Organic compound having mtor inhibitory activity and use thereof

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

Organic compounds with mTOR inhibitory activity and uses thereof Field of the Invention

[0001] 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.

[0002] Background of the Invention

[0003] 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).

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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. Summary of the Invention

[0010] Summary of the Invention

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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,

[0015] 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 requiring mTOR inhibition.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] In an eighth aspect, the present invention provides a method for preparing the compound of the present invention.

[0021] These and other aspects of the invention are described in more detail below.

[0022] Detailed Description of the Invention

[0023] 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,

[0024] in:

[0025] W is N or CR3;

[0026] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein at most three, preferably at most two, of A1, A2, A3, A4 and A5 are N;

[0027] L represents a valence bond, optionally replaced by one or more R L Substituted C 1-6 Alkylene, -NR a -, -O-, -CO-, -SO- or -SO2-;

[0028] A stands for 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 with one or more independently selected R4;

[0029] Ring B is connected to A2 or A3, indicating C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0030] R1 is: absent; hydrogen; halogen; cyano; hydroxyl; C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylthio, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-、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 Substituents of cycloalkyl group; 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 by one or more independently selected from halogen, cyano, hydroxy, C 1-6 Alkyl and NR a R b Substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-;

[0031] R2 is H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2- or (C 1-6 alkyl)-SO(NH)-;

[0032] R3 is hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 cyanoalkyl;

[0033] R4 are each 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 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated 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 SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge;

[0034] R a and Rb are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl or C 3-8 Cycloalkyl-C 1-6 Alkylene-;

[0035] R L are independently hydrogen, halogen, CN, hydroxy, NH2 and C 1-3 haloalkyl; and

[0036] Indicates that the ring is aromatic.

[0037] 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:

[0038] W is N or CR3;

[0039] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein at most three, preferably at most two, of A1, A2, A3, A4 and A5 are N;

[0040] L represents a valence bond, optionally replaced by one or more R L Substituted C 1-6 Alkylene, -NR a -, -O-, -CO-, -SO- or -SO2-;

[0041] A stands for 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 with one or more independently selected R4;

[0042] Ring B is connected to A2 or A3, indicating C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0043] R1 is: absent; hydrogen; halogen; cyano; hydroxyl; C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected from halogen, cyano, hydroxyl, NRa R b NR a R b CO-、NR a R b SO-、NR a R b SO2-、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 Substituents of cycloalkyl groups; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-;

[0044] R2 is H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 alkyl)-SO(NH)-;

[0045] R3 is hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 cyanoalkyl;

[0046] R4 are each 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 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated 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 SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge;

[0047] R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-;

[0048] R L are independently hydrogen, halogen, CN, hydroxy, NH2 and C 1-3 haloalkyl; and

[0049] Indicates that the ring is aromatic.

[0050] 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:

[0051] W is N or CR3;

[0052] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein at most three, preferably at most two, of A1, A2, A3, A4 and A5 are N;

[0053] L represents a valence bond, optionally replaced by one or more R L Substituted C 1-6 Alkylene, -NR a -, -O-, -CO-, -SO- or -SO2-;

[0054] A stands for 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 with one or more independently selected R4;

[0055] Ring B is connected to A2 or A3, indicating C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0056] R1 is: absent; hydrogen; halogen; cyano; hydroxyl; C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected from halogen, cyano, hydroxyl, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-、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 Substituents of cycloalkyl groups; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 Alkyl)-SO2-; NR a Rb CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-;

[0057] R2 is H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 alkyl)-SO(NH)-;

[0058] R3 is hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 cyanoalkyl;

[0059] R4 are each independently halogen, cyano, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated 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 SO2-, (C 1-6alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge;

[0060] R a and R b are independently hydrogen, C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-;

[0061] R L are independently hydrogen, halogen, CN, hydroxy, NH2 and C 1-3 haloalkyl; and

[0062] Indicates that the ring is aromatic.

[0063] In some embodiments, three of A1, A2, A3, A4, and A5 are N, and the others are C or CH.

[0064] In some embodiments, two of A1, A2, A3, A4, and A5 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.

[0065] 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.

[0066] In some embodiments, the compounds of formula (I) of the present invention have one or more structures selected from the following:

[0067] 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).

[0068] L

[0069] In some embodiments, L represents a valence bond, C 1-6 Alkylene, -NR a -, -O-, -CO- or -SO2-. In some embodiments, L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 Alkyl)-, -N(C 3-8 Cycloalkyl-C 1-6 In some embodiments, L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 Alkyl)- or -CO-, preferably a valence bond, C 1-6 Alkylene or -N(C 1-6 alkyl)-.

[0070] In some embodiments, L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 Alkyl)- or -CO-, preferably represents a valence bond, C 1-6 Alkylene, -NH- or -N(C 1-6 alkyl)-.

[0071] In some embodiments, L represents a valence bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -NH-, -N(C 1-6 Alkyl)-, -N(C 3-8 Cycloalkyl-C 1-6 In some embodiments, L is a valence bond. In some embodiments, L is C 1-6 In some embodiments, L is -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-. In some embodiments, L is -NH-, -N(C 1-6alkyl)- or -N(C 3-8 Cycloalkyl-C 1-6 In some embodiments, L is -O-, -CO-, -SO-, or -SO2-. 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 -SO2-.

[0072] A and R4

[0073] 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 C 1-6 Alkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, more preferably C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, more preferably 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more, for example one to three independently selected R4. In some embodiments, A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl, each optionally substituted with one or more, eg, one to three, independently selected R4.

[0074] In some embodiments, A represents C 1-6 Alkyl groups, such as C 1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, is each optionally substituted with one or more, such as one to three, independently selected R4.

[0075] In some embodiments, A represents C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, is each optionally substituted with one or more, eg, one to three, independently selected R4.

[0076] In some embodiments, A represents C 3-8 Cycloalkenyl, such as C 3-6 Cycloalkenyl, such as cyclopentenyl, cyclohexenyl or cyclohexadienyl, is each optionally substituted with one or more, eg, one to three, independently selected R4.

[0077] 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 of which is optionally substituted with one or more, for example, one to three independently selected R4. 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-dioxythiomorpholine 1,1-dioxide, tetrahydro-2H(1,1-dioxy)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 R4.

[0078] In some embodiments, A represents Each is optionally substituted with one or more, eg, one to three, independently selected R4.

[0079] In some embodiments, A represents C 6-10 Aryl, such as phenyl or naphthyl, is each optionally substituted with one or more, such as one to three, independently selected R4.

[0080] 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 R4.

[0081] In some embodiments, A represents in,

[0082] X is O, -CH2- or -NH-;

[0083] Y is N or CH;

[0084] R4 are each independently located on the same or different ring members and are each 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 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy, 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 SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2- or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge;

[0085] R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-, preferably each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl;

[0086] p is 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3;

[0087] m and n are each independently 0, 1, 2 or 3; and

[0088] Said A is connected to the rest of the formula (I) through Y.

[0089] 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.

[0090] In other embodiments, X and Y are not carbon. In further embodiments, Y is N and X is O, -NH- or -CH2-. In other further embodiments, Y is CH and X is O or -NH-, preferably O.

[0091] 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.

[0092] In some embodiments, the compound of formula (I) of the present invention has formula (Ii):

[0093] wherein the variables are as defined herein.

[0094] In some embodiments, the compound of formula (I) of the present invention has formula (Ij):

[0095] 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.

[0096] In some embodiments, A represents In other embodiments, A represents

[0097] In some embodiments, there may be 0, 1, 2, 3 or 4 R4. It will be appreciated that when there are two or more R4, each R4 may be the same or different and may be located in the same or different positions. In some embodiments, there is one or more R4, and at least one of the R4 is located in the ortho position of Y. In other embodiments, there are two or more R4, and two of the R4 may together form C 1-3 Alkylene bridges, such as As shown in .

[0098] In some embodiments, R4 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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)-SO2- and (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 Alkylene bridge.

[0099] In some embodiments, R4 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 Halogenated alkyl, 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)-SO2-, or two R4 together form C 1-3 Alkylene bridge.

[0100] In some embodiments, R4 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 Halogenated alkyl, 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)-SO2-, or two R4 together form C 1-3 Alkylene bridge.

[0101] In some embodiments, R4 is independently selected from cyano, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Haloalkyl and C 1-6 Halogenated alkoxy.

[0102] In some embodiments, R4 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)-SO2-.

[0103] In some embodiments, R4 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2- and (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 Alkylene bridge.

[0104] In some embodiments, R4 is independently selected from cyano, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, NR a R b -CO- and (C 1-6 Alkyl)-CO-, or two R4 together form C 1-3 Preferably, R4 is independently selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C1-6 Deuterated alkoxy, C 1-6 Haloalkoxy and NR a R b -CO-, or two R4 together form C 1-3 More preferably, R4 are each independently selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy and C 1-6 Haloalkoxy, or two R4 together form C 1-3 Alkylene bridge.

[0105] In some embodiments, R4 is independently selected from cyano, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy.

[0106] In some embodiments, A represents C 1-6 Alkyl groups, such as C 1-4 alkyl, each optionally substituted by one or more, for example one to three, independently selected R4, wherein R4 is as defined herein. Preferably, R4 is each independently selected from cyano, NR a R b 、(C 1-6 Alkyl)-SO2- and (C 1-6 Alkyl)-SO(NH)-, more preferably NR a R b , where R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl.

[0107] In some embodiments, A represents C 1-6 Alkyl groups, such as C 1-4 alkyl, each optionally substituted by one or more, for example one to three, independently selected R4, wherein R4 is 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, NR a Rb -CO-, (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, preferably selected from halogen, cyano, hydroxy, (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, more preferably selected from cyano, (C 1-6 Alkyl)-SO2- or (C 1-6 alkyl)-SO(NH)-.

[0108] In some embodiments, A represents C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl, each optionally substituted by one or more, for example one to three, independently selected R4, wherein R4 is 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy and NR a R b , is preferably selected from cyano, hydroxy and NH2, more preferably cyano.

[0109] In some embodiments, A represents C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl, each optionally substituted by one or more, for example one to three, independently selected R4, wherein R4 is 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy and NR a R b , preferably selected from cyano, C 1-6 Alkoxy, hydroxy and NH2, more preferably cyano and C 1-6 Alkoxy.

[0110] In some embodiments, A represents C 3-8 Cycloalkenyl, such as C 3-6 Cycloalkenyl, each optionally substituted by one or more, for example one to three, independently selected R4, wherein R4 is independently selected from cyano, hydroxy, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy and NR a R b , preferably selected from cyano, hydroxyl, NH2. In some embodiments, A represents C 3-8 Cycloalkenyl, such as C 3-6 Cycloalkenyl, optionally substituted with one or more C 1-6 Alkyl groups such as methyl are substituted.

[0111] 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 R4, the heterocycloalkyl being a monocyclic or bicyclic cyclic group (including spirocyclic), and any N and S heteroatoms of the heterocycloalkyl being optionally oxidized, for example in the form of NO, SO, SO2. Preferably, R4 is each independently selected from halogen, cyano, hydroxyl, 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 More preferably, R4 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 Halogenated alkyl, C 1-6 Haloalkoxy, NRa R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 Alternatively, R4 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- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 alkyl.

[0112] In some embodiments, A represents 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, each optionally substituted by one or more, for example one to three independently selected R4, wherein R4 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl and NR a R b , or two R4 together form 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy and (C 1-6 Alkyl)-CO-, or two R4 together form C1-3 Alkylene bridge; more preferably selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy and C 1-6 Halogenated alkoxy.

[0113] 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 R4, wherein R4 is independently selected from cyano, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, 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 NH2-CO-, NH(C 1-6 Alkyl)-CO- or N(C 1-6 Alkyl)(C 1-6 In some embodiments, A represents C 6-10 Aryl, optionally NH(C 1-6 alkyl)-CO-substituted.

[0114] In some embodiments, A represents a 5-10 membered, preferably a 5-7 membered, heteroaryl group, such as a 5- or 6-membered heteroaryl group, containing 1, 2 or 3 heteroatoms independently selected from N, O or S, each of which is optionally substituted by one or more, such as one to three independently selected R4, wherein R4 is independently selected from cyano, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl; preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl and C 1-6 more preferably selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0115] In some embodiments, A represents wherein R4 are independently selected from halogen, cyano, hydroxyl, 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 Preferably, R4 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 More preferably, R4 are each independently selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkyl, C 1-6 Preferably, R4 is independently selected from cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6Deuterated 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)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 alkyl.

[0116] In some embodiments, A represents Wherein R4 is independently selected from cyano, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, and NR a R b , or two R4 together form 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 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, and (C 1-6 Alkyl)-CO-, or two R4 together form C 1-3 Alkylene bridge; more preferably selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy, and C 1-6 Halogenated alkoxy.

[0117] In some embodiments, A represents Wherein Y is C or N, and when there is more than one R4, at least one of said R4 is located in the ortho position of Y. Further, said R4 located in the ortho position of Y is selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, NH(C 1-6 alkyl)-CO-, (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2- or (C 1-6 Alkyl)-SO(NH)-, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 The haloalkyl group is, for example, a methyl group, a deuterated methyl group or a trifluoromethyl group.

[0118] In some embodiments, A is selected from:

[0119] In some embodiments, A is selected from:

[0120] B and R2

[0121] In some embodiments, Ring B is linked to A2. In other embodiments, Ring B is linked to A3.

[0122] In some embodiments, Ring B represents C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 In other embodiments, ring B represents C 6-10 aryl or 5-10 membered heteroaryl.

[0123] In some embodiments, Ring B represents C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl, such as cyclobutane, cyclopentyl, or cyclohexyl.

[0124] 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.

[0125] In some embodiments, Ring B represents C 6-10 Aryl, such as phenyl or naphthyl, preferably phenyl.

[0126] 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.

[0127] 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.

[0128] In some embodiments, R2 is H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 In some embodiments, R2 is H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 In some embodiments, R2 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 In other embodiments, R2 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 In other embodiments, R2 is H, C 1-6 Alkyl or NH(C 1-6 In other embodiments, R2 is H or C 1-6 alkyl.

[0129] In some embodiments, B represents C 6-10Aryl or 5-10 membered heteroaryl, preferably 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, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 Alkyl)CO-, preferably selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 Alkyl)CO-, more preferably selected from H, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-.

[0130] In some embodiments, B represents C 6-10 Aryl (e.g. phenyl or naphthyl), and R2 is selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 Alkyl)CO-, preferably selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 Alkyl)CO-, more preferably NH(C 1-6 alkyl)CO-.

[0131] In other embodiments, B represents a 5-10 membered heteroaryl, for example a 5-10 membered, for example a 5-7 membered, further 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 R2 is selected from H, halogen, oxo, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably selected from H or C 1-6 alkyl.

[0132] In some embodiments, B represents a 5-10 membered heteroaryl group, and R2 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, preferably selected from H, C 1-6 Alkyl and C 1-6 Hydroxyalkyl.

[0133] In some embodiments, Selected from: cyclopentyl, oxacyclopentyl,

[0134] R1

[0135] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; 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 by one or more independently selected C 1-6 Alkyl substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 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.

[0136] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C1-6 Alkoxy)-CO-substituted; 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)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 wherein optionally, the 3-10 membered heterocycloalkyl group is a 3-10 membered, preferably 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 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.

[0137] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 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.

[0138] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3wherein 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.

[0139] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; 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.

[0140] In some embodiments, R1 is: halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2 or C 1-6 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.

[0141] In some embodiments, R1 is: cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, such as cyano, methyl or CF3.

[0142] In some embodiments, R1 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 by one or more independently selected from halogen, cyano, hydroxyl, NR a R b (such as NH2), NR a R b CO-、NR a R b SO-、NR a R b SO2-、C 1-6 Alkoxy, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6Alkyl)-SO2-, (C 1-6 Alkyl)-SO(NH)-, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl groups; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-.

[0143] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; hydroxy; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b (such as NH2), 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 Substituents of cycloalkyl group; 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-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-.

[0144] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b (such as NH2), C 1-6 Alkoxy, (C1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; C 3-8 Cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 Aryl (e.g. phenyl); (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-.

[0145] In some embodiments, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b (such as NH2), C 1-6 Alkoxy, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; C 3-8 Cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 Aryl (e.g. phenyl); (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-.

[0146] In some embodiments, R1 is: hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more, for example one, two or three, independently selected from halogen, cyano, hydroxy, NR a R b (such as NH2), C 1-6 Alkoxy, and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl; 3-10 membered heterocycloalkyl; C 6-10 Aryl (e.g. phenyl); (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-.

[0147] In some embodiments, R1 is: halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b(such as NH2) and C 1-6 Substituents of alkoxy group; C 3-8 cycloalkyl; or 3-10 membered heterocycloalkyl.

[0148] In some embodiments, R1 is C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy-substituted C 1-6 Haloalkyl, C substituted by amino 1-6 Haloalkyl, or C substituted by hydroxy 1-6 Halogenated alkyl.

[0149] In some embodiments, R1 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, R1 is azetidinyl, oxetanyl, azepanyl, oxolanyl, azepanyl, oxetanyl, azepanyl, oxepanyl. Preferably, R1 is azetidinyl, oxetanyl, more preferably R1 is oxetanyl.

[0150] In some embodiments, R1 is selected from the group consisting of: absent, hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, methyl, CF2H-, CF3, (CF3)CH2-, (CF3)(CH3)CH-, (CF3)CHF-, (CF3)CF2-, fluoropropyl; CN-CH2-, (CN)(CH3)CH-, (CN)(CH3O)CH-, hydroxypropyl, (CF3)(OH)CH-, (CF3)(O H)2C-, (CF3)(NH2)CH-, (CF3)(CH3O)CH-, CH3O-C(O)-CH(CH3)-, cyclopropyl-(CH2)-, cyclopropyl, oxetanyl, phenyl, CH3CO-, Et-SO2-, NH2CO-, (CH3)2-PO-, EtO-, CF3O-, cyclobutyl-O-, oxane-O-, pyridyl-O-, (N-methyl)pyrazolyl-O-, Benzyl and CH3-NH-SO2-.

[0151] W and R3

[0152] In some embodiments, W is N or CR3, and R3 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 Preferably, R3 is hydrogen, deuterium, halogen, cyano or C 1-6Alkyl (such as C 1-4 More preferably, R3 is hydrogen, deuterium, halogen or C 1-6 Alkyl (such as C 1-4 Most preferably, R3 is hydrogen, deuterium or halogen, such as hydrogen or halogen.

[0153] In some embodiments, R3 is hydrogen, halogen, cyano, or C 1-3 In other embodiments, R3 is hydrogen, halogen, or cyano. In other embodiments, R3 is hydrogen or halogen.

[0154] In some embodiments, W is N or CR3, wherein R3 is H or halogen. In other embodiments, W is N. In other embodiments, W is CH. In some embodiments, W is CR3, wherein R3 is deuterium. In other embodiments, W is CR3, wherein R3 is halogen. In some embodiments, W is CR3, wherein R3 is C 1-6 Alkyl (such as C 1-4 alkyl).

[0155] R a and R b

[0156] In some embodiments, R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R a and R b In some embodiments, R a and R b One of them is hydrogen, and the other is optionally replaced by C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R a and R b All are optional 1-6 Alkoxy-substituted C 1-6 Alkyl. For example, R a C 1-6 Alkyl and R b For optional C 1-6 Alkoxy-substituted C 1-6 alkyl.

[0157] In some embodiments, R a is hydrogen, and R b C 3-8 Cycloalkyl-C 1-6 Alkylene-.

[0158] 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:

[0159] W is N or CR3;

[0160] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0161] 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 -SO2-;

[0162] A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4;

[0163] Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl or pyrazinyl;

[0164] R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; 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 3-8Cycloalkyloxy, 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 by one or more independently selected C 1-6 Alkyl substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 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;

[0165] R2 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 alkyl)CO-;

[0166] R3 is hydrogen, deuterium, halogen or C 1-6 Alkyl (such as C 1-4 alkyl);

[0167] R4 are 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, NR a R b NRa R b -CO-(e.g. NH(C 1-6 Alkyl)-CO-), (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2- and (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge;

[0168] R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-; and

[0169] Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

[0170] 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:

[0171] W is N or CR3;

[0172] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0173] L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 alkyl)- or -CO-;

[0174] A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4;

[0175] Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl or pyridyl;

[0176] R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; 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)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 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;

[0177] R2 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 alkyl)CO-;

[0178] R3 is hydrogen, deuterium or halogen;

[0179] R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C1-3 alkylene bridge;

[0180] R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and

[0181] Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

[0182] 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:

[0183] W is N or CR3;

[0184] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0185] L represents a valence bond, C 1-6 Alkylene or -N(C 1-6 alkyl)-;

[0186] A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4;

[0187] Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl or pyridyl;

[0188] R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 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;

[0189] R2 is H, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-;

[0190] R3 is hydrogen, deuterium or halogen;

[0191] R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 alkylene bridge;

[0192] R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and

[0193] Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

[0194] 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:

[0195] W is N or CR3;

[0196] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0197] L represents a valence bond, C 1-6 Alkylene or -N(C 1-6 alkyl)-;

[0198] A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4;

[0199] Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl or pyridyl;

[0200] R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 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;

[0201] R2 is H, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-;

[0202] R3 is hydrogen, deuterium or halogen;

[0203] R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 alkylene bridge;

[0204] R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and

[0205] Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

[0206] 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:

[0207] W is N or CR3;

[0208] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0209] L represents a valence bond;

[0210] 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 R4;

[0211] Ring B is connected to A2 or A3, preferably connected to A2, 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;

[0212] R1 is: halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2 or C 1-6 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;

[0213] R2 is H or C 1-6 alkyl;

[0214] R3 is hydrogen, deuterium or halogen;

[0215] R4 are each independently selected from cyano, hydroxyl, 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

[0216] 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).

[0217] 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:

[0218] W is N or CR3;

[0219] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0220] L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 Alkyl)- or -CO-, preferably represents a valence bond, C 1-6 Alkylene, -NH- or -N(C 1-6 alkyl)-;

[0221] A stands for 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 with one or more independently selected R4;

[0222] Ring B is connected to A2 or A3, preferably connected to A2, 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;

[0223] R1 is cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, such as cyano, methyl or CF3;

[0224] R2 is H or C 1-6 Alkyl; preferably, R2 is H;

[0225] R3 is hydrogen, deuterium or halogen; preferably, R3 is hydrogen or deuterium;

[0226] R4 are 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)-SO2-;

[0227] R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and

[0228] 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).

[0229] 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:

[0230] W is N or CR3;

[0231] A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 are N and the others are C or CH;

[0232] L represents a valence bond;

[0233] A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4;

[0234] Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl or pyridyl, more preferably pyrazolyl or pyridyl;

[0235] R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 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;

[0236] R2 is H, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-;

[0237] R3 is hydrogen, deuterium or halogen;

[0238] R4 are each independently selected from cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, NR a R b -CO- and (C 1-6 Alkyl)-CO-, or two R4 together form C 1-3 alkylene bridge;

[0239] R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and

[0240] Optionally, the compound of formula (I) has the structure of any one of formulas (Ia) to (Ih), preferably (Ia), (Ic), (If) or (Ih).

[0241] 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:

[0242] or a pharmaceutically acceptable salt, tautomer, stereoisomer, deuterated derivative or solvate thereof.

[0243] 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.

[0244] definition

[0245] 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.

[0246] 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.

[0247] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogens are fluorine and chlorine.

[0248] The term "alkyl" alone or as part of another group refers to a fully saturated straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms. Alkyl is preferably C 1-6 Alkyl (having 1-6 carbon atoms), more preferably C 1-4 Alkyl or C 1-3 Representative examples of alkyl groups 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.

[0249] The term "alkylene" alone or as part of another group refers to a fully saturated straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms. 1-6 Alkylene, preferably C 1-3 Alkylene, more preferably C 1-2 Representative examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and the like.

[0250] The term "haloalkyl" 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 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. Preferably, the haloalkyl group is C 1-6 Haloalkyl, more preferably C 1-4 Haloalkyl or C 1-3 Representative examples of haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl, and trifluoropropyl.

[0251] 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 C 1-6 Hydroxyalkyl, more preferably C 1-4 Hydroxyalkyl or C 1-3 Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0252] The term "cyanoalkyl" refers to an alkyl group as defined herein wherein 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. Preferably, the cyanoalkyl group is C 1-6 Cyanoalkyl, more preferably C 1-4 Cyanoalkyl or C 1-3 Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, cyanoethyl, cyanopropyl, and the like.

[0253] The term "alkoxy" or "alkyloxy" are used interchangeably to denote an alkyl group as defined above attached through an oxygen bridge. Alkoxy is preferably C 1-6 Alkoxy, more preferably C 1-4 Alkoxy or C 1-3 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentoxy (including n-pentoxy, isopentoxy, neopentoxy, etc.), hexyloxy, heptyloxy, octyloxy, etc.

[0254] The term "alkylthio" or "alkylthio" are used interchangeably to denote an alkyl group as defined above attached through a sulphur bridge. Alkylthio is preferably C 1-6 Alkylthio, more preferably C 1-4 Alkylthio or C 1-3 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, etc.), pentylthio (including n-pentylthio, isopentylthio, neopentylthio, etc.), hexylthio, heptylthio, octylthio, etc.

[0255] The term "haloalkoxy" or "haloalkyloxy" are used interchangeably to denote an alkoxy group as defined above which is substituted with one or more halogens. 1-6 Haloalkoxy, more preferably C 1-4 Haloalkoxy or C 1-3 Halogenated alkoxy.

[0256] The term "hydroxyalkoxy" refers to an alkoxy group as defined above which is substituted by one or more hydroxy groups. 1-6 Hydroxyalkoxy, more preferably C 1-4 Hydroxyalkoxy or C 1-3 Hydroxyalkoxy.

[0257] The term "cyanoalkoxy" denotes an alkoxy group as defined above which is substituted by one or more cyano groups. 1-6 Cyanoalkoxy, more preferably C 1-4Cyanoalkoxy or C 1-3 Cyanoalkoxy.

[0258] 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).

[0259] 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 C 1-6 Deuterated alkoxy, more preferably C 1-4 Deuterated alkoxy or C 1-3 Deuterated alkoxy.

[0260] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms. 3-8 Cycloalkyl, more preferably C 5-8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0261] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms and containing one or more double bonds. 3-8 Cycloalkenyl, more preferably C 5-8 Representative examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0262] 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 will be appreciated that heterocycloalkyl may be substituted with fully unsaturated or partially unsaturated substituents. The carbon members of the heterocycle may be replaced by -CO-, and any N and S heteroatoms may be optionally oxidized (e.g., in NO, SO, SO2) and any N heteroatoms may be optionally quaternized (e.g., in [NR] + Cl - 、[NR] + OH -Thus, the term "heterocycloalkyl" 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. Heterocycloalkyl is preferably a 3-10 membered heterocycloalkyl, more preferably a 3-8 membered heterocycloalkyl or a 5-8 membered heterocycloalkyl. The heterocycloalkyl group may be attached to the remainder of the molecule via 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, oxazepanyl, and the like. Heterocycloalkyl can be attached to the rest of the molecule via a carbon atom or a heteroatom, as long as chemically feasible. When a heterocycloalkyl contains only oxygen as a heteroatom, it may be referred to as an "oxepanyl."

[0263] The term "aryl" refers to an aromatic carbon ring having one or more rings, preferably 1 or 2 rings. 6-10 Representative examples include, but are not limited to, phenyl (i.e., C6 aryl), naphthyl, and the like.

[0264] 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. References to "heteroaryl" herein include 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 a heteroaryl group may be optionally oxidized (e.g., in NO, SO, SO2) and any N heteroatom may be optionally quaternized (e.g., in [NR] + Cl - 、[NR] + OH -The heteroaryl group is preferably a 5-10 membered heteroaryl group, more preferably a 5-7 membered heteroaryl group, and most preferably a 5- or 6-heteroaryl group. Representative examples thereof include, but are not limited to, pyrrolyl, furyl, 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.

[0265] The term "cyano" refers to CN.

[0266] The term "hydroxy" refers to OH.

[0267] The term "NH2" represents an amino group. The term "-NH(C 1-6 Alkyl)" means a C 1-6 Alkyl substituted amino. The term "-N(C 1-6 Alkyl)(C 1-6 Alkyl)" means a group consisting of two identical or different C 1-6 Alkyl-substituted amino, for example, dimethylamino, (methyl)(ethyl)amino-, and the like.

[0268] The term "-CO-" or "-C(=O)-" represents a carbonyl group.

[0269] The term "-SO-" represents a sulfinyl group.

[0270] The term "-SO2-" represents a sulfonyl group.

[0271] The term "-PO-" represents a phosphoryl group.

[0272] The term "oxo" refers to =0.

[0273] A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -NR a R b Indicates that the group is attached to the rest of the molecule through a nitrogen atom, -C1-3 Alkylene-C 3-8 Cycloalkyl means that the point of attachment of the group is at C 1-3 When the attachment point of the substituent is obvious to those skilled in the art (e.g., for halogen, hydroxy, NR a R b etc.), “-” can be omitted.

[0274] 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.

[0275] 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.

[0276] Indicates that the ring is saturated, partially unsaturated or aromatic.

[0277] 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 the aromatic ring and is chemically feasible and stable.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0283] 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.

[0284] 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.

[0285] Herein, references to formula (I) also include subformulas thereof, such as formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and / or (Ij).

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0292] 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.

[0293] 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%.

[0294] As used herein, the term "isotopic derivative" refers to a compound that contains unnatural ratios 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, whether or not radioactive, which 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 their pharmaceutically acceptable salts include, but are not limited to, isotopes of hydrogen (e.g.,2 H. 3 H); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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."

[0307] 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.

[0308] 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.

[0309] 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.

[0310] The expression A "and / or" B includes A alone, B alone, and the case of A+B.

[0311] 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.

[0312] effect

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] In some embodiments, the compounds of the invention are useful in treating organ fibrosis, such as idiopathic pulmonary fibrosis.

[0320] 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.

[0321] Pharmaceutical compositions and administration

[0322] 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.

[0323] 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.

[0324] 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.

[0325] Drug combinations

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] Preparation method of the compound of the present invention

[0332] 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.

[0333] 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.

[0334] In the preparation of the compounds of the present invention, group protection (e.g., amino protecting groups, hydroxy protecting groups) may be necessary, which can be readily determined by those skilled in the art. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. Unless otherwise specified, the raw materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods below, methods similar to those given below, or methods known in the art.

[0335] 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.

[0336] Synthesis Scheme A:

[0337] As illustrated in Scheme A, the compounds of the present invention can be synthesized by a method comprising the following steps:

[0338] 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;

[0339] 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;

[0340] 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)Cl2 / H3PO4 and heating in a solvent such as dioxane / water to obtain a compound of formula A4; and

[0341] Step 4: Compound A4 is deprotected under the action of acid to obtain compound A5.

[0342] Synthesis Scheme B:

[0343] As illustrated in Scheme B, the compounds of the present invention can be synthesized by a method comprising the following steps:

[0344] 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;

[0345] Step 2: reacting the compound of formula B2 in the presence of a base such as Cs2CO3 in a solvent such as DMF to obtain a compound of formula B3;

[0346] 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;

[0347] Step 4: Compound B4 is reacted by Suzuki coupling in the presence of a coupling agent such as Pd(dppf)Cl2 / H3PO4 in a solvent such as dioxane / water with heating to obtain compound B5;

[0348] Step 5: heating the compound of formula B5 in the presence of a catalyst such as RuPhos-G2, a base such as Cs2CO3, and a solvent such as dioxane to obtain a compound of formula B6;

[0349] Step 6: Deprotecting the compound of formula B6 under the action of an acid such as HCl to obtain a compound of formula B7;

[0350] Synthesis Scheme C:

[0351] wherein R1, X and p are as defined above for formula (I):

[0352] As illustrated in Scheme C, the compounds of the present invention can be synthesized by a method comprising the following steps:

[0353] 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;

[0354] 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;

[0355] Step 3: heating the compound of formula C3 with a cyaniding agent such as Zn(CN)2 in the presence of a catalyst such as Pd2(dba)3 / DPPF in the presence of a solvent such as DMF to obtain a compound of formula C4;

[0356] Step 4: reacting the compound of formula C4 with a Grignard reagent to obtain a compound of formula C5;

[0357] 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;

[0358] Step 6: The compound of formula C6 is heated in the presence of POCl3, for example, at 100-150°C to perform ring closure to obtain the compound of formula C7.

[0359] Synthesis Scheme D:

[0360] As illustrated in Scheme D, the compounds of the present invention can be synthesized by a method comprising the following steps:

[0361] Step 1: reacting the compound of formula D1 with a base such as DIPEA in a solvent such as THF at a temperature of 80° C. to obtain the compound of formula D2;

[0362] Step 2: The compound of formula D2 is reacted in a solvent such as NMP under the action of a base such as DIPEA and heated at 130° C. to obtain a compound of formula D3;

[0363] Step 3: Deprotecting the compound of formula D3 to obtain a compound of formula D4;

[0364] Step 4: Adding halogen to the compound of formula D4 to obtain a compound of formula D5;

[0365] Step 5: The compound of formula D5 undergoes Suzuki reaction or other coupling with a suitable reagent to obtain a compound of formula D6;

[0366] 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.

[0367] Synthesis Scheme E:

[0368] As illustrated in Scheme E, the compounds of the present invention can be synthesized by a method comprising the following steps:

[0369] Step 1: reacting a compound of formula E1 with hydrazine hydrate in a solvent such as ethanol to obtain a compound of formula E2;

[0370] 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;

[0371] 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.

[0372] 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;

[0373] Step 5: Deprotection of the compound of formula E5 under the action of an acid such as HCl to obtain the compound E6;

[0374] Step 6: Compound E6 is reacted with iodine in the presence of a base such as KOH to obtain compound E7;

[0375] 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;

[0376] 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. Example

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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:

[0382] Synthesis Example

[0383] In the method for preparing the target compound provided by the present invention, the column chromatography uses silica gel (100-200 mesh) produced by Leyan Company; the thin layer chromatography uses GF254 (0.25 mm); the nuclear magnetic resonance chromatography (NMR) is measured using a Bruker AVANCE NEO-400 nuclear magnetic resonance instrument; and the liquid chromatography-mass spectrometry (LC / MS) uses an Agilent Technologi ESI 1260 / 1290 liquid chromatography-mass spectrometer.

[0384] In addition, all operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection.

[0385] In the present invention, the method used by LCMS is as follows:

[0386] Method A: Shim-pack Scepter C18-120, 3 μm, 4.5*50 mm; mobile phase A: water / 0.01% TFA, mobile phase B: ACN / 0.01% TFA; flow rate: 1.8 mL / min; gradient: 5-95% B in 1.3 min, hold 95% B for 1.7 min, and finally decrease to 5% B in 0.01 min; detection wavelength 214, 254 nm, column temperature 45°C.

[0387] Method B: Shim-pack Scepter C18-120, 3 μm, 3.0*33 mm; mobile phase A: water / 0.01% TFA, mobile phase B: ACN / 0.01% TFA; flow rate: 1.8 mL / min; gradient: 5% B to 95% B in 0.5 min, hold 0.8 min; detection wavelength 214, 254 nm, column temperature 45°C.

[0388] 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 phase B at 20%, 0.01-1.80min, increase phase B from 20% to 95%, 1.80-2.50min, maintain phase B at 95%, in 2.50-2.51min, reduce phase B from 95% to 20%, 2.51-2.90min, maintain phase B at 20%; detection wavelength 254 / 220nm, column temperature 40℃.

[0389] Method D: Shimadzu LC-2020; column: YMC-Triart C18, 50*4.6 mm, 5 μm; mobile phase A: water / 0.1% TFA, mobile phase B: acetonitrile / 0.1% TFA; flow rate: 2.5 mL / min; gradient: 20% B to 95% B in 3.4 min, hold for 0.8 min, then 20% B for 0.8 min; detection wavelength: 254 / 220 nm, column temperature: 40°C.

[0390] Method E: Sepax GP-C18, 50×4.6 mm, 5 μm; mobile phase A: water / 0.1% TFA, mobile phase B: acetonitrile; flow rate: 2.5 mL / min; gradient: 20% B in 0.01 min, maintained at 95% B in 1.79 min, and finally decreased to 20% B in 0.7 min; detection wavelengths 220, 254 nm, column temperature 40°C.

[0391] In the present invention, the method used for chiral analysis (SFC) is as follows:

[0392] 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.

[0393] Method B: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-ADHS 150x4.6mm_5μm, CN049; mobile phase A: Hexane, mobile phase B: EtOH, flow rate: 1.0ml / min; 10.0min; detection wavelength 254nm, column temperature 35°C.

[0394] Method C: (Waters UPCC system equipped with a PDA detector), column: RegisPack-IK_250x4.6mm_5μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH, flow rate: 2.0ml / min; 6.0min; detection wavelength: 210nm, column temperature: 35℃.

[0395] Method D: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IG_100x3.0mm_3μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH, flow rate: 2.0ml / min; 6.0min; detection wavelength: 210nm, column temperature: 35℃.

[0396] 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.

[0397] 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°C.

[0398] Method G: (SHIMADZY LC-20ADxr system equipped with a PDA detector), column: Daicel_ChiralPak-AD 4.6mm I.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°C.

[0399] Method H: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IHS 150x4.6mm_5μm, CN004; mobile phase A: n-hexane, mobile phase B: EtOH, flow rate: 1.0ml / min; 15.0min; detection wavelength 254nm, column temperature 35°C.

[0400] Method I: (Waters UPCC system equipped with a PDA detector), column: Daicel_ChiralPAK-IC_100x3.0mm_3μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH, flow rate: 2.0ml / min; 7.0min; detection wavelength: 210nm, column temperature: 35℃.

[0401] Method J: (SHIMADZU NEXERA XR-20ADXR), column: Daicel Chiral PAK-IGS 150x4.6mm_5μm, AV021; mobile phase A: n-hexane, mobile phase B: ETOH, flow rate: 1.0ml / min; 20.0min; detection wavelength 248nm, column temperature 35°C.

[0402] 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 0.1min, 5-40% B within 4min, maintain to 40% B within 1min, and finally drop to 5% B in 1min; detection wavelength 220nm, 254nm, flow rate: 2.5mL / min, column temperature 40℃.

[0403] 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, maintain to 40% B within 2 min, and finally drop to 5% B in 1 min; detection wavelength 220 nm, 254 nm, flow rate: 2.5 mL / min, column temperature 40°C.

[0404] 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 0.1min, 5-40% B within 4min, maintain to 40% B within 1min, and finally drop to 5% B in 1min; detection wavelength 220nm, 254nm, flow rate: 2.5mL / min, column temperature 40℃.

[0405] Method O: Opti-Chiral IDH-3, 100*4.6mm, 3um; mobile phase A: CO2, mobile phase B: methanol; gradient: 5% B at 0.1min, 5-40% B within 4min, maintain to 40% B within 1min, and finally drop to 5% B in 1min; detection wavelength 220nm, 254nm, flow rate: 2.5mL / min, column temperature 40℃.

[0406] 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, maintain to 40% B within 1min, and finally drop to 5% B in 1min; detection wavelength 220nm, 254nm, flow rate: 2.5mL / min, column temperature 40℃.

[0407] Synthesis of Intermediate 3-(Fluoromethyl)morpholine (2a)

[0408] Step 1: Synthesis of 4-benzyl-3-(fluoromethyl)morpholine

[0409] 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 obtain the title compound (1.0 g, 99.1% yield, colorless oil). LC-MS (ESI) m / z: 210.2 [M+H] + .

[0410] Step 2: Synthesis of 3-(fluoromethyl)morpholine

[0411] 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] + .

[0412] Synthesis of intermediate ((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (3a)

[0413] 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 nitrogen, 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] + .

[0414] Synthesis of Intermediate (R)-1-(3-methylpiperazin-1-yl)ethan-1-one (4a)

[0415] Step 1: Synthesis of tert-butyl (R)-4-acetyl-2-methylpiperazine-1-carboxylate

[0416] (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] + .

[0417] Step 2: Synthesis of (R)-1-(3-methylpiperazin-1-yl)ethan-1-one

[0418] (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] + .

[0419] 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

[0420] Step 1: Synthesis of 2,6-difluoro-4-iodonicotinaldehyde

[0421] 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. The reaction mixture was quenched by the addition of 2N dilute hydrochloric acid and 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 yield the crude product (55 g, 98.6% yield, light yellow oil).

[0422] Step 2: Synthesis of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine

[0423] 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 a crude product (45 g, 83.7% yield, black oil). LC-MS (ESI) m / z: 264.0 [M+H] + .

[0424] Step 3: Synthesis of 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-iodo-1H-pyrazolo[3,4-b]pyridine

[0425] Under N2 protection, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (341 mg, 2.28 mmol) and DIEA (590 mg, 4.56 mmol) were added to a solution of 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.14 mmol) in NMP (2 mL). 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] + .

[0426] 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)

[0427] 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 O2 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] + .

[0428] 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

[0429] 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 separated and purified by silica gel column chromatography (PE:EA, 50% EA) to give the title compound (40 mg, yield 62.8%) as a yellow solid. LC-MS (ESI) m / z: 461.2 [M+H] + .

[0430] 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

[0431] 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-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).

[0432] 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

[0433] 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

[0434] 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), Cs2CO3 (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, and extracted with EA (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography (H2O:CH3CN, 33% CH3CN) to give the title compound (10.0 mg, yield 10.2%, light yellow solid). LC-MS (ESI) m / z: 498.20 [M+H] + .

[0435] 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

[0436] 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,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).

[0437] 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

[0438] Step 1: Synthesis of 4-(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylmorpholine

[0439] 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 hours 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 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, yield 61.8%) as a yellow solid. LC-MS (ESI) m / z: 345.0, 347.0 [M+H] + .

[0440] 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

[0441] 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 hours 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] + .

[0442] 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

[0443] 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)Cl2 (31 mg, 0.047 mmol) and K3PO4 (301 mg, 1.42 mmol) were added to 1,4- The reaction mixture was stirred at 100°C for 12 hours, cooled to room temperature, and water (10 mL) was added. The mixture was extracted with EA (15 mL × 3). The organic phases were combined and 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 used directly in the next reaction (210 mg, yellow solid). LC-MS (ESI) m / z: 494.2 [M+H] + .

[0444] 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

[0445] 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 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, yield 23.0%), as a yellow solid. 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=4.8H z,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).

[0446] 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

[0447] 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

[0448] 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 extracted with EA (15 mL×3). The organic phases were combined, washed sequentially with water (30 mL x 5) and saturated brine (30 mL x 2), dried over anhydrous Na2SO4, 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] + .

[0449] 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

[0450] 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: 20mL / min, 18min) to obtain the target compound (10.0mg, yield 10.0%, yellow solid). LC-MS (ESI) m / z: 437.2[M+H] + . 1 H 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,1 H), 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).

[0451] 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

[0452] Step 1: 3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

[0453] 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 nitrogen, the reaction mixture was stirred at 50°C for 3 hours. 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] + .

[0454] 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

[0455] 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 hr. 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] + .

[0456] Step 3: 3-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylbenzamide

[0457] 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 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] + .

[0458] 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

[0459] 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), Cs2CO3 (159 mg, 0.50 mmol) and CuI (37 mg, 0.20 mmol) were added to NMP (15 mL) in sequence. The reaction mixture was purged with N2 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 extracted with EA (30.0 mL × 2). The organic phases were combined, washed with saturated brine (80.0 mL × 5), dried over anhydrous Na2SO4, 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] + .

[0460] 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

[0461] 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-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).

[0462] 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

[0463] Step 1: 6-Chloro-4-(3,3-dimethylmorpholinyl)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-d]pyrimidine

[0464] 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] + .

[0465] 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

[0466] 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 give the title compound (0.97 g, yield 72.4%, light yellow solid). LC-MS (ESI) m / z: 429.3 [M+H] + .

[0467] Step 3: 6-(8-aza-3-oxabicyclo[3.2.1]octan-8-yl)-4-(3,3-dimethylmorpholinyl)-1H-pyrazolo[3,4-d]pyrimidine

[0468] 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 obtain the title compound (630 mg, 81.3% yield, as a yellow solid). LC-MS (ESI) m / z: 345.4 [M+H] + .

[0469] 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

[0470] 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 solution 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] + .

[0471] 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

[0472] 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). Cs2CO3 (171 mg, 0.52 mmol) and Pd(dppf)Cl2 (13 mg, 0.02 mmol) were then added. The reaction mixture was stirred at 100°C for 2 hrs under N2 protection. 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 organic phases were combined, 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] + .

[0473] 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

[0474] 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), and 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 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (80 mg, crude product, colorless oil). LC-MS (ESI) m / z: 441.2 [M+H] + .

[0475] 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

[0476] 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), Cs2CO3 (148 mg, 0.45 mmol), and CuI2 (35 mg, 0.18 mmol) were added sequentially to NMP (5 mL). Under N2 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] + .

[0477] 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

[0478] 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] + . 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).

[0479] 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

[0480] 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

[0481] 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). The reaction mixture was stirred at 120°C overnight under N2 protection. After the reaction mixture was cooled to room temperature, it was 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] + .

[0482] 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

[0483] 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 nitrogen, the reaction mixture was stirred at room temperature overnight. The residue was concentrated under reduced pressure, and purified by pre-HPLC (column: Shimadzu LC-20AP; Xtimate C18, 21.2*250 mm, 5 μm; 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 obtain the title compound (5.4 mg, yield: 16.4%), as a white solid. LC-MS (ESI) m / z: 396.2 [M+H] + . 1 H 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).

[0484] 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

[0485] Step 1: Synthesis of 6-fluoro-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

[0486] 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] + .

[0487] 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)

[0488] 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 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with EA (200 mL × 2). The combined organic phases were washed with saturated NaCl (500 mL × 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 afford the title compound (21 g, 72.0% yield, as a white solid). LC-MS (ESI) m / z: 441.2 [M+H] + .

[0489] 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

[0490] 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 Pd2(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 (H2O:CH3CN, 35% CH3CN) to obtain the target compound (30 mg, yield 6.2%, light yellow oil). LC-MS (ESI) m / z: 428.2 [M+H] + .

[0491] 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

[0492] 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] + .

[0493] 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

[0494] 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), Cs2CO3 (85 mg, 0.26 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (12 mg, 0.08 mmol) and CuI2 (33 mg, 0.18 mmol) were added. Under N2 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 H2O (20 mL), extracted with EA (10 mL x 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, brownish-yellow solid). LC-MS (ESI) m / z: 494.2 [M+H] + .

[0495] 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

[0496] 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] + . 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).

[0497] 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

[0498] Step 1: Synthesis of (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylmorpholine

[0499] 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 hours 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, 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),3.8 1–3.74(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).

[0500] Step 2: Synthesis of 8-(6-chloro-5-((R)-3-methylmorpholinyl)pyridazin-3-yl)-3-oxa-8-azabicyclo[3.2.1]octane

[0501] (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 yield the title compound (1.25 g, 79.6% yield, as a yellow solid). LC-MS (ESI) m / z: 325.2 [M+H] + .

[0502] Step 3: Synthesis of 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazine-3-carbonitrile

[0503] 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)2 (155 mg, 1.32 mmol), dppf (375 mg, 0.68 mmol), and Pd2(dba)3 (310 mg, 0.34 mmol) were added sequentially to DMF (30 mL). N2 was purged for 2 minutes, and the reaction mixture was then microwaved at 140°C for 4 hours and cooled 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 target compound (1.04 g, yield 97.4%, brown solid). LC-MS (ESI) m / z: 316.2 [M+H] + .

[0504] Step 4: Synthesis of (6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-((R)-3-methylmorpholinyl)pyridazin-3-yl)(cyclopropyl)methanamine

[0505] 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] + .

[0506] 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

[0507] (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 hr, 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] + .

[0508] 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

[0509] 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, which was then extracted with EA (80 mL x 2). The combined organic phases were washed with saturated NaHCO3 (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-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).

[0510] 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

[0511] 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]-morpholin-3-yl]methanol and

[0512] 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

[0513] Step 1: Synthesis of 4-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

[0514] (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] + .

[0515] Step 2: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

[0516] 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 atmosphere 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] + .

[0517] 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

[0518] 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 Cs2CO3 (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 N2 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] + .

[0519] 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

[0520] 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. It was concentrated under reduced pressure. An excess of saturated aqueous Na2CO3 was added to the reaction mixture until alkaline, 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 give the title compound (292 mg, 86.7% yield, as a white solid). LC-MS (ESI) m / z: 346.3 [M+H] + .

[0521] 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

[0522] (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). CsCO (543 mg, 1.67 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (79 mg, 0.56 mmol), and CuI (106 mg, 0.56 mmol) were added sequentially. Under N2 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 Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (150 mg, 54.5% yield, yellow solid). LC-MS (ESI) m / z: 496.2 [M+H] + .

[0523] 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

[0524] (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 separated and 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] + .

[0525] 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

[0526] (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 um: Phase A: Supercritical CO2; Phase B: 0.1% NH3H2O ​​in MeOH, gradient: 50, flow rate: 120 mL / min, 7.24 min) to obtain the target compound P1 (6.4 mg, yield 5.1%), as a white solid. LC-MS (ESI) m / z: 412.2 [M+H] + SFC (Method A): RT = 1.490 min. 1 H 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).

[0527] 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. 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).

[0528] 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]pyridin-6-yl)-3-oxa-8-azabicyclo[3.2.1]octane and

[0529] 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

[0530] 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

[0531] 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 obtain the target compound (900 mg, 47.9% yield, light yellow solid). LC-MS (ESI) m / z: 414.2 [M+H] + .

[0532] 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

[0533] 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 weak base 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] + .

[0534] 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

[0535] 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] + .

[0536] 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

[0537] 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), Na2CO3 (157 mg, 1.48 mmol) and Pd(dppf)Cl2 (43 mg, 0.06 mmol) were added. Under N2 protection, the reaction mixture was stirred at 100°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was separated and purified by reverse-phase silica gel column chromatography (H2O:CH3CN, 42% CH3CN) to obtain the title compound (184 mg, 73.3% yield, light yellow solid). LC-MS (ESI) m / z: 424.2 [M+H] + .

[0538] 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

[0539] 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] + .

[0540] 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

[0541] 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 Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (162 mg, yellow oil). LC-MS (ESI) m / z: 576.2 [M+H] + .

[0542] 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

[0543] 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*250 mm, 5 μm: 0.1% FA; B%: 38-68, flow rate: 20 mL / min, 20 min) to obtain the target compound P1 (22.6 mg, yield 16.4%, white solid). LC-MS (ESI) m / z: 492.2 [M+H] + . 1 H 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).

[0544] and P2 (13.4 mg, yield 9.7%, white solid). LC-MS (ESI) m / z: 492.2 [M+H] + . 1 H 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).

[0545] 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

[0546] 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

[0547] Step 1: Synthesis of (S)-4-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

[0548] (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] + .

[0549] Step 2: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)methyl)morpholine

[0550] (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 with 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] + .

[0551] 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

[0552] 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 Cs2CO3 (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 N2 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] + .

[0553] 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

[0554] 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 N2 protection. The mixture was concentrated under reduced pressure to give the crude product (900 mg, crude product, yellow solid). LC-MS (ESI) m / z: 346.2 [M+H] + .

[0555] 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

[0556] ((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] + .

[0557] 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

[0558] ((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 nitrogen protection, the reaction mixture was stirred at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with water and EA, extracted with EA (50 mL x 2), and 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] + .

[0559] 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

[0560] ((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 under an H2 atmosphere overnight. 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] + .

[0561] 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

[0562] ((3R)-4-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(1,1,1-trifluoropropane-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), and the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, 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] + .

[0563] 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

[0564] ((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*250mm, 5um; mobile phase A: 0.1% TFA / H2O; 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%), as a white solid. 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).

[0565] 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

[0566] The compound ((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 (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 target compound P1 (10 mg, yield 25.0%, white solid). LC-MS (ESI) m / z: 508.2 [M+H] + SFC (Method B) RT = 4.363 min. 1H NMR (400 MHz, DMSO-d6) 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). and P2 (17 mg, yield 42.5%, white solid), LC-MS (ESI) m / z: 508.2 [M+H] + SFC (Method B) RT = 5.230 min. 1 H 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).

[0567] 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

[0568] 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

[0569] ((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). An N2 atmosphere was bubbled through the tube for 2 minutes, and the reaction mixture was then stirred at 150°C in a microwave for 1 hour and 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] + .

[0570] 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

[0571] 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), Cs2CO3 (174 mg, 0.54 mmol), and CuI (68 mg, 0.36 mmol) were added sequentially to NMP (10 mL). After bubbling under N2 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 x 2). The combined organic phases were washed with saturated brine (80 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, 35% EA) to obtain the crude product (23.4 mg, crude product, colorless oil). LC-MS (ESI) m / z: 521.2 [M+H] + .

[0572] 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

[0573] 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*250mm, 5um: 0.1% FA; B%: 22-52, flow rate: 20mL / min, 30min) to obtain the target compound P1 (1.87mg, yield 9.5%, white solid), 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).

[0574] 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

[0575] Step 1: Synthesis of (R)-4-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylmorpholine

[0576] 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 microwaved 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).

[0577] Step 2: Synthesis of 8-(7-((R)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-8-azabicyclo[3.2.1]octane

[0578] (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, 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 = 1:4) to obtain the title compound (139 mg, 47.0% yield, as a white solid).

[0579] 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

[0580] 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.

[0581] 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

[0582] 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), K3PO4 (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 organic phases were combined and 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 isolated and purified by silica gel column chromatography (PE:EA = 1:4) to obtain the title compound (81 mg, yield 56.3%), as a white solid. LC-MS (ESI) m / z: 479.9 [M+H] + .

[0583] 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

[0584] 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 a 6 M aqueous hydrochloric acid / THF solution (2 mL / 4 mL). The reaction mixture was stirred at 50°C for 1 hour, 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to afford the title compound (30 mg, 38.0% yield) as a white solid. 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,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).

[0585] 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

[0586] 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

[0587] 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 hours 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] + . 1H 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).

[0588] 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

[0589] 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 (8.0 g, 18.17 mmol) was dissolved in DMF (120 mL), and (R)-3-methylmorpholine hydrochloride (2.76 g, 27.26 mmol), Cs2CO3 (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 organic phases were combined, 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] + .

[0590] 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)

[0591] 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. The mixture was concentrated under reduced pressure, and saturated aqueous NaHCO₃ was added to the residue until weakly alkaline. The residue 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] + .

[0592] 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

[0593] 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 minutes, followed by the slow addition of I2 (11.19 g, 44.08 mmol) over 2.5 hours. The mixture was then stirred at 30°C for 1 hour. An excess of saturated aqueous Na2SO3 was added to the reaction mixture, which was then 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 afford the title compound (5.4 g, 53.8% yield, as a pale yellow solid). LC-MS (ESI) m / z: 456.2 [M+H] + .

[0594] 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)

[0595] 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(CH3COO)2 (4.74 g, 23.72 mmol) under N2 atmosphere, and the reaction mixture was stirred at 50°C under O2 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 organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by normal phase column chromatography (PE / EA = 1 / 1) to obtain the target compound (4.6 g, yield 64.1%, white solid). LC-MS (ESI) m / z: 606.2 [M+H] + .

[0596] 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

[0597] 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), Pd2(dba)3 (12 mg, 0.013 mmol) and Pd(dppf)Cl2 (19 mg, 0.026 mmol) were added sequentially to a microwave tube containing DMA (2 mL). After bubbling under N2 for 2 mins, the reaction mixture was stirred at 150°C in a microwave apparatus 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] + .

[0598] 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

[0599] 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 obtain a crude product, which was then suspended in a PE / EA mixture (PE / EA = 1 / 1), filtered, and the collected solid was lyophilized to yield 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-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).

[0600] 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

[0601] 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

[0602] 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, and then extracted 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 obtain the title compound (2.8 g, 87.0% yield, yellow solid). LC-MS (ESI) m / z: 586.2 [M+H] + .

[0603] 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

[0604] 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(PPh3)2Cl2 (1.85 g, 5.12 mmol). The reaction mixture was stirred at 100°C for 16 hours under N2 protection and then cooled to room temperature. Excess water and EA were added to the reaction mixture, which was then 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 added with 2N aqueous hydrochloric acid (20 mL). The mixture was stirred at 25°C for 2 hours 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] + .

[0605] 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

[0606] 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 Cs2CO3 (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 N2 protection and 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] + .

[0607] 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

[0608] 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 NH4Cl 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] + .

[0609] 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

[0610] 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). 4N hydrochloric acid / dioxane solution (2 mL) was added, and 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-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),2.85–2.7 7(m,1H),2.02–1.88(m,4H),1.76(d,J=7.1Hz,3H),0.91(d,J=5.8Hz,3H).

[0611] and P2: the second peak, (4 mg, yield 13.5%, white solid). 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).

[0612] 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

[0613] 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

[0614] 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 Na2SO4, 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] + .

[0615] 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

[0616] 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 for 16 hours under N2 protection. 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 for 3 hours under N2 protection. 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] + .

[0617] 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

[0618] 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), Cs2CO3 (148 mg, 0.45 mmol), and CuI (58 mg, 0.30 mmol) in sequence. The reaction solution was bubbled with N2 for 3 minutes, then stirred at 150°C in a microwave oven 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] + .

[0619] 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

[0620] 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 mixture 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] + . 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).

[0621] 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

[0622] 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-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),4.1 4–4.02(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).

[0623] 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

[0624] 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 overnight under N2 protection. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA / H2O; mobile phase B: gradient: 30-60% B, flow rate: 20 mL / min, 20 min) to obtain the first eluting peak of the target compound P1 (5.0 mg, yield 5.5%, white solid). LC-MS (ESI) m / z: 482.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 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, 4.4% yield, white solid) eluted later. 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).

[0625] 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

[0626] 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

[0627] 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 N2 protection for 36 hours and then cooled to room temperature. Water was added, and 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 silica gel column chromatography (PE:EA, 40% EA). The title compound (100 mg, 56.5% yield) was obtained as a yellow solid. LC-MS (ESI) m / z: 536.3 [M+H] + .

[0628] 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

[0629] 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 solution was stirred at 50°C for 18 hrs and cooled to room temperature. The reaction mixture was neutralized by adding saturated aqueous K2CO3 (5 mL), 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: 0.1% TFA; B%: 20-50, flow rate: 20 mL / min, 18 min) to obtain the title compound (10.0 mg, yield 11.8%, off-white solid). LC-MS (ESI) m / z: 452.2 [M+H] + . 1 H 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).

[0630] 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

[0631] 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

[0632] 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 hours. 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] + .

[0633] 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

[0634] 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 protection for 2 hrs. The residue was concentrated under reduced pressure, and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um; mobile phase A: 0.1% FA / H2O; mobile phase B: ACN, gradient: 20-50% B, flow rate: 20 mL / min, 30 min) to obtain the title compound (12.0 mg, yield 47.4%, white solid). 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).

[0635] 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

[0636] 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), K2CO3 (38 mg, 0.28 mmol) and H2O2 (14 mg, 0.41 mmol) were added to the reaction solution, and the reaction mixture was stirred at room temperature for 12 hrs. Saturated Na2SO3 solution (10 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with EA (20 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, 20*250mm, 10um: mobile phase A: 0.05% NH3.H2O / H2O; mobile phase B: ACN, gradient: 15-45% B, flow rate: 24mL / min, 20min) was used to separate and purify the target compound (5mg, yield 8.3%, white solid). 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).

[0637] 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

[0638] Step 1: Synthesis of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0639] 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, white solid). LC-MS (ESI) m / z: 272.9 [M+H] + .

[0640] Step 2: Synthesis of 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,3-dimethylmorpholine

[0641] 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] + .

[0642] 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

[0643] 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, 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 = 1:4) to obtain the title compound (248 mg, 82.7% yield, as a white solid). LC-MS (ESI) m / z: 429.1 [M+H] + .

[0644] 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

[0645] 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 product 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.

[0646] 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

[0647] 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)-N1,N2-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 Cs2CO3 (285 mg, 0.9 mmol) were added to NMP (10 mL) in sequence. 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 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 (88 mg, 50.9% yield, as a white solid). LC-MS (ESI) m / z: 495.0 [M+H] + .

[0648] 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

[0649] (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 a 6 M aqueous hydrochloric acid / THF solution (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 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to afford the title compound (57 mg, 69.2% yield, as a white solid). LC-MS (ESI) m / z: 412.07 [M+H] + . 1 H 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).

[0650] 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

[0651] 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

[0652] ((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, and the mixture was 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 target compound (550 mg, yield 83.4%, white solid). LC-MS (ESI) m / z: 622.2 [M+H] + .

[0653] 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

[0654] ((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 N2 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, and the mixture was extracted with DCM (5 mL × 2). The organic phase was concentrated under reduced pressure to obtain the title compound (30 mg, 14.9% yield, off-white solid). LC-MS (ESI) m / z: 624.2 [M+H] + .

[0655] 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

[0656] 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), and Zn(0) (9 mg, 0.14 mmol), Zn(CN)2 (17 mg, 0.14 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol) and Pd2(dba)3 (5 mg, 0.005 mmol) were added to the solution. The reaction mixture was stirred at 150°C for 1 hrs under N2 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] + .

[0657] 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

[0658] 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 product was concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC (column: Xtimate C18, 21.2*250mm, 5um: 0.1% FA; B%: 30-60, flow rate: 20mL / min, 20min) 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 (6.0mg, off-white solid). 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).

[0659] 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

[0660] 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 N2 protection for 16 hours. The residue was concentrated under reduced pressure and 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-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).

[0661] 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

[0662] 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-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).

[0663] 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

[0664] 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

[0665] 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 under N2 protection for 30 minutes 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] + .

[0666] 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

[0667] 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 N2 protection for 6 hrs. The reaction mixture was poured into a 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 x 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] + . 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).

[0668] 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

[0669] 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

[0670] 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 CO 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 target compound (1.40 g, yield 83.5%, brown solid). LC-MS (ESI) m / z: 508.3 [M+H] + .

[0671] 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

[0672] 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 mins. 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-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).

[0673] Example 36 and Example 37: (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

[0674] 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

[0675] Under 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 saturated NH4Cl (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 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 (1.32 g, 82.9% yield, brown solid). LC-MS (ESI) m / z: 578.2 [M+H] + .

[0676] 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

[0677] 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 residue was concentrated under reduced pressure, and saturated NaHCO₃ solution was added, extracted with EA. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 0% to 100% EA) to obtain a crude product. This was then purified by Prep-HPLC (column: Xtimate C₁₈, 21.2 x 250 mm, 5 μm; 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, 40 mm ID x 250 mm, 10 μm: Supercritical CO₂, B%: 40, solvent: ethanol, flow rate: 120 mL / min, 7.5 min) to obtain the target compound P1 (31.53 mg, 36.9% yield, white solid). LC-MS (ESI) m / z: 494.2 [M+H] + SFC (Method C): RT = 2.939 min. 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,2 H), 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 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 (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).

[0678] 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

[0679] 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

[0680] 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 NH4Cl solution (10 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was extracted with EA (20 mL x 2). The organic phases were combined, dried over anhydrous Na2SO4, 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] + .

[0681] 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

[0682] 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 a 4N hydrochloric acid / 1,4-dioxane (1 mL) solution was added, and the reaction mixture was reacted at 50 ° C under N2 protection for 6 hrs. The residue was concentrated under reduced pressure, and saturated NaHCO₃ solution was added to the residue until alkaline, followed by EA (5 mL) and water (5 mL). 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 (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).

[0683] 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

[0684] 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 N2 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 separated and 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. 1 H 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 = 12.3 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. 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,3 H),3.57(d,J=10.9Hz,2H),3.53–3.47(m,1H),3.41(s,3H),3.08(d,J=1 1.6Hz,1H),2.87–2.78(m,1H),2.03–1.90(m,5H),0.88(d,J=6.0Hz,3H).

[0685] 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

[0686] 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

[0687] 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] + .

[0688] 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

[0689] 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: 20mL / min, 20min) to obtain the title compound (10.0mg, yield 23.4%, off-white solid). LC-MS (ESI) m / z: 496.2[M+H] + . 1 H 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),3.4 3–3.34(m,1H),2.93–2.79(m,1H),2.18–1.97(m,4H),0.99(d,J=5.9Hz,3H).

[0690] 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

[0691] 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 CO2; mobile phase B: MeOH, B%: 25, flow rate: 140 mL / min, 16 min) to obtain the target 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-d4) δ7.76 (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 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-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).

[0692] 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

[0693] 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

[0694] 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%, as a yellow solid). LC-MS (ESI) m / z: 512.2 [M+H] + .

[0695] 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

[0696] 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 reaction 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*250mm, 5um; mobile phase A: 0.1% FA / H2O; mobile phase B: ACN, gradient: 35-65% B, flow rate: 20mL / min, 20min) to obtain the title compound (5.0mg, yield 5.4%), as a white solid. 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,3 H),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).

[0697] 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

[0698] 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

[0699] 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 mixture, 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] + .

[0700] 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

[0701] 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*250mm, 5um; mobile phase A: 0.1% FA / H2O; 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-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),3.89–3.7 8(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).

[0702] 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

[0703] 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 N₂ protection for 2 hours. The product 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-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).

[0704] 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

[0705] 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

[0706] 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 H2O (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). The title compound (26 mg, 60.7% yield, colorless oil) was obtained. LC-MS (ESI) m / z: 519.2 [M+H] + .

[0707] 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

[0708] 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 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] + . 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).

[0709] 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

[0710] 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

[0711] 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 CH3CN (10 mM) was slowly added to the solution. L) solution, and then 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, yield 72.8%, yellow-green solid). LC-MS (ESI) m / z: 432.2 [M+H] + .

[0712] 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

[0713] 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] + .

[0714] 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

[0715] 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 I2 (220 mg, 0.87 mmol) was slowly added. The reaction mixture was stirred at 25°C under N2 protection for 1 hr. The reaction was terminated with aqueous Na2SO3. EA (10 mL) and H2O (10 mL) were added to the residue, and the mixture was extracted with EA (10 mL x 2). The organic phases were combined, 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] + .

[0716] 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

[0717] 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. for 18 hrs under O2 atmosphere 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, yellow solid). LC-MS (ESI) m / z: 624.2 [M+H] + .

[0718] 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

[0719] 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 organic phases were combined, washed with saturated aqueous NaCl solution (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] + .

[0720] 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

[0721] 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*250mm, 5μm; mobile phase A: 0.1% FA / H2O; mobile phase B: ACN, gradient: 35-65% B, flow rate: 20mL / min, 30min) to obtain the title compound (11.0mg, yield 37.4%, off-white solid). LC-MS (ESI) m / z: 439.2 [M+H] + . 1 H 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).

[0722] 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

[0723] 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

[0724] 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 hours, 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 = 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] + .

[0725] 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

[0726] 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 6 M 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] + .

[0727] 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

[0728] 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)-N1,N2-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 Cs2CO3 (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, cooled to room temperature, and water (15 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL × 3). The organic phases were combined and washed 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 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.

[0729] 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

[0730] 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 6M aqueous hydrochloric acid / THF solution (2 mL / 4 mL) and stirred overnight at 50°C. 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] + . 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).

[0731] 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

[0732] 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

[0733] 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 then K2CO3 (71.8 mg, 0.52 mmol), 2,4,6-trimethylolpropane (70 mg, 0.52 mmol), and 2,4,6-trimethylolpropane (100 mg, 0.17 mmol) were added in sequence. The reaction mixture was stirred at 100°C for 16 hours under N2 protection and cooled to room temperature. The 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 obtain a crude product (70 mg, 85.8% yield, pale yellow oil) which was directly used for the next reaction. LC-MS (ESI) m / z: 494.2 [M+H] + .

[0734] 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

[0735] 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 NaHCO3 solution (10 mL) and 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, 5um: Mobile phase A: water (containing 0.1% FA); Mobile phase B: ACN, gradient: 22-52% B, flow rate: 20mL / min, 20min) was used for separation and purification to obtain the title compound (30mg, yield 55.1%, white solid). LC-MS (ESI) m / z: 410.2[M+H] + . 1 H 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).

[0736] 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

[0737] 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

[0738] ((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 N protection for 30 min. Water (25 mL) was added to the reaction mixture, which was extracted with DCM. The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous NaSO, 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] + .

[0739] 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

[0740] (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 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, which was then 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 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] + .

[0741] 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

[0742] 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 then Zn(CN)2 (88 mg, 0.75 mmol), Zn(0) (49 mg, 0.75 mmol), Pd2(dba)3 (23 mg, 0.025 mmol) and Pd(dppf)Cl2 (36 mg, 0.050 mmol) were added in sequence. The reaction mixture was reacted at 150°C under N2 protection for 1 hour and 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 x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (120 mg, yield 88.9%, brown oil). LC-MS ((ESI) m / z: 541.2 [M+H] + .

[0743] 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

[0744] 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. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA, 60% EA) followed by reverse-phase column chromatography (HO: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-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).

[0745] 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

[0746] 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

[0747] 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, which was directly used for the next reaction (35 mg, yield 69.9%, yellow oil). LC-MS (ESI) m / z: 594.2 [M+H] + .

[0748] 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

[0749] 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, 5um; 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, yield 7.1%, white solid). 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).

[0750] 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

[0751] 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

[0752] 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 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. 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] + .

[0753] 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

[0754] 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 N2 protection for 2 hr. 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%, yellow solid). LC-MS (ESI) m / z: 311.2 [M+H] + .

[0755] 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

[0756] 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 hr. 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 obtain the title compound (100 mg, 56.9% yield, as a white solid). LC-MS (ESI) m / z: 437.0 [M+H] + .

[0757] 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

[0758] 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 N 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 x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous Na2SO4, 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] + .

[0759] 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

[0760] (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), Pd2(dba)3 (6.3 mg, 0.0070 mmol) and Pd( dppf)Cl2 (10 mg, 0.014 mmol) was added sequentially to DMA (3 mL). The reaction mixture was stirred at 150°C for 2 hrs under N2 protection. Water (15 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 (15 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated 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] + .

[0761] 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

[0762] 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 hours, then 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% 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, yield 32.2%), as a white solid. LC-MS (ESI) m / z: 402.2 [M+H] + . 1 H 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=2.1 Hz,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).

[0763] 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

[0764] Step 1: Synthesis of (R)-1-benzyl-2-methylpiperidin-4-one

[0765] (R)-2-Methylpiperidin-4-one (2.80 g, 18.72 mmol) was dissolved in ACN (40 mL), and KCO (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 NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA, 15% EA) to obtain the title compound (3.42 g, 89.9% yield, colorless oil). LC-MS (ESI) m / z: 204.2 [M+H] + .

[0766] Step 2: Synthesis of (2R)-1-benzyl-2-methylpiperidin-4-ol

[0767] ((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] + .

[0768] Step 3: Synthesis of (2R)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine

[0769] (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 obtain the title compound (3.30 g, 64.2% yield, as a colorless oil). LC-MS (ESI) m / z: 320.4 [M+H]+ .

[0770] Step 4: Synthesis of (2R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpiperidine

[0771] (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] + .

[0772] 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

[0773] 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. Water and EA were added to the reaction mixture, which was then extracted with EA (80 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (2.03 g, 100% yield, yellow oil). LC-MS (ESI) m / z: 542.4 [M+H] + .

[0774] 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

[0775] 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 N2 protection for 16 hrs. The mixture was concentrated under reduced pressure, and a saturated NaHCO3 solution was added to the residue until alkaline. The mixture was extracted with DCM (50 mL x 2). The organic phases were combined, washed with a saturated NaHCO3 solution (80 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, 0% to 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] + .

[0776] 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

[0777] (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 under N2 protection for 2 hrs. The reaction 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 residue was concentrated under reduced pressure, and 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] + .

[0778] 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

[0779] (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. The reaction mixture was stirred at 50°C under O₂ atmosphere for 16 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 × 2). The combined organic phases were washed with saturated brine (50 mL × 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 target compound (100 mg, yield 75.8%, yellow solid). LC-MS (ESI) m / z: 620.2 [M+H] + .

[0780] 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

[0781] (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)2 (28 mg, 0.24 mmol), zinc powder (16 mg, 0.24 mmol), Pd2(dba)3 (3.7 mg, 0.004 mmol), and Pd(dppf)Cl2 (5.9 mg, 0.008 mmol) were added sequentially to DMA (30 mL). The reaction mixture was stirred at 150°C under N...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof, in: W is N or CR3; A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein at most three, preferably at most two, of A1, A2, A3, A4 and A5 are N; L represents a valence bond, optionally replaced by one or more R L Substituted C 1-6 Alkylene, -NR a -, -O-, -CO-, -SO- or -SO2-; A stands for 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 with one or more independently selected R4; Ring B is connected to A2 or A3, indicating C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; R1 is: absent; hydrogen; halogen; cyano; hydroxyl; C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, each optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-、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 Substituents of cycloalkyl group; 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 by one or more independently selected from halogen, cyano, hydroxy, C 1-6 Alkyl and NR a R b Substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 alkyl)-SO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 alkyl)-PO-; R2 is H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, NR a R b NR a R b CO-、NR a R b SO-、NR a R b SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2- or (C 1-6 alkyl)-SO(NH)-; R3 is hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 cyanoalkyl; R4 are each 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 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated 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 SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge; R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl or C 3-8 Cycloalkyl-C 1-6 Alkylene-; R L are independently hydrogen, halogen, CN, hydroxy, NH2 and C 1-3 haloalkyl; and Indicates that the ring is aromatic.

2. 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: in, Include The ring is aromatic; 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).

3. 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 valence bond, C 1-6 Alkylene, -NR a -, -O-, -CO- or -SO2-; or 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 -SO2-; or L represents a valence bond, C 1-6 Alkylene, -NH-, -N(C 1-6 Alkyl)- or -CO-, preferably a valence bond, C 1-6 Alkylene or -N(C 1-6 alkyl)-; or L represents a valence bond.

4. A compound according to any one of the preceding claims, wherein A represents C or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic derivative such as a deuterated derivative or solvate thereof 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 C 1-6 Alkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, more preferably C 3-8 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, more preferably 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each optionally substituted by one or more, for example one to three independently selected R4; or A represents C 1-6 alkyl or 3-10 membered heterocycloalkyl, each optionally substituted by one or more, e.g., one to three, independently selected R4; optionally, the 3-10 membered heterocycloalkyl is a 3-10 membered, e.g., 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 5-7 membered, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Or, A means Each is optionally substituted with one or more, eg, one to three, independently selected R4.

5. 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 is O, -CH2- or -NH-; Y is N or CH; R4 are each independently located on the same or different ring members and are 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 Halogenated alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated 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 SO2-, (C 1-6 alkyl)-CO-, (C 1-6 alkyl)-SO-, (C 1-6 Alkyl)-SO2-, or (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge; R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-, preferably each independently hydrogen or C 1-6 alkyl; p is 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3; m and n are each independently 0, 1, 2 or 3; and Said A is connected to the rest of the formula (I) through Y.

6. 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.

7. 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 are 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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)-SO2- and (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge; Alternatively, R4 are 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 Halogenated alkyl, 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)-SO2-, or two R4 together form C 1-3 alkylene bridge; Alternatively, R4 are each independently selected from cyano, hydroxyl, 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 Halogenated alkoxy.

8. 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, in, A means wherein R4 are independently selected from halogen, cyano, hydroxyl, 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 Preferably, R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- or (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 Alkylene bridge, where R a and R b are each independently hydrogen or C 1-6 More preferably, R4 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 Halogenated alkyl, C 1-6 haloalkoxy; or, Where A represents wherein Y is C or N, and when there is more than one R4, at least one of said R4 is located in the ortho position of Y; optionally, said R4 located in the ortho position of 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 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, NH(C 1-6 alkyl)-CO-, (C 1-6 alkyl)-CO-, (C 1-6 Alkyl)-SO2- or (C 1-6 Alkyl)-SO(NH)-, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 The haloalkyl group is, for example, a methyl group, a deuterated methyl group or a trifluoromethyl group.

9. 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 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 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; Optionally, Ring B is linked to A2.

10. 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 R2 is H, halogen, CN, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 Preferably, R2 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 More preferably, R2 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 alkyl)CO-; yet more preferably, R2 is H, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-, such as H or C 1-6 alkyl.

11. 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 R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; 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 by one or more independently selected C 1-6 Alkyl substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 wherein optionally, the 3-10 membered heterocycloalkyl group is a 3-10 membered, preferably 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 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; Alternatively, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; 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)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 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; Alternatively, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 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; Alternatively, R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; 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; Alternatively, R1 is: halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2 or C 1-6 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.

12. 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 CR3, and R3 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 Preferably, R3 is hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl (such as C 1-4 More preferably, R3 is hydrogen, deuterium, halogen or C 1-6 Alkyl (such as C 1-4 alkyl); most preferably, R3 is hydrogen, deuterium or halogen, such as hydrogen or halogen.

13. 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 CR3; A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 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 -SO2-; A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4; Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl or pyrazinyl; R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy, (C 1-6 Alkoxy)-CO- and C 3-8 Substituents of cycloalkyl group; 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 by one or more independently selected C 1-6 Alkyl substituents substituted; (C 1-6 alkyl)-CO-; (C 1-6 Alkyl)-SO2-; NR a R b CO-;NR a R b SO2-; or (C 1-3 Alkyl)(C 1-3 wherein optionally, the 3-10 membered heterocycloalkyl group is a 3-10 membered, preferably 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 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 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 alkyl)CO-; R3 is hydrogen, deuterium, halogen or C 1-6 Alkyl (such as C 1-4 alkyl); R4 are 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 Halogenated alkyl, C 1-6 Halogenated alkoxy, 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)-SO2- and (C 1-6 Alkyl)-SO(NH)-, or two R4 together form C 1-3 alkylene bridge; R a and R b are each independently hydrogen, optionally replaced by C 1-6 Alkoxy-substituted C 1-6 Alkyl, or C 3-8 Cycloalkyl-C 1-6 Alkylene-; and Indicates that the ring is aromatic; 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).

14. 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 CR3; A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 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-; A stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4; Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl or pyridyl; R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; 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)-SO2-; NR a R b CO-; or (C 1-3 Alkyl)(C 1-3 wherein optionally, the 3-10 membered heterocycloalkyl group is a 3-10 membered, preferably 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 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 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or NH(C 1-6 alkyl)CO-; R3 is hydrogen, deuterium or halogen; R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 alkylene bridge; R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and Indicates that the ring is aromatic; 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).

15. 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 CR3; A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 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 stands for 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, heteroaryl, e.g., 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S), each optionally substituted with one or more independently selected R4; Ring B is connected to A2 or A3, preferably to A2, indicating that C 6-10 aryl (e.g. phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. 5-10 membered, e.g. 5-7 membered, e.g. 5- or 6 membered heteroaryl, containing 1, 2 or 3 heteroatoms independently selected from N, O or S); preferably, ring B represents phenyl, pyrazolyl, imidazolyl or pyridyl; R1 is: absent; hydrogen; halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2, C 1-6 Alkoxy and (C 1-6 Alkoxy)-CO-substituted; C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl or C 6-10 Aryl; (C 1-6 alkyl)-SO2-; or (C 1-3 Alkyl)(C 1-3 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, C 1-6 Alkyl or NH(C 1-6 alkyl)CO-; R3 is hydrogen, deuterium or halogen; R4 are 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 Halogenated alkyl, C 1-6 Haloalkoxy, NR a R b NR a R b -CO-, (C 1-6 alkyl)-CO- and (C 1-6 Alkyl)-SO2-, or two R4 together form C 1-3 alkylene bridge; R a and R b are each independently hydrogen or optionally replaced by C 1-6 Alkoxy-substituted C 1-6 alkyl; and Indicates that the ring is aromatic; 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).

16. 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 CR3; A1, A2, A3 and A5 are each independently C, N or CH, and A4 is C or N, wherein two of A1, A2, A3, A4 and A5 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 R4; Ring B is connected to A2 or A3, preferably connected to A2, 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 is: halogen; cyano; C 1-6 Alkyl, optionally substituted by one or more independently selected from halogen, cyano, hydroxy, NH2 or C 1-6 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 C 1-6 alkyl; R3 is hydrogen, deuterium or halogen; R4 are each independently selected from cyano, hydroxyl, 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 Indicates that the ring is aromatic; 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).

17. 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.

18. 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.

19. 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, together with a pharmaceutically acceptable carrier, diluent or excipient, and optionally one or more additional active agents.

20. 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.

21. 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.

22. 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 a condition requiring mTOR inhibition.

23. The method of claim 20 or the use of claim 21 or the compound of 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, a nervous system disease, a metabolic disease, an 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). leukemia and 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; it can be used as an immunosuppressive drug to prevent transplant organ rejection, and for vascular stent coatings to exert an anti-rejection effect.

24. 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 rejection or for use in vascular stent coating.

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