvent was removed under reduced pressure, and saturated aqueous NH₄Cl solution was added to the residue, which was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH, 0%-5% MeOH) to obtain the title compound (2.2 g, 78.33% yield, white oily liquid).

步骤5：(R)-5-甲基-1,4-氧杂氮杂环庚烷的合成
Step 5: Synthesis of (R)-5-methyl-1,4-oxazepane

将(R)-4-苯基-5-甲基-1,4-氧杂氮杂环庚烷(2.2g,10.72mmol)溶于干燥的MeOH(50mL)中，然后加入Pd/C(2.28g,21.43mmol,10％on carbon)。反应混合物在H2氛围下27℃搅拌2hrs，然后过滤，减压除去溶剂，得到目标化合物(1g,收率81.02％，白色油状液体)。LC-MS(ESI)m/z:116.1[M+H]+。(R)-4-Phenyl-5-methyl-1,4-oxazepane (2.2 g, 10.72 mmol) was dissolved in dry MeOH (50 mL), followed by the addition of Pd/C (2.28 g, 21.43 mmol, 10% on carbon). The reaction mixture was stirred at 27°C under a hydrogen atmosphere for 2 hours, then filtered and the solvent removed under reduced pressure to yield the title compound (1 g, 81.02% yield, white oily liquid). LC-MS (ESI) m/z: 116.1 [M+H] + .

步骤6：8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 6: Synthesis of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在N2保护下，将8-(4-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(1g,2.27mmol)溶解于DMF(10mL)中，并加入(R)-5-甲基-1,4-氧杂氮杂环庚烷(0.78g,6.81mmol)、Cs2CO3(0.74g,2.27mmol)和Ruphos Pd G2(0.18g,0.23mmol)。反应混合物在130℃下搅拌2hrs。冷却至室温，用EA(10mL×3)萃取，减压浓缩，残余物经硅胶柱层析分离纯化(PE:EA，78％ EA)，收集有机层，得到目标化合物(800mg,收率82.39％，白色固体)。LC-MS(ESI)m/z:428.56[M+H]+。Under N₂ protection, 8-(4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1 g, 2.27 mmol) was dissolved in DMF (10 mL), and (R)-5-methyl-1,4 - oxazepane (0.78 g, 6.81 mmol), Cs₂CO₃ (0.74 g, 2.27 mmol), and Ruphos Pd G₂ (0.18 g, 0.23 mmol) were added. The reaction mixture was stirred at 130°C for 2 hrs. The mixture was cooled to room temperature, extracted with EA (10 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 78% EA). The organic layer was collected to obtain the title compound (800 mg, 82.39% yield, as a white solid). LC-MS(ESI)m/z:428.56[M+H] + .

步骤7：8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 7: Synthesis of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(800mg,1.87mmol)的MeOH(5mL)溶液中，加入4N HCl/二噁烷(10mL)，反应混合物在N2保护下50℃搅拌16hrs。冷却至室温，减压除去溶剂，加入饱和NaHCO3水溶液，用DCM(20mL×3)萃取，合并有机相，用饱和NaHCO3水溶液(20mL×3)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩得到粗产品(400mg,收率62.24％，黄色固体)，直接用于下一步。LC-MS(ESI)m/z:344.20[M+H]+。To a solution of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (800 mg, 1.87 mmol) in MeOH (5 mL) was added 4N HCl/dioxane (10 mL). The reaction mixture was stirred at 50°C under N₂ protection for 16 hr. After cooling to room temperature, the solvent was removed under reduced pressure, and saturated aqueous NaHCO₃ was added. The mixture was extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated aqueous NaHCO₃ (20 mL x 3 ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to afford the crude product (400 mg, 62.24% yield, as a yellow solid), which was used directly in the next step. LC-MS(ESI)m/z:344.20[M+H] + .

步骤8：8-(3-碘-4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 8: Synthesis of 8-(3-iodo-4-((R)-5-methyl-1,4-oxazepan-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(400mg,1.16mmol)和KOH(130.70mg,2.33mmol)溶解于DMF(5mL)中，再分批缓慢加入I2(354.74mg,1.40mmol)。在N2保护下，反应液在25℃下搅拌1hr。加入饱和Na2SO3水溶液，用EA(30mL×3)萃取，合并有机层，用水洗涤两次，无水Na2SO4干燥，过滤。减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，18％EA)得到目标化合物(120mg,收率21.95％，黄色固体)。LC-MS(ESI)m/z:470.34[M+H]+。8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (400 mg, 1.16 mmol) and KOH (130.70 mg, 2.33 mmol) were dissolved in DMF (5 mL), and I₂ (354.74 mg, 1.40 mmol) was slowly added portionwise. Under N₂ protection, the reaction solution was stirred at 25°C for 1 hr. Saturated aqueous Na₂SO₃ was added, and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed twice with water, dried over anhydrous Na₂SO₄ , and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 18% EA) to afford the title compound (120 mg, 21.95% yield, as a yellow solid). LC-MS(ESI)m/z:470.34[M+H] + .

步骤9：8-(3-碘-4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 9: Synthesis of 8-(3-iodo-4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将8-(3-碘-4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(120mg,0.26mmol)、1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(711.21mg,2.56mmol)、醋酸铜(92.88mg,0.51mmol)依次加入到吡啶(5mL)中。反应混合物在空气氛围下80℃搅拌16hrs。冷却至室温，向反应混合物中加入水(30mL)，用EA(30mL×3)萃取，合并有机相，用饱和食盐水(30mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(0-15％EtOAc/PE，得到目标化合物(120mg,收率75.76％，白色的油状物)。LC-MS(ESI)m/z:620.50[M+H]+。8-(3-iodo-4-((R)-5-methyl-1,4-oxazepan-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.26 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (711.21 mg, 2.56 mmol), and copper acetate (92.88 mg, 0.51 mmol) were added sequentially to pyridine (5 mL). The reaction mixture was stirred at 80°C under air atmosphere for 16 hours. After cooling to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-15% EtOAc/PE) to obtain the title compound (120 mg, 75.76% yield, white oil). LC-MS (ESI) m/z: 620.50 [M+H] + .

步骤10：8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1-四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 10: Synthesis of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

微波管中，将8-(3-碘-4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(120mg,0.19mmol)溶于DMF(5mL)中，加入(1,10-菲罗啉)(三氟甲基)铜(I)(95％)(181.84mg,0.58mmol)，反应液中鼓N23mins，然后在微波下80℃下搅拌6hrs。冷却至室温，反应混合物中加入水(20mL)中，用EA(40mL×3)萃取，合并有机相，用饱和食盐水(80mL×5)洗涤，无水Na2SO4干燥，减压浓缩，残余物经反向硅胶柱层析分离纯化(H2O：CH3CN，90％CH3CN)，得到目标化合物(60mg,收率55.16％，黄色固体)。LC-MS(ESI)m/z:562.2[M+H]+。In a microwave tube, 8-(3-iodo-4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.19 mmol) was dissolved in DMF (5 mL), and (1,10-phenanthroline)(trifluoromethyl)copper(I) (95%) (181.84 mg, 0.58 mmol) was added. N2 was bubbled through the reaction solution for 3 mins, and then stirred at 80°C under microwave for 6 hrs. After cooling to room temperature, the reaction mixture was added to water (20 mL) and extracted with EA (40 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 5), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H 2 O:CH 3 CN, 90% CH 3 CN) to obtain the title compound (60 mg, 55.16% yield, yellow solid). LC-MS (ESI) m/z: 562.2 [M+H] + .

步骤11：8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷的合成
Step 11: Synthesis of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

向8-(4-((R)-5-甲基-1,4-氧杂氮杂环庚烷-4-基)-1-(1-四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂双环[3.2.1]辛烷(40mg,0.071mmol)的DCM(5mL)溶液中，加入TFA(5mL)。反应混合物在25℃下搅拌16hrs。减压浓缩，残留物中加入饱和NaHCO3水溶液(50mL)，用DCM(30mL×2)萃取，合并有机相，用饱和NaHCO3(50mL×2)洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析分离纯化(PE：EA，75％EA)，再经Prep-HPLC(柱:TriartC18,250*20.0mml.D.,S-5um,12nm；流动相A:H2O(10mmol NH4HCO3)，流动相B:CH3CN；流速:17mL/min；温度:25℃；检测波长:254nm/220nm)分离纯化，得到目标化合物(23.17mg,收率45.42％，白色固体)。LC-MS(方法C)：RT＝1.48min，(ESI)m/z:478.20[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),7.87(s,1H),6.87–6.75(m,1H),6.48(s,1H),4.63–4.51(m,2H),4.10–4.01(m,1H),3.95–3.84(m,1H),3.80–3.63(m,4H),3.61–3.51(m,4H),3.42–3.36(m,1H),2.25–2.13(m,1H),2.04–1.79(m,5H),1.05(d,J＝6.4Hz,3H).To a solution of 8-(4-((R)-5-methyl-1,4-oxazepan-4-yl)-1-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (40 mg, 0.071 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25° C. for 16 hrs. The mixture was concentrated under reduced pressure. Saturated aqueous NaHCO₃ solution (50 mL) was added to the residue, and the mixture was extracted with DCM (30 mL×2). The combined organic phases were washed with saturated NaHCO₃ (50 mL×2), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE:EA, 75% EA), and further by Prep-HPLC (column: Triart C18, 250*20.0 mml.D., S-5 um, 12 nm; mobile phase A: H₂O (10 mmol NH₄HCO₃ ) , mobile phase B: CH₃CN ; flow rate: 17 mL/min; temperature: 25°C; detection wavelength: 254 nm/220 nm) to obtain the title compound (23.17 mg, yield 45.42%, white solid). LC-MS (Method C): RT = 1.48 min, (ESI) m/z: 478.20 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s,1H),7.87(s,1H),6.87–6.75(m,1H),6.48(s,1H),4.63–4.51(m,2H),4.10–4.01(m,1H),3.95–3.84(m,1H) ,3.80–3.63(m,4H),3.61–3.51(m,4H),3.42–3.36(m,1H),2.25–2.13(m,1H),2.04–1.79(m,5H),1.05(d,J＝6.4Hz,3H).

实施例243：8-(4-((2R,4R)-4-甲氧基-2,4-二甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b] 吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷
Example 243: 8-(4-((2R,4R)-4-methoxy-2,4-dimethylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

步骤1：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 1: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(1.50g,4.20mmol)和KOH(700mg,12.5mmol)溶解于DMF(15.0mL)中，再分批缓慢加入I2(2.12g,8.38mmol)。反应液在25℃下搅拌2hrs。用EA(80mL×3)萃取，合并有机相，再用水洗涤两次,，无水Na2SO4干燥，过滤。减压除去溶剂，残余物经硅胶柱层析分离纯化(5％ MeOH/DCM)得到目标化合物(1.30g,收率64.09％，黄色液体)。LC-MS(ESI)m/z:484.1[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (1.50 g, 4.20 mmol) and KOH (700 mg, 12.5 mmol) were dissolved in DMF (15.0 mL). I₂ (2.12 g, 8.38 mmol) was slowly added portionwise. The reaction mixture was stirred at 25°C for 2 hrs. Extraction was performed with EA (80 mL x 3). The combined organic phases were washed twice with water, dried over anhydrous Na₂SO₄ , and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (5% MeOH/DCM) to obtain the title compound (1.30 g, 64.09% yield, as a yellow liquid). LC-MS(ESI)m/z:484.1[M+H] + .

步骤2：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 2: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

往(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(1.30g,2.69mmol)、1-(四氢-2H-吡喃-2-基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(3.70g,13.3mmol)的吡啶(15.0mL)溶液中加入醋酸铜(974mg,2.38mmol)。反应液80℃敞口搅拌16hrs。冷却至室温，向反应混合物中加入水(30.0mL)，用EA(20.0mL×3)萃取，合并有机相，用饱和食盐水(20.0mL×2)洗涤，无水Na2SO4干燥，过滤，减压浓缩，残余物经硅胶柱层析分离纯化(5％ MeOH in DCM)，得到目标化合物(1.60g,收率93.90％，黄色固体)。LC-MS(ESI)m/z:634.2[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (1.30 g, 2.69 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.70 g, 13.3 mmol) in pyridine (15.0 mL) was added copper acetate (974 mg, 2.38 mmol). The reaction mixture was stirred open at 80°C for 16 hrs. After cooling to room temperature, water (30.0 mL) was added to the reaction mixture, which was then extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in DCM) to obtain the title compound (1.60 g, 93.90% yield, yellow solid). LC-MS (ESI) m/z: 634.2 [M+H] + .

步骤3：(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇的合成
Step 3: Synthesis of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol

在N2氛围下，在室温下向(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-3-碘-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(1.60g,2.53mmol)的DMF(20.0mL)溶液中加入(1,10-菲罗啉)(三氟甲基)铜(I)(1.00g,3.21mmol)。反应混合物在微波下80℃下搅拌3hrs。冷却至室温，加入H2O(20.0mL)，并用EA(20.0mL×3)萃取，合并有机相，用Na2SO4干燥，减压浓缩，残余物硅胶柱层析分离纯化(5％ MeOH/DCM)，得到目标化合物(1.20g,收率82.54％，黄色固体)。LC-MS(ESI)m/z:576.3[M+H]+。To a solution of (2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (1.60 g, 2.53 mmol) in DMF (20.0 mL) was added (1,10-phenanthroline)(trifluoromethyl)copper(I) (1.00 g, 3.21 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 80°C under microwave for 3 hrs. The mixture was cooled to room temperature, H 2 O (20.0 mL) was added, and the mixture was extracted with EA (20.0 mL×3). The organic phases were combined, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH/DCM) to obtain the title compound (1.20 g, 82.54% yield, yellow solid). LC-MS (ESI) m/z: 576.3 [M+H] + .

步骤4：8-(4-((2R)-4-甲氧基-2,4-二甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 4: Synthesis of 8-(4-((2R)-4-methoxy-2,4-dimethylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

将(2R)-1-(6-(3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-2,4-二甲基哌啶-4-醇(700mg,1.22mmol)溶于DMF(10.0mL)中，降温到0℃，再向其中加入NaH(70.0mg,1.75mmol)，保持0℃搅拌30min。之后将CH3I(1.61mL,19.9mmol)缓慢滴加到反应液中，室温搅拌16hrs。反应完成后，向其中加入10.0mL H2O淬灭反应，并用EA(20.0mL×3)萃取，合并有机相，用无水Na2SO4干燥，减压浓缩，残余物经硅胶柱层析分离纯化(5％ MeOH in DCM)，得到目标化合物(120mg,收率16.74％，黄色固体)。LC-MS(ESI)m/z:590.3[M+H]+。(2R)-1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,4-dimethylpiperidin-4-ol (700 mg, 1.22 mmol) was dissolved in DMF (10.0 mL), cooled to 0°C, and NaH (70.0 mg, 1.75 mmol) was added. The mixture was stirred at 0°C for 30 min. CH 3 I (1.61 mL, 19.9 mmol) was then slowly added dropwise to the reaction solution, and stirred at room temperature for 16 hrs. After completion of the reaction, 10.0 mL of H 2 O was added to quench the reaction, and the mixture was extracted with EA (20.0 mL × 3). The organic phases were combined, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in DCM) to obtain the title compound (120 mg, 16.74% yield, yellow solid). LC-MS (ESI) m/z: 590.3 [M+H] + .

步骤5：8-(4-((2R,4R)-4-甲氧基-2,4-二甲基哌啶-1-基)-1-(1H-吡唑-3-基)-3-(三氟甲基)-1-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷的合成
Step 5: Synthesis of 8-(4-((2R,4R)-4-methoxy-2,4-dimethylpiperidin-1-yl)-1-(1H-pyrazol-3-yl)-3-(trifluoromethyl)-1-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane

在室温下，向8-(4-((2R)-4-甲氧基-2,4-二甲基哌啶-1-基)-1-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基)-3-氧杂-8-氮杂二环[3.2.1]辛烷(120mg,0.200mmol)的DCM(3.00mL)溶液中滴加TFA(3.00mL)，然后反应液在室温下搅拌16hrs。加入水并用EA(20.0mL×3)萃取，合并有机相，用Na2SO4干燥，减压出去溶剂得粗品，粗品经Prep-HPLC(Triart C18,250*20.0mml.D.,S-5um,12nm，流动相A：H2O(0.1％FA)，流动相B:CH3CN，检测波长:254nm/220nm，流速：17mL/min，柱温25℃)分离纯化，得到目标产物(26.9mg,收率26.2％，白色固体)。LC-MS(方法C)：RT＝1.82min，(ESI)m/z:506.3[M+H]+。1H NMR(400MHz,CDCl3)δ7.79(s,1H),6.99(s,1H),6.20(s,1H),4.56(s,2H),3.89(dd,J＝19.1,10.9Hz,2H),3.69(d,J＝10.8Hz,2H),3.64–3.56(m,1H),3.47–3.40(m,1H),3.29(s,3H),2.85–2.75(m,1H),2.21–2.00(m,5H),1.91–1.71(m,3H),1.31(s,3H),1.09(d,J＝6.4Hz,3H).To a solution of 8-(4-((2R)-4-methoxy-2,4-dimethylpiperidin-1-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane (120 mg, 0.200 mmol) in DCM (3.00 mL) was added TFA (3.00 mL) dropwise at room temperature, and the reaction was stirred at room temperature for 16 hrs. Water was added and extracted with EA (20.0 mL x 3). The organic phases were combined and dried over Na₂SO₄ . The solvent was removed under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC (Triart C18, 250*20.0 mm L·D., S-5 μm, 12 nm, mobile phase A: H₂O (0.1% FA), mobile phase B: CH₃CN , detection wavelength: 254 nm/220 nm, flow rate: 17 mL/min, column temperature 25°C) to obtain the desired product (26.9 mg, yield 26.2%, white solid). LC-MS (Method C): RT = 1.82 min, (ESI) m/z: 506.3 [M+H] ⁺ . 1 H NMR (400MHz, CDCl 3 )δ7.79(s,1H),6.99(s,1H),6.20(s,1H),4.56(s,2H),3.89(dd,J＝19.1,10.9Hz,2H),3.69(d,J＝10.8Hz,2H),3.64–3.56(m,1H ),3.47–3.40(m,1H),3.29(s,3H),2.85–2.75(m,1H),2.21–2.00(m,5H),1.91–1.71(m,3H),1.31(s,3H),1.09(d,J＝6.4Hz,3H).

生物学实施例Biological Examples

如无特别说明，以下生物学实施例中所用的实验材料、试剂、操作和方法均可从市售渠道获得或基于现有技术容易地获知或制备。待测化合物指本发明的实施例化合物和对照化合物。Unless otherwise specified, the experimental materials, reagents, procedures, and methods used in the following biological examples can be obtained from commercial sources or can be easily known or prepared based on existing technologies. The test compounds refer to the example compounds and control compounds of the present invention.

实施例A：细胞内mTOR激酶活性抑制实验Example A: Intracellular mTOR kinase activity inhibition experiment

通过检测mTORC1复合物的底物S6(S6(S235/236)或mTORC2复合物的底物AKT(S473)的磷酸化水平，采用In-Cell Western(ICW)的方法测试了本申请的化合物在KYSE410细胞中对mTOR激酶活性的抑制作用。The inhibitory effect of the compounds of the present application on mTOR kinase activity in KYSE410 cells was tested by In-Cell Western (ICW) method by detecting the phosphorylation level of S6 (S235/236), a substrate of the mTORC1 complex, or AKT (S473), a substrate of the mTORC2 complex.

将在RPMI1640培养基(Gibco,#11875093)(含10％ FBS和10％P/S)中培养的KYSE410细胞(人食管癌细胞，浙江美森细胞科技有限公司)(CTCC-003-0062)以每孔3×103个细胞的密度接种于96孔板内。将96孔板置于37℃、5％ CO2培养箱中培养36hrs。实验的第三天，每孔加入用100％ DMSO稀释的、不同浓度的测试化合物(DMSO终浓度为0.1％)，于37℃、5％ CO2培养箱中继续培养0.5-2hrs后，依次进行以下步骤：3.7％甲醛固定细胞，Triton X-100通透细胞，封闭液封闭细胞，进行一抗孵育，荧光二抗显色后，Odyssey SA仪器读板，GraphPad7.0软件统计分析数据，计算出IC50值。KYSE410 cells (human esophageal carcinoma cells, Zhejiang Meisen Cell Technology Co., Ltd.) (CTCC-003-0062) cultured in RPMI1640 medium (Gibco, #11875093) (containing 10% FBS and 10% P/S) were seeded into 96-well plates at a density of 3 × 10 cells per well. The 96-well plates were incubated at 37°C in a 5% CO incubator for 36 hours. On the third day of the experiment, test compounds diluted in 100% DMSO at varying concentrations (final DMSO concentration: 0.1%) were added to each well. After incubation at 37°C in a 5% CO2 incubator for 0.5-2 hr, the following steps were performed: cell fixation with 3.7% formaldehyde, permeabilization with Triton X-100, blocking with blocking solution, incubation with primary antibody, and development with fluorescent secondary antibody. The plate was read using an Odyssey SA instrument, and data were statistically analyzed using GraphPad 7.0 software for calculation of IC50 values.

本实验的具体说明如下：The specific instructions for this experiment are as follows:

实验材料Experimental Materials

(1)测试化合物：本发明的化合物：(1) Test compound: Compound of the present invention:

(2)实验所用细胞：KYSE410，人食管癌细胞，浙江美森细胞科技有限公司(CTCC-003-0062)(2) Cells used in the experiment: KYSE410, human esophageal cancer cells, Zhejiang Meisen Cell Technology Co., Ltd. (CTCC-003-0062)

试剂及耗材
Reagents and consumables

实验步骤Experimental procedures

1.化合物准备1. Compound Preparation

(1)母液配制：将待测化合物用DMSO(Solarbio D8371)溶解成10mM的母液于1.5mL EP管中，保存在4℃冰箱中，备用。(1) Preparation of stock solution: Dissolve the test compound in DMSO (Solarbio D8371) to a 10 mM stock solution in a 1.5 mL EP tube and store in a 4°C refrigerator for later use.

(2)化合物稀释1：化合物母液用DMSO进行3X梯度稀释，一共稀释10个浓度(2000,666.7,222.2,74.1,24.7,8.23,2.74,0.91,0.3,0.1μM)，待用。(2) Compound dilution 1: The compound stock solution was diluted 3X with DMSO to a total of 10 concentrations (2000, 666.7, 222.2, 74.1, 24.7, 8.23, 2.74, 0.91, 0.3, 0.1 μM) and set aside.

(3)化合物稀释2：上述(2)中梯度稀释的化合物先用细胞培养基稀释50X，而后加入一定的体积到含有细胞的96孔实验板中，得到设定的终浓度(2,0.67,0.22,0.074,0.025,0.008,0.0027,0.0009,0.0003,0.0001μM)，DMSO的终浓度为0.1％。(3) Compound dilution 2: The compound prepared in step (2) was diluted 50X with cell culture medium and then added to a certain volume of a 96-well plate containing cells to obtain the desired final concentrations (2, 0.67, 0.22, 0.074, 0.025, 0.008, 0.0027, 0.0009, 0.0003, 0.0001 μM). The final DMSO concentration was 0.1%.

2.实验孔板布局:96孔板2. Experimental plate layout: 96-well plate

3.细胞给药处理3. Cellular Drug Treatment

(1)KYSE410细胞培养：RPMI 1640培养基(Gibco,#11875093)+10％ FBS(Gibco 10099141C)+10％Penicilin/Streptomycin(10％ P/S)(Absin abs9244)。(1) KYSE410 cell culture: RPMI 1640 medium (Gibco, #11875093) + 10% FBS (Gibco 10099141C) + 10% Penicilin/Streptomycin (10% P/S) (Absin abs9244).

(2)细胞铺板：KYSE410细胞以3×103个细胞/孔铺于96孔板，37℃,5％CO2培养箱中培养36hrs，平行准备2块实验板，1块96-孔实验板用于评估化合物mTORC1的活性，另一块96-孔实验板用于mTORC2活性检测.(2) Cell plating: KYSE410 cells were plated at 3 × 10 3 cells/well in a 96-well plate and cultured in a 37°C, 5% CO 2 incubator for 36 hrs. Two experimental plates were prepared in parallel: one 96-well plate was used to evaluate the mTORC1 activity of the compound, and the other 96-well plate was used to detect mTORC2 activity.

(3)细胞给药：实验第三天，将化合物准备1中的步骤(3)稀释的化合物按一定体积加入到96孔板中，得到设定的终浓度(2,0.67,0.22,0.074,0.025,0.008,0.0027,0.0009,0.0003μM)，DMSO的终浓度为0.1％，DMSO作为空白对照。轻轻拍打板壁，使其混合均匀，37℃，5％CO2培养箱中孵育0.5 -2hrs。(3) Cell administration: On the third day of the experiment, the compound diluted in step (3) of compound preparation 1 was added to a 96-well plate at a predetermined volume to obtain the desired final concentrations (2, 0.67, 0.22, 0.074, 0.025, 0.008, 0.0027, 0.0009, 0.0003 μM). The final concentration of DMSO was 0.1%, and DMSO was used as a blank control. The plate was gently tapped to mix well and incubated in a 37°C, 5% CO2 incubator for 0.5-2 hrs.

4.细胞固定，荧光染料标记的二抗染色4. Cell Fixation and Fluorescent Dye-labeled Secondary Antibody Staining

(1)细胞固定、透化：移去上述3中步骤(3)实验板中的培养基，沿孔壁缓慢加入200μL的1x PBS，清洗细胞；移去1x PBS后，每孔加入150μL 3.7％的甲醛，室温放置20mins，固定细胞。1x PBS清洗后，每孔中加入100μL 0.1％ Triton X-100,室温5mins，增加细胞通透性。(1) Cell fixation and permeabilization: Remove the culture medium from the experimental plate in step (3) above and slowly add 200 μL of 1x PBS along the well wall to wash the cells. After removing the 1x PBS, add 150 μL of 3.7% formaldehyde to each well and let it stand at room temperature for 20 minutes to fix the cells. After washing with 1x PBS, add 100 μL of 0.1% Triton X-100 to each well and let it stand at room temperature for 5 minutes to increase cell permeability.

(2)细胞封闭，一抗孵育：移去上述(1)中的0.1％Triton X-100,1X TBST清洗细胞5次，每次清洗5mins。随后每孔中加入100μL封闭液，室温静置1.5hrs后，移去封闭液。第一块板中，每孔中加入50μL的兔抗pAKT(S473)抗体(1：400稀释)以及鼠抗ɑ-tubulin抗体(1：1000稀释)混合液，室温孵育2hrs。(2) Cell blocking and primary antibody incubation: Remove the 0.1% Triton X-100 in step (1) and wash the cells 5 times with 1X TBST, each wash lasting 5 minutes. Then, add 100 μL of blocking solution to each well, let it stand at room temperature for 1.5 hours, and then remove the blocking solution. In the first plate, add 50 μL of a mixture of rabbit anti-pAKT (S473) antibody (1:400 dilution) and mouse anti-α-tubulin antibody (1:1000 dilution) to each well and incubate at room temperature for 2 hours.

第二块板中，每孔中加入50μL的兔抗pS6(S235/236)抗体(1：1000稀释)以及鼠抗ɑ-tubulin抗体(1：1000稀释)混合液，室温孵育2hrsIn the second plate, 50 μL of a mixture of rabbit anti-pS6 (S235/236) antibody (1:1000 dilution) and mouse anti-α-tubulin antibody (1:1000 dilution) was added to each well and incubated at room temperature for 2 hours.

(3)荧光标记的抗体染色：移去上述步骤(2)中的一抗，1X TBST清洗细胞5次，每次清洗5mins，然后2块实验板的每孔中均加入50μL荧光标记的羊抗兔(IRDye800CW)抗体(1：1000稀释)以及羊抗鼠抗体(IRDye680RD)(1：2000稀释)，室温静置1hrs后，1X TBST清洗细胞5次，每次清洗5mins。(3) Fluorescently labeled antibody staining: Remove the primary antibody in step (2) above, wash the cells 5 times with 1X TBST, each wash for 5 minutes, then add 50 μL of fluorescently labeled goat anti-rabbit (IRDye800CW) antibody (1:1000 dilution) and goat anti-mouse antibody (IRDye680RD) (1:2000 dilution) to each well of the two experimental plates, let it stand at room temperature for 1 hour, and then wash the cells 5 times with 1X TBST, each wash for 5 minutes.

5.读板，数据处理：5. Plate reading and data processing:

(1)根据Odyssey SA仪器说明书设置参数，分别在700nm以及800nm的波长范围读取各个孔荧光信号。(1) Set the parameters according to the Odyssey SA instrument manual and read the fluorescence signal of each well at a wavelength of 700 nm and 800 nm.

(2)数据处理、分析：首先同一样品孔的800nm通道的荧光强度用内参700nm通道的荧光强度进行矫正，然后按照下面的公式计算化合物对mTOR活性的抑制，再用GraphPad7.0软件计算化合物抑制mTOR活性的IC50。(2) Data processing and analysis: First, the fluorescence intensity of the 800 nm channel of the same sample well was corrected with the fluorescence intensity of the internal reference 700 nm channel. Then, the inhibition of the compound on mTOR activity was calculated according to the following formula. Then, the IC50 of the compound's inhibition of mTOR activity was calculated using GraphPad 7.0 software.

pAKT或pS6抑制率(％)＝(1-(信号(化合物)-本底)/(信号(DMSO)-本底))*100pAKT or pS6 inhibition rate (%) = (1-(signal (compound) - background)/(signal (DMSO) - background))*100

结果显示，本发明实施例的化合物显示出优异的抑制mTOR激酶的活性，其IC50<1000nM，优选<500nM，更优选<100nM。作为示例，下表1.1和1.2具体提供了一些实施例化合物的mTOR激酶抑制IC50值。表1.1和1.2中的“+++++”表示测试化合物抑制mTOR激酶活性的IC50为<100nM,“++++”表示测试化合物抑制mTOR激酶活性的IC50为100～500nM。The results show that the compounds of the present invention exhibit excellent mTOR kinase inhibition activity, with IC50 values <1000 nM, preferably <500 nM, and more preferably <100 nM. As examples, Tables 1.1 and 1.2 below provide specific mTOR kinase inhibition IC50 values for some of the compounds of the present invention. "++++++" in Tables 1.1 and 1.2 indicates that the test compound has an IC50 of <100 nM for mTOR kinase inhibition, while "++++" indicates that the test compound has an IC50 of 100-500 nM for mTOR kinase inhibition.

表1.1 mTOR激酶(mTORC1)抑制活性
Table 1.1 mTOR kinase (mTORC1) inhibitory activity

表1.2 mTOR激酶(mTORC2)抑制活性
Table 1.2 mTOR kinase (mTORC2) inhibitory activity

实施例B：H460细胞增殖抑制活性实验Example B: H460 cell proliferation inhibitory activity experiment

将在RPMI-1640培养基(Gibco,#11875093)(含10％ FBS和10％P/S)中培养的NCI-H460细胞(人大细胞肺癌细胞，南京科佰生物科技有限公司(CBP60138)以每孔3×103个细胞的密度接种于96孔板内。将96-孔板置于37℃、5％ CO2培养箱中培养过夜(过夜贴壁步骤)。第二天，每孔加入用100％ DMSO稀释的、不同浓度的待测化合物(DMSO终浓度为0.1％)，每个浓度设置一个重复。于37℃、5％ CO2培养箱中继续培养72小时后，每孔加入10μL CCK8(Beyotime，#C0042)，在放置于37℃、5％ CO2培养箱中孵育2小时，然后用Tecan酶标仪在450nm处检测其吸光值，根据吸光值直接计算细胞的存活率，GraphPad7.0软件统计分析数据，计算出IC50值。数据显示在表2中。NCI-H460 cells (human large cell lung cancer cells, Nanjing Kebai Biotechnology Co., Ltd. (CBP60138)) cultured in RPMI-1640 medium (Gibco, #11875093) (containing 10% FBS and 10% P/S) were seeded into 96-well plates at a density of 3×10 3 cells per well. The 96-well plates were incubated in a 37°C, 5% CO 2 incubator overnight (overnight adhesion step). The next day, different concentrations of the test compound diluted in 100% DMSO (final DMSO concentration of 0.1%) were added to each well, with one replicate for each concentration. After further incubation at 37°C, 5% CO 2 for 72 hours, 10 μL of CCK8 (Beyotime, #C0042) was added to each well and placed in a 37°C, 5% CO 2 incubator. The cells were incubated in a 2- well incubator for 2 hours. The absorbance was then measured at 450 nm using a Tecan microplate reader. Cell viability was directly calculated based on the absorbance. GraphPad 7.0 software was used for statistical analysis, and the IC 50 value was calculated. The data are shown in Table 2.

细胞存活率(％)＝[(实验孔-空白孔)/(对照孔-空白孔)]x 100Cell survival rate (%) = [(experimental well - blank well) / (control well - blank well)] x 100

结果显示，本发明的化合物对H460细胞增殖显示出良好的抑制作用，其IC50在<1000nM，优选<500nM，更优选<100nM的范围。作为示例，下表2具体提供了一些实施例化合物对H460细胞增殖的抑制活性IC50值。表2中的“+++++”表示测试化合物对H460细胞增殖的抑制的IC50小于100nM,“++++”表示测试化合物对H460细胞增殖的抑制的IC50 100～500nM。The results show that the compounds of the present invention exhibited a good inhibitory effect on H460 cell proliferation, with an IC50 in the range of <1000nM, preferably <500nM, and more preferably <100nM. As an example, Table 2 below specifically provides the IC50 values of the inhibitory activity of some example compounds on H460 cell proliferation. "+++++" in Table 2 indicates that the IC50 of the test compound for inhibiting H460 cell proliferation is less than 100nM, and "++++" indicates that the IC50 of the test compound for inhibiting H460 cell proliferation is 100-500nM.

表2.本发明的化合物对H460细胞增殖的抑制活性IC50值
Table 2. IC50 values of the inhibitory activity of the compounds of the present invention on H460 cell proliferation

通过引用将本发明中所提及的所有参考文献均完整合并入本文，就如同每一篇文献均单独列出一样。应理解，在阅读了本发明的公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落入本申请所附权利要求书所限定的范围内。All references mentioned in this application are incorporated herein by reference in their entirety, just as if each reference were listed separately. It should be understood that after reading the disclosure of this application, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope of the claims appended hereto.

Claims (24)

式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，
A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof,
其中：in: W是N或CR3；W is N or CR 3 ; A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中至多三个、优选至多两个是N；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein at most three, preferably at most two, of A 1 , A 2 , A 3 , A 4 and A 5 are N; L表示价键、任选被一个或多个RL取代的C1-6亚烷基、-NRa-、-O-、-CO-、-SO-或-SO2-；L represents a valence bond, a C 1-6 alkylene group optionally substituted with one or more RL , -NR a -, -O-, -CO-, -SO- or -SO 2 -; A表示C1-6烷基、C2-6链烯基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected R 4 ; 环B与A2或A3连接，表示C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；Ring B is connected to A 2 or A 3 and represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 3-10 membered heterocycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group; R1是：不存在；氢；卤素；氰基；羟基；C1-6烷基、C1-6烷氧基、C1-6烷硫基、C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个独立地选自卤素、氰基、羟基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、C1-6烷氧基、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、(C1-6烷基)-SO(NH)-、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基-、3-10元杂环烷基-C1-6亚烷基-、C6-10芳基-C1-6亚烷基-或5-10元杂芳基-C1-6亚烷基-，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自卤素、氰基、羟基、C1-6烷基和NRaRb的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-； R1 is: absent; hydrogen; halogen; cyano; hydroxy; C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from halogen, cyano , hydroxy , NRaRb, NRaRbCO- , NRaRbSO- , NRaRbSO2- , C1-6 alkoxy , ( C1-6 alkyl)-CO-, ( C1-6 alkyl ) -SO-, ( C1-6 alkyl) -SO2- , ( C1-6 alkyl)-SO(NH)-, ( C1-6 alkoxy ) -CO- and C3-8 cycloalkyl; C3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene-, 3-10 membered heterocycloalkyl-C 1-6 alkylene-, C 6-10 aryl-C 1-6 alkylene-, or 5-10 membered heteroaryl-C 1-6 alkylene-, wherein said C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, and NR a R b ; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; R2是H、卤素、CN、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氰基烷基、NRaRb、NRaRbCO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-； R2 is H, halogen, CN, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, NRaRb , NRaRbCO-, NRaRbSO-, NRaRbSO2- , ( C1-6 alkyl ) -CO-, ( C1-6 alkyl )-SO-, ( C1-6 alkyl ) -SO2- , or ( C1-6 alkyl )-SO(NH)-; R3是氢、氘、卤素、氰基、羟基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或C1-6氰基烷基；R 3 is hydrogen, deuterium, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 1-6 cyanoalkyl; R4各自独立地是卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；each R 4 is independently halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy , C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 - , (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge; Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基或C3-8环烷基-C1-6亚烷基-；R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-; RL各自独立地是氢、卤素、CN、羟基、NH2和C1-3卤代烷基；和 RL are each independently hydrogen, halogen, CN, hydroxy, NH2 , and C1-3haloalkyl ; and 表示所处的环是芳香性的。 Indicates that the ring is aromatic. 根据权利要求1所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中所述式(I)具有选自如下结构中的一种或多种：
The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein the formula (I) has one or more structures selected from the following:
其中，包含的环是芳香性的；Among them, The ring is aromatic; 优选地，所述式(I)具有(Ia)、(Ic)、(If)或(Ih)任一者的结构，更优选具有(Ic)或(If)的结构，最优选具有(Ic)的结构。Preferably, the formula (I) has the structure of any one of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If), and most preferably has the structure of (Ic). 根据权利要求1或2所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中L表示价键、C1-6亚烷基、-NRa-、-O-、-CO-或-SO2-；或者L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-或-SO2-；或者L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-，优选价键、C1-6亚烷基或-N(C1-6烷基)-；或者L表示价键。The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein L represents a bond, C 1-6 alkylene, -NR a -, -O-, -CO- or -SO 2 -; or L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO- or -SO 2 -; or L represents a bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)- or -CO-, preferably a bond, C 1-6 alkylene or -N(C 1-6 alkyl)-; or L represents a bond. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中A表示C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，优选表示C1-6烷基、C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，更优选表示C3-8环烯基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基，还更优选表示3-10元杂环烷基或5-10元杂芳基，各自任选被一个或多个、例如一至三个独立选择的R4取代；或者，A表示C1-6烷基或3-10元杂环烷基，各自任选被一个或多个、例如一至三个独立选择的R4取代；任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基，和所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基；A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, more preferably represents C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, still more preferably represents 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more, for example one to three, independently selected R 4 ; or A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl, each optionally substituted by one or more, for example one to three, independently selected R 4 -substituted; optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, for example, 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the 5-10 membered heteroaryl is a 5-10 membered, preferably a 5-7 membered, heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, for example, a 5- or 6-membered heteroaryl; 或者，A表示 各自任选被一个或多个、例如一至三个独立选择的R4取代。Or, A means Each is optionally substituted with one or more, eg, one to three, independently selected R 4 . 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中A表示其中，A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein A represents in, X是O、-CH2-或-NH-；X is O, -CH 2 -, or -NH-; Y是N或CH；Y is N or CH; R4各自独立地位于相同或不同的环成员上，并且各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷氧基、C1-6卤代烷氧基、C1-6氰基烷氧基、C3-8环烷基、C3-8环烷基-C1-6亚烷基-、NRaRb、NRaRb-CO-、NRaRbSO-、NRaRbSO2-、(C1-6烷基)-CO-、(C1-6烷基)-SO-、(C1-6烷基)-SO2-、或(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently located on the same or different ring members and is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkoxy, C 1-6 haloalkoxy, C 1-6 cyanoalkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkylene-, NR a R b , NR a R b -CO-, NR a R b SO-, NR a R b SO 2 -, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 alkyl)-SO 2 -, or (C 1-6 alkyl)-SO(NH)-, or two R 4 together to form a C 1-3 alkylene bridge; Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基、或C3-8环烷基-C1-6亚烷基-，优选各自独立地是氢或C1-6烷基；R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-, preferably each independently hydrogen or C 1-6 alkyl; p是0、1、2、3或4，优选是0、1、2或3；p is 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3; m和n各自独立地是0、1、2或3；和m and n are each independently 0, 1, 2 or 3; and 所述A通过Y与式(I)的其余部分连接。Said A is connected to the rest of the formula (I) through Y. 根据权利要求5所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中m为1且n为1，或者m为1且n为2，或者m为2且n为1，或者m为2且n为2。The compound according to claim 5, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein m is 1 and n is 1, or m is 1 and n is 2, or m is 2 and n is 1, or m is 2 and n is 2. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein: R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO- (e.g. NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - and (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge; 或者，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；Alternatively, each R 4 is independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO- (e.g. NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge; 或者，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基和C1-6卤代烷氧基。Alternatively, R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, 其中，A表示其中R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-或(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基；优选地，R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-或(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥，其中Ra和Rb各自独立地是氢或C1-6烷基；更优选地，R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基、C1-6卤代烷氧基；Among them, A represents wherein R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein R a and R b are each independently hydrogen or C 1-6 alkyl; preferably, R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge, wherein Ra and R b are each independently hydrogen or C 1-6 alkyl; more preferably, R 4 are each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; 或者，or, 其中A表示其中Y为C或N，且当存在一个以上的R4时，至少一个所述R4位于Y的邻位；任选地，所述位于Y邻位的R4选自卤素、氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NH2、NH(C1-6烷基)-CO-、(C1-6烷基)-CO-、(C1-6烷基)-SO2-或(C1-6烷基)-SO(NH)-，优选选自C1-6烷基、C1-6氘代烷基或C1-6卤代烷基，例如是甲基、氘代甲基或三氟甲基。Where A represents wherein Y is C or N, and when there is more than one R 4 , at least one of said R 4 is located in the ortho position to Y; optionally, said R 4 located in the ortho position to Y is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NH 2 , NH(C 1-6 alkyl)-CO-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - or (C 1-6 alkyl)-SO(NH)-, preferably selected from C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 haloalkyl, for example, methyl, deuterated methyl or trifluoromethyl. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中环B表示C3-8环烷基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元杂环烷基)、C6-10芳基或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元杂芳基)，优选表示C6-10芳基或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元杂芳基)；更优选地，环B表示苯基或含有1、2或3个独立地选自N、O或S的杂原子的5-7元、例如5或6元杂芳基；例如，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基或吡嗪基，优选表示苯基、吡唑基、咪唑基、三唑基、噻唑基或吡啶基，更优选表示苯基、吡唑基、咪唑基或吡啶基；The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein ring B represents C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl or 5-10 membered heteroaryl (e.g. 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), preferably represents C 6-10 membered aryl or 5-10 membered heteroaryl (for example, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S); more preferably, ring B represents phenyl or 5-7 membered, for example, 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; for example, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyridonyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl or pyridinyl, more preferably represents phenyl, pyrazolyl, imidazolyl or pyridinyl; 任选地，环B与A2连接。Optionally, Ring B is linked to A2 . 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中R2是H、卤素、CN、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-；优选地，R2是H、卤素、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-；更优选地，R2是H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-；还更优选地，R2是H、C1-6烷基或NH(C1-6烷基)CO-，例如H或C1-6烷基。A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein R 2 is H, halogen, CN, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or NH(C 1-6 alkyl)CO-; preferably, R 2 is H, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or NH(C 1-6 alkyl)CO-; more preferably, R 2 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl or NH(C 1-6 alkyl)CO-; still more preferably, R 2 is H, C 1-6 alkyl or NH(C 1-6 alkyl)CO-, for example H or C 1-6 alkyl. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C1-6烷氧基；C1-6卤代烷氧基；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基、3-10元杂环烷基-C1-6亚烷基、C6-10芳基-C1-6亚烷基或5-10元杂芳基-C1-6亚烷基，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自C1-6烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 1-6 alkoxy; C 1-6 haloalkoxy; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; C 3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene, 3-10 membered heterocycloalkyl-C 1-6 alkylene, C 6-10 aryl-C 1-6 alkylene or 5-10 membered heteroaryl-C 1-6 alkylene, wherein the C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from C 1-6 alkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO 2 -; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C 6-10- membered aryl is phenyl, or the 5-10-membered heteroaryl is a 5-10-membered, preferably 5-7, for example 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; 或者，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；Alternatively, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C 6-10- membered aryl is phenyl, or the 5-10-membered heteroaryl is a 5-10-membered, preferably 5-7, for example 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; 或者，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；Alternatively, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl; 或者，R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；Alternatively, R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl; 或者，R1是：卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2或C1-6烷氧基的取代基取代；或3-10元杂环烷基，其中所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，例如氧杂环丁烷基。Alternatively, R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetane. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中W是N或CR3，且R3是氢、氘、卤素、氰基、C1-6烷基(如C1-4烷基)或C1-6卤代烷基(如C1-4卤代烷基)；优选地，R3是氢、氘、卤素、氰基或C1-6烷基(如C1-4烷基)；更优选地，R3是氢、氘、卤素或C1-6烷基(如C1-4烷基)；最优选地，R3是氢、氘或卤素，例如氢或卤素。A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein W is N or CR 3 and R 3 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl (such as C 1-4 alkyl) or C 1-6 haloalkyl (such as C 1-4 haloalkyl); preferably, R 3 is hydrogen, deuterium, halogen, cyano or C 1-6 alkyl (such as C 1-4 alkyl); more preferably, R 3 is hydrogen, deuterium, halogen or C 1-6 alkyl (such as C 1-4 alkyl); most preferably, R 3 is hydrogen, deuterium or halogen, for example hydrogen or halogen. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein: W是N或CR3；W is N or CR 3 ; A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH; L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-、-N(C3-8环烷基-C1-6亚烷基-)-、-O-、-CO-或-SO2-；L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, -N(C 3-8 cycloalkyl-C 1-6 alkylene-)-, -O-, -CO-, or -SO 2 -; A表示C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ; 环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基、吡啶基、吡啶酮基、哒嗪基、嘧啶基或吡嗪基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a pyridyl group, a pyridonyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group; R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基、(C1-6烷氧基)-CO-和C3-8环烷基的取代基取代；C1-6烷氧基；C1-6卤代烷氧基；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；C3-8环烷基氧基、3-10元杂环烷基氧基、C6-10芳基氧基、5-10元杂芳基氧基、C3-8环烷基-C1-6亚烷基、3-10元杂环烷基-C1-6亚烷基、C6-10芳基-C1-6亚烷基或5-10元杂芳基-C1-6亚烷基，其中所述C3-8环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基各自任选被一个或多个独立地选自C1-6烷基的取代基取代；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；NRaRbSO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy, (C 1-6 alkoxy)-CO- and C 3-8 cycloalkyl; C 1-6 alkoxy; C 1-6 haloalkoxy; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; C 3-8 cycloalkyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkyl-C 1-6 alkylene, 3-10 membered heterocycloalkyl-C 1-6 alkylene, C 6-10 aryl-C 1-6 alkylene or 5-10 membered heteroaryl-C 1-6 alkylene, wherein said C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more substituents independently selected from C 1-6 alkyl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; NR a R b SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, the C 6-10 aryl is phenyl, or the 5-10 membered heteroaryl is a 5-10 membered, preferably 5-7, for example 5 or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R2是H、卤素、氧代基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基或NH(C1-6烷基)CO-； R2 is H, halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-; R3是氢、氘、卤素或C1-6烷基(如C1-4烷基)；R 3 is hydrogen, deuterium, halogen or C 1-6 alkyl (such as C 1-4 alkyl); R4各自独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、C3-8环烷基、NRaRb、NRaRb-CO-(例如NH(C1-6烷基)-CO-)、(C1-6烷基)-CO-、(C1-6烷基)-SO2-和(C1-6烷基)-SO(NH)-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from halogen, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl, NR a R b , NR a R b -CO- (e.g. NH(C 1-6 alkyl)-CO-), (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO 2 - and (C 1-6 alkyl)-SO(NH)-, or two R 4 together form a C 1-3 alkylene bridge; Ra和Rb各自独立地是氢、任选被C1-6烷氧基取代的C1-6烷基、或C3-8环烷基-C1-6亚烷基-；和R a and R b are each independently hydrogen, C 1-6 alkyl optionally substituted by C 1-6 alkoxy, or C 3-8 cycloalkyl-C 1-6 alkylene-; and 表示所处的环是芳香性的； Indicates that the ring is aromatic; 任选地，所述式(I)具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。Optionally, the formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih). 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein: W是N或CR3；W is N or CR 3 ; A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH; L表示价键、C1-6亚烷基、-NH-、-N(C1-6烷基)-或-CO-；L represents a valence bond, C 1-6 alkylene, -NH-, -N(C 1-6 alkyl)-, or -CO-; A表示C1-6烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ; 环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基、三唑基、噻唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group or a pyridyl group; R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基；(C1-6烷基)-CO-；(C1-6烷基)-SO2-；NRaRbCO-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，所述C6-10芳基是苯基，或所述5-10元杂芳基是含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7、例如5或6元杂芳基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO 2 -; NR a R b CO-; or (C 1-3 alkyl) (C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and the C 6-10- membered aryl is phenyl, or the 5-10-membered heteroaryl is a 5-10-membered, preferably 5-7, for example 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R2是H、C1-6烷基、C1-6羟基烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl, C1-6 hydroxyalkyl or NH( C1-6 alkyl)CO-; R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen; R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge; Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and 表示所处的环是芳香性的； Indicates that the ring is aromatic; 任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。Optionally, the compound of formula (I) has the structure of any one of formulae (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih). 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein: W是N或CR3；W is N or CR 3 ; A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH; L表示价键、C1-6亚烷基或-N(C1-6烷基)-；L represents a valence bond, C 1-6 alkylene or -N(C 1-6 alkyl)-; A表示C1-6烷基、C3-8环烯基、3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)、C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，各自任选被一个或多个独立选择的R4取代；A represents C 1-6 alkyl, C 3-8 cycloalkenyl, 3-10 membered heterocycloalkyl (e.g. 3-10 membered, e.g. 6-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, preferably 5-7 membered, e.g. 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted by one or more independently selected R 4 ; 环B与A2或A3连接，优选与A2连接，表示C6-10芳基(例如苯基或萘基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示苯基、吡唑基、咪唑基或吡啶基；Ring B is connected to A2 or A3 , preferably to A2, and represents a C6-10 aryl group (e.g., phenyl or naphthyl) or a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., 5-7 membered, heteroaryl group, e.g., a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a phenyl group, a pyrazolyl group, an imidazolyl group or a pyridyl group; R1是：不存在；氢；卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2、C1-6烷氧基和(C1-6烷氧基)-CO-的取代基取代；C3-8环烷基、3-10元杂环烷基或C6-10芳基；(C1-6烷基)-SO2-；或(C1-3烷基)(C1-3烷基)-PO-；其中任选地，所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，或所述C6-10芳基是苯基；R 1 is: absent; hydrogen; halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 , C 1-6 alkoxy and (C 1-6 alkoxy)-CO-; C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 aryl; (C 1-6 alkyl)-SO 2 -; or (C 1-3 alkyl)(C 1-3 alkyl)-PO-; wherein optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, or the C 6-10 aryl is phenyl; R2是H、C1-6烷基或NH(C1-6烷基)CO-； R2 is H, C1-6 alkyl or NH( C1-6 alkyl)CO-; R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen; R4各自独立地选自氰基、羟基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6烷硫基、C1-6羟基烷基、C1-6卤代烷基、C1-6卤代烷氧基、NRaRb、NRaRb-CO-、(C1-6烷基)-CO-和(C1-6烷基)-SO2-，或者两个R4一起形成C1-3亚烷基桥；R 4 is each independently selected from cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, NR a R b , NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 alkyl)-SO 2 -, or two R 4 together form a C 1-3 alkylene bridge; Ra和Rb各自独立地是氢或任选被C1-6烷氧基取代的C1-6烷基；和R a and R b are each independently hydrogen or C 1-6 alkyl optionally substituted by C 1-6 alkoxy; and 表示所处的环是芳香性的； Indicates that the ring is aromatic; 任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构。Optionally, the compound of formula (I) has the structure of any one of formulae (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih). 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein: W是N或CR3；W is N or CR 3 ; A1、A2、A3和A5各自独立地是C、N或CH，和A4是C或N，其中A1、A2、A3、A4和A5中的两个是N，且其它为C或CH；A 1 , A 2 , A 3 and A 5 are each independently C, N or CH, and A 4 is C or N, wherein two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the others are C or CH; L表示价键；L represents a valence bond; A表示3-10元杂环烷基(例如含有1、2或3个独立地选自N、O或S的杂原子的3-10元、例如6-10杂环烷基)或5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、优选5-7元杂芳基，例如5或6元杂芳基)，优选表示3-10元杂环烷基，各自任选被一个或多个独立选择的R4取代；A represents a 3-10 membered heterocycloalkyl group (e.g. a 3-10 membered, e.g. a 6-10 membered, heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S) or a 5-10 membered heteroaryl group (e.g. a 5-10 membered, preferably a 5-7 membered, e.g. a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S), preferably a 3-10 membered heterocycloalkyl group, each optionally substituted by one or more independently selected R 4 ; 环B与A2或A3连接，优选与A2连接，表示5-10元杂芳基(例如含有1、2或3个独立地选自N、O或S的杂原子的5-10元、例如5-7元杂芳基，例如5或6元杂芳基)；优选地，环B表示吡唑基；Ring B is connected to A 2 or A 3 , preferably connected to A 2 , and represents a 5-10 membered heteroaryl group (e.g., a 5-10 membered, e.g., a 5-7 membered, e.g., a 5- or 6 membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents a pyrazolyl group; R1是：卤素；氰基；C1-6烷基，任选被一个或多个独立地选自卤素、氰基、羟基、NH2或C1-6烷氧基的取代基取代；或3-10元杂环烷基，其中所述3-10元杂环烷基是含有1、2或3个独立地选自N、O或S的杂原子的3-10元、优选3-8元杂环烷基，例如氧杂环丁烷基；R 1 is: halogen; cyano; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxy, NH 2 or C 1-6 alkoxy; or 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is a 3-10 membered, preferably 3-8 membered, heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, such as oxetane; R2是H或C1-6烷基； R2 is H or C1-6 alkyl; R3是氢、氘或卤素； R3 is hydrogen, deuterium or halogen; R4各自独立地选自氰基、羟基、C1-6烷基、C1-6氘代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷基和C1-6卤代烷氧基；和R 4 is each independently selected from cyano, hydroxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; and 表示所处的环是芳香性的； Indicates that the ring is aromatic; 任选地，所述式(I)化合物具有式(Ia)至(Ih)中任一者的结构，优选具有(Ia)、(Ic)、(If)或(Ih)的结构，更优选具有(Ic)或(If)的结构。Optionally, the compound of formula (I) has the structure of any one of formulae (Ia) to (Ih), preferably has the structure of (Ia), (Ic), (If) or (Ih), more preferably has the structure of (Ic) or (If). 根据权利要求1所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中所述化合物选自：





或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物。The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein the compound is selected from:





or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof. 根据前述权利要求任一项所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中所述同位素衍生物为氘代衍生物。A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative, or solvate thereof, wherein the isotopic derivative is a deuterated derivative. 药物组合物，包含权利要求1-18任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物以及可药用的载体、稀释剂或赋形剂，以及任选的一种或多种另外的活性剂。A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof and a pharmaceutically acceptable carrier, diluent or excipient, and optionally one or more additional active agents. 在患者中预防或治疗对mTOR抑制有响应的疾病或状况的方法，该方法包括给患者施用治疗有效量的权利要求1-18任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物。A method for preventing or treating a disease or condition responsive to mTOR inhibition in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative, such as a deuterated derivative, or solvate thereof. 权利要求1-18任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物在制备用于治疗或预防对mTOR抑制有响应的疾病或用于需要mTOR抑制的状况的药物中的用途。Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof in the preparation of a medicament for treating or preventing a disease responsive to mTOR inhibition or for a condition requiring mTOR inhibition. 用于治疗或预防mTOR抑制有响应的疾病或用于需要mTOR抑制的状况的权利要求1-18任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物。A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof for use in the treatment or prevention of a disease responsive to mTOR inhibition or for use in a condition requiring mTOR inhibition. 根据权利要求20所述的方法或根据权利要求21所述的用途或根据权利要求22所述的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物，其中对mTOR抑制有响应的疾病或需要mTOR抑制的状况选自癌症、神经系统疾病、代谢性疾病、自身免疫性疾病和特发性肺纤维化；例如，所述癌症选自黑色素瘤、乳腺癌，结直肠癌、肺癌、前列腺癌、胆管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食管癌、卵巢癌、胰腺癌、皮肤癌、甲状腺癌、子宫癌、宫颈癌和白血病(包括急性淋巴细胞白血病和慢性髓性白细胞)、多发性骨髓瘤、淋巴管肌瘤、室管膜下巨细胞星形细胞瘤、淋巴瘤、软组织肉瘤、肉瘤、脑膜瘤、胶质母细胞瘤、非霍奇金淋巴瘤、难治性中枢神经系统淋巴瘤、结节性硬化相关血管纤维瘤；所述神经系统疾病为神经性退行性疾病，例如选自阿尔茨海默病、帕金森病、亨廷顿病；所述代谢性疾病选自糖尿病、胰岛素抵抗、肥胖和衰老；所述自身免疫性疾病是特异性皮炎、类风湿关节炎，系统性红斑狼疮、皮肌炎、多发性硬化病；可用作预防移植器官排斥反应的免疫抑制药物,以及用于血管支架涂层，发挥抗排异作用。The method according to claim 20 or the use according to claim 21 or the compound according to claim 22 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, wherein the disease responsive to mTOR inhibition or the condition requiring mTOR inhibition is selected from cancer, nervous system disease, metabolic disease, autoimmune disease and idiopathic pulmonary fibrosis; for example, the cancer is selected from melanoma, breast cancer, colorectal cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, thyroid cancer, uterine cancer, cervical cancer and leukemia (including acute lymphoblastic leukemia), The invention relates to a novel therapeutic agent for the treatment of a variety of diseases, including hematologic malignancies, leukemia, chronic myeloid leukemia, multiple myeloma, lymphangioleiomyomas, subependymal giant cell astrocytomas, lymphomas, soft tissue sarcomas, sarcomas, meningiomas, glioblastomas, non-Hodgkin's lymphomas, refractory central nervous system lymphomas, and tuberous sclerosis-associated angiofibromas; the nervous system diseases are neurodegenerative diseases, such as those selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease; the metabolic diseases are selected from diabetes, insulin resistance, obesity, and aging; the autoimmune diseases are atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and multiple sclerosis; the drug can be used as an immunosuppressive drug for preventing transplant organ rejection, and can be used in vascular stent coatings to exert an anti-rejection effect. 权利要求1-18任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素衍生物如氘代衍生物或溶剂合物作为免疫抑制剂的用途，例如用于预防移植器官排斥反应或用于血管支架涂层。Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof as an immunosuppressant, for example for preventing transplant organ rejection or for use in vascular stent coating.
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