BTK-targeted proteolysis targeting chimera compound, composition containing compound and use thereof

Abstract

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, a pharmaceutical composition containing the compound and a use thereof in treating and / or preventing BTK-related diseases.

Description

Targeting btk protein degradation targeting intercalators and compositions and uses thereof

[0001] Reference to Related Applications

[0002] This application claims priority to Chinese Patent Application No. 202411140990.9, filed on August 19, 2024, the entire contents of which are incorporated herein by reference as part of the specification. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, in particular relates to protein degradation targeting intercalators having degradation and / or inhibitory activity on mutant BTK, also relates to pharmaceutical compositions comprising them, and their preparation methods and uses. BACKGROUND

[0004] Bruton’s tyrosine kinase (BTK) is a member of the Src-related Tec family of cytoplasmic tyrosine kinases. BTK is a key kinase in the BCR signaling pathway. When the BCR signaling pathway is activated, the signal is transmitted through immunoglobulin lambda (lgλ) to induce the phosphorylation of Src kinase family members, which catalyzes the dual phosphorylation of Tyr551 and Tyr223 sites in BTK to activate BTK. Activated BTK promotes the phosphorylation of downstream phospholipase C gamma (PLCγ), and phosphorylated PLCγ hydrolyzes 4,5-bisphosphate phosphatidylinositol (PIP2) to generate inositol triphosphate (IP3) and diacyl glycerol (DAG). IP3 promotes intracellular calcium release, and DAG cooperates with calcium ions to activate protein kinases (MAPKs), mammalian target of rapamycin (mTOR), and other signaling pathways, thereby regulating the expression of genes and cytokines. On the other hand, BTK can activate IκB kinase, which in turn promotes the phosphorylation of IκB and induces its dissociation from nuclear factor kappa-B (NF-κB). NF-κB dissociated from IκB translocates into the nucleus due to the exposure of its nuclear localization sequence, and specifically binds to NF-κB sites on DNA to play a role in regulating cell function.

[0005] BTK is an important component of normal and malignant B-cell receptor signaling. BTK plays a key role in the B-cell antigen receptor signaling pathway and is required for the development, activation, and survival of B-cells. BTK is a validated molecular target that can be found in many B-cell leukemias and lymphomas, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), waldenstrom’s macroglobulinemia (WM), and marginal zone lymphoma (MZL).

[0006] Some covalent BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, etc., are covalently bound to the C481 of the BTK protein kinase domain, thereby achieving the purpose of inhibiting the enzyme activity of BTK. After long-term use of these drugs, the amino acid residue C481 on BTK may mutate, so that the original inhibitor can no longer form a covalent bond with BTK, and the inhibitory activity of BTK is greatly weakened, thereby causing the human body to develop resistance to covalent BTK inhibitors. The known BTK resistance mutations are mainly concentrated in the ATP binding site of BTK, i.e. C481. When C481 is replaced by phenylalanine (C481F), tyrosine (C481Y) or arginine (C481R), etc., it will have a spatial conflict with ATP or BTKi, thereby affecting the covalent binding of BTKi. In addition, L528W is also a common BTK resistance mutation, which is located below the kinase domain of BTK and does not have a direct interaction with ATP, but can impair the kinase activity of BTK.

[0007] Proteolysis targeting chimera (PROTAC) is a targeted protein degradation technology that uses small molecule compounds to regulate protein levels. PROTAC has a different mode of action compared to traditional small molecule drugs and can use unique targets to send proteins to proteasomes to achieve the purpose of chemically degrading proteins. Its core concept is to use artificial small molecule compounds to recruit a specific ubiquitin ligase and degrade proteins by ubiquitinating target proteins. This technology has better tolerance compared to traditional drugs in the case of target protein mutations, etc. due to the iterative mode of degradation.

[0008] PROTACs can overcome some drug resistance mechanisms faced by small molecule inhibitors, such as mutations in target proteins, up-regulation of expression, changes in active sites, etc., because PROTACs do not need to bind tightly to target proteins or inhibit their enzyme activity, but only need to recruit them to the vicinity of E3 ligases to be ubiquitinated and degraded.

[0009] PROTAC is a promising anticancer strategy that can break through the limitations of traditional small molecule inhibitors, providing more target options and higher treatment efficiency. Currently, several drugs developed based on PROTAC technology have entered the clinical trial stage, showing certain antitumor activity. Therefore, it is necessary to further develop new PROTACs for the treatment of BTK-related diseases. SUMMARY

[0010] The present application provides a novel BTK protein degradation targeting chimera, compositions comprising the same, and methods of making and using the same. The compounds have degradation and / or inhibition activity on BTKs including mutations (e.g., C481S, L528W, or T474I) or combinations of mutations (e.g., T474I-L528W, C481S-L528W, or T474I-C481S), and also have excellent pharmacokinetic properties, and can be used for preventing and / or treating BTK-related diseases, such as tumors or autoimmune system diseases.

[0011] To this end, the present application adopts the following technical solutions:

[0012] In one aspect, the present application relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0013] wherein,

[0014] X1 is N, CD or CH;

[0015] X2 is N or CR2;

[0016] R1 is a bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R;

[0017] R2 is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more groups selected from D, halogen, -(CH2) t -OH, oxo, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy;

[0018] t is 0, 1 or 2;

[0019] R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0020] R5is halogen;

[0021] R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0022] R s and R t are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0023] m is 0, 1, 2 or 3;

[0024] n is 0, 1, 2, 3 or 4;

[0025] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0026] L A is a bond or a bivalent linking group;

[0027] U is a group that binds to an E3 ubiquitin ligase.

[0028] In another aspect, the present application relates to a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0029] wherein,

[0030] X1is N, CD, or CH;

[0031] R1’is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration; 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0032] R5is halogen;

[0033] R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0034] R s and R t are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0035] m is 0, 1, 2, or 3;

[0036] n is 0, 1, 2, 3, or 4;

[0037] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0038] L B is a bivalent linking group;

[0039] U is a group that binds to an E3 ubiquitin ligase.

[0040] In another aspect, the present application relates to a compound of Formula (VII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0041] wherein,

[0042] R1is a bond, or a divalent radical selected from a 5- or 6-membered monocyclic arene or heteroarene or a 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R;

[0043] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein the C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0044] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0045] n is 0, 1 or 2;

[0046] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0047] L A is a bond or a divalent linking group;

[0048] U is a group that binds to an E3 ubiquitin ligase.

[0049] In another aspect, the present application relates to a compound of Formula (VII A ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0050] wherein,

[0051] Y3is N or CH;

[0052] R2is H, D, halogen, C1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0053] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to complete deuterium;

[0054] n is 0, 1 or 2;

[0055] L A is a bond or a divalent linking group;

[0056] U is a group that binds to an E3 ubiquitin ligase.

[0057] In another aspect, the present application relates to a compound of Formula (VII B ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0058] wherein,

[0059] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to complete deuterium;

[0060] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to complete deuterium;

[0061] n is 0, 1 or 2;

[0062] L A is a bond or a divalent linking group;

[0063] U is a group that binds to an E3 ubiquitin ligase.

[0064] In another aspect, the present application relates to a compound of Formula (VII Ca compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0065] wherein,

[0066] R2is H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0067] each R t is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0068] n is 0, 1, or 2;

[0069] L A is a bond or a bivalent linking group;

[0070] U is a group that binds to an E3 ubiquitin ligase.

[0071] In another aspect, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0072] wherein,

[0073] R1is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, or 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl are optionally substituted with one or more R; each R t is independently H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0074] n is 0, 1 or 2;

[0075] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0076] L B is a divalent linking group;

[0077] U is a group that binds to an E3 ubiquitin ligase.

[0078] In another aspect, the present application relates to a pharmaceutical composition comprising a compound of the present application, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient.

[0079] In another aspect, the present application relates to a unit dosage form comprising a pharmaceutical composition of the present application.

[0080] In another aspect, the present application relates to a kit comprising a first container comprising a compound of the present application, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition; and optionally, a second container comprising another therapeutic agent; and optionally, a third container comprising a pharmaceutical excipient for diluting or suspending the compound and / or another therapeutic agent.

[0081] In another aspect, the present application relates to the use of a compound of the present application, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present application, or a unit dosage form of the present application, or a kit of the present application, in the manufacture of a medicament for treating and / or preventing a BTK-related disease.

[0082] In another aspect, the present application relates to a method of inducing BTK inhibition and / or degradation in a cell, the method comprising contacting the cell with a compound of the present application, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present application, or a unit dosage form of the present application, or a kit of the present application. In a particular embodiment, the contacting can be performed in vitro or in vivo.

[0083] In another aspect, the present application relates to a method of treating and / or preventing a BTK related disease in a subject, comprising administering to the subject a compound of the present application, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present application, or a unit dosage form of the present application or a kit of the present application.

[0084] In another aspect, the present application relates to the use of a compound of the present application, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present application, or a unit dosage form of the present application or a kit of the present application, in the treatment and / or prevention of a disease caused by BTK.

[0085] In specific embodiments, the present application relates to a BTK selected from wild-type BTK or mutant BTK. In specific embodiments, the mutant BTK is a BTK having at least one mutation site. In specific embodiments, the mutant BTK is a single mutant BTK or a double mutant BTK. In more specific embodiments, the single mutant BTK is selected from BTK E108K, BTK Y133E, BTK R134E, BTK P385A, BTK T387A, BTK V416L, BTK A428D, BTK M437R, BTK T474A, BTK T474I, BTK T474M, BTK T474S, BTK C481F, BTK C481G, BTK C481R, BTK C481S, BTK C481T, BTK C481W, BTK C481Y, BTK L512M, BTK E513G, BTK F517L, BTK L528W, BTK L547P or BTK Y551F. In more specific embodiments, the double mutant BTK is selected from BTK Y133E-R134E, BTK P385A-T387A, BTK T474A-C481S, BTK T474I-C481S, BTK T474I-L528, BTK T474M-C481S, BTK T474M-C481T, BTK T474M-L512M, BTK T474M-E513G, BTK T474M-F517L, BTK T474M-L547P, BTK T474S-C481S, BTK C481S-L528W or BTK C481F-Y551F.

[0086] In particular embodiments, the BTK-related disease to which the application relates is selected from an autoimmune disease, an inflammatory disease, or a tumor. In particular embodiments, the autoimmune disease is selected from rheumatoid arthritis, psoriasis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute post-viral encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, stiff-man syndrome, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma, vulvodynia, complications resulting from organ transplants, diabetes, asthma, atopic dermatitis, ulcerative colitis, Crohn's disease, or Alzheimer's disease. In particular embodiments, the inflammatory disease is selected from keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonitis, myocarditis, gastritis, gastroenteritis, cholecystitis, or appendicitis. In particular embodiments, the tumor is selected from a solid tumor or a hematological tumor. In more particular embodiments, the solid tumor is selected from a brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestinal cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tract tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, or vaginal cancer.In more specific embodiments, the hematological tumor is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), acute myeloid leukemia with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma, Burkitt's lymphoma, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma.

[0087] Other objects and advantages of the application will become apparent to those skilled in the art from the subsequent detailed description, examples, and claims.

[0088] Definitions

[0089] Chemical Definitions

[0090] The definitions of specific functional groups and chemical terms are described in more detail below.

[0091] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl groups.

[0092] "C 1-6"Alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, C 1-4 Alkyl groups are particularly preferred. Examples of alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). Each alkyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, whether or not modified by "substituted," with suitable substituents as defined below.

[0093] "C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4 Alkenyl groups are particularly preferred. Examples of alkenyl groups include, but are not limited to, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1 -butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Each alkenyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, whether or not modified by "substituted," with suitable substituents as defined below.

[0094] "C 2-6 "Akynyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 Akynyl groups are particularly preferred. In some embodiments, the akynyl group does not contain any double bonds. The one or more carbon triple bonds can be internal (e.g., in 2-butylynyl) or terminal (e.g., in 1-butylynyl). Examples of akynyl groups include, but are not limited to, ethynyl (C2), 1 -propynyl (C3), 2-propynyl (C3), 1 -butynyl (C4), 2-butylynyl (C4), pentynyl (C5), hexynyl (C6), and the like. Each akynyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate, whether or not modified by "substituted," with suitable substituents as defined below.

[0095] "C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0096] "C 1-6 "Alkylene" refers to a divalent group formed by removing a hydrogen from each of two hydrogens on a C 1-6 alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 Alkylene groups are particularly preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0097] "C 0-6 Alkylene" includes a bond and C 1-6 alkylene groups as defined above.

[0098] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0099] "C 1-6 haloalkyl" and "C 1-6 haloalkoxy" refers to the above "C 1-6 alkyl" and "C 1-6"Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1- 2-Haloalkyl. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 is more preferred. 1-2 Haloalkoxy groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0100] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl. Cycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be fused, spirocyclic, bridged, or a combination thereof. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[3.1.1]heptyl (C7), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), etc. 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 ), etc. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, with suitable substituents defined as follows.

[0101] "3 to 14 membered heterocyclyl" or refers to a 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 7 membered heterocyclyl is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6 membered heterocyclyl is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5 to 6 membered heterocyclyl, which is a 5 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be fused, spiro, bridged, or combinations thereof. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl, aryl, or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Each heterocyclyl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents as defined below, whether or not preceded by the designation "substituted."

[0102] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: 2-azabicyclo[2.1.1]hexane, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptane, piperazine, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azaheptanyl, oxaheptanyl, and thianyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azaoctyl, oxaoctyl, and thianyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0103] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene). In some embodiments, C 6-10Aryl is particularly preferred, more preferably C6 aryl. Aryl also includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the aryl ring system. Each aryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0104] "5- to 10-membered heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-described heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the heteroaryl ring, in which case the number of carbon atoms designates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Each heteroaryl group is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as defined below, whether or not modified by "substituted."

[0105] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0106] Exemplary substituents on carbon include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb)2, -C(=NR bb )R aa )2, -C(=NR bb )OR aa )2, -OC(=NR bb )R aa )2, -OC(=NR bb )OR aa )2, -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NRbb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0107] or two geminal hydrogens on a carbon atom are replaced with a group =0, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc ;

[0108] each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0109] each R bb is independently selected from hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(Rcc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0110] R cc each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0111] R dd each occurrence is independently selected from the group consisting of: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee, -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0112] each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0113] each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg group is substituted;

[0114] R gg each independently is: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1- 6alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0115] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2Rcc -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd , R aa , R bb , R cc , and R dd are as described above.

[0116] “Deuterated” or“D” means that one or more hydrogens in a compound or group are replaced by deuterium; deuterated can be mono-substituted, di-substituted, poly-substituted, or per-substituted. The terms“one or more deuterated” and“one or more deuterium substitutions” are used interchangeably.

[0117] “Non-deuterated compound” means a compound having a proportion of deuterium atoms no greater than the natural isotopic content of deuterium (0.015%).

[0118] Deuterium has an isotopic content at the site of deuterium substitution that is at least greater than the natural isotopic content of deuterium by 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.

[0119] Other Definitions

[0120] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using standard procedures for salt formation known in the art, for example, ion exchange procedures. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, bisulfite, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by counterion with pharmaceutically acceptable anions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0121] A "subject" for administration includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, swine, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0122] "Disease," "disorder," and "condition" are used interchangeably herein.

[0123] Unless otherwise indicated, the term "treatment" as used herein includes actions that occur while a subject has a particular disease, disorder, or condition, that decrease the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition ("therapeutic treatment"), and also includes actions that occur before a subject has a particular disease, disorder, or condition ("prophylactic treatment").

[0124] "Combination" and related terms refer to the administration of a therapeutic agent of the application simultaneously or sequentially. For example, a compound of the application can be administered simultaneously or sequentially in separate unit dosage forms or as a single unit dosage form together with another therapeutic agent.

[0125] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit the biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the application can vary depending on such factors as the biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. Effective amounts include therapeutically and prophylactically effective amounts.

[0126] Unless otherwise indicated, a "therapeutically effective amount" of a compound, as used herein, is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of symptoms, or enhances the therapeutic efficacy of another therapeutic agent.

[0127] As used herein, unless otherwise noted, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with the disease, disorder or condition, or to prevent the disease, disorder or condition from recurring. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the process of preventing the disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or enhances the prophylactic efficacy of other prophylactic agents. DETAILED DESCRIPTION

[0128] Compounds

[0129] As used herein, a "compound of the application" refers to a compound of Formula (A), Formula (B), Formula (I) - Formula (X) (including subsets of each formula, such as Formula (VII A ) compounds), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0130] In one embodiment, the application relates to a compound of Formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0131] wherein,

[0132] Ring A is phenyl or 5- or 6-membered heteroaryl;

[0133] X1is N, CD or CH;

[0134] X2is N or CR2;

[0135] R1is a bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the divalent radicals above are optionally substituted with one or more R;

[0136] R2is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 alkoxy and C t -OH, oxo, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3groups optionally substituted with one or more D up to complete deuteration;

[0137] t is 0, 1, or 2;

[0138] R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to complete deuteration;

[0139] R5is halogen;

[0140] R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D up to complete deuteration;

[0141] R s and R t are independently H, D, halogen, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino is optionally substituted with one or more R up to complete deuteration;

[0142] m is 0, 1, 2, or 3;

[0143] n is 0, 1, 2, 3, or 4;

[0144] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0145] L A is a bond or a divalent linking group;

[0146] U is a group that binds to an E3 ubiquitin ligase.

[0147] In another embodiment, the present application relates to a compound of Formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is phenyl or 6-membered heteroaryl.

[0148] In another embodiment, the present application relates to a compound of Formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is In one embodiment, the present application relates to a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0149] wherein,

[0150] X1is N, CD or CH;

[0151] X2is N or CR2;

[0152] R1is a bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R;

[0153] R2is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more groups selected from D, halogen, -(CH2) t -OH, oxo, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy;

[0154] t is 0, 1 or 2;

[0155] R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0156] R5is halogen;

[0157] R6is C 1-6alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0158] R s and R t are independently H, D, halo, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0159] m is 0, 1, 2 or 3;

[0160] n is 0, 1, 2, 3 or 4;

[0161] each R is independently selected from D, halo, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0162] L A is a bond or a divalent linking group;

[0163] U is a group that binds to an E3 ubiquitin ligase.

[0164] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1is N.

[0165] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X2is CR2.

[0166] In one embodiment of R2, R2is H, halo or C 1-3 alkyl optionally substituted with 1-5 halo.

[0167] In one embodiment of R2, R2is H, F, CHF2, CF3, CH3or CH(CH3)(CF3).

[0168] In another embodiment of R2, R2is H.

[0169] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R3and R4are both H.

[0170] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R5is F.

[0171] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R6is CH3or CD3.

[0172] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein m is 0.

[0173] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 0.

[0174] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1, R t is F, CH3or CD3.

[0175] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a chemical bond.

[0176] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a divalent radical selected from 5-membered monocyclic heteroarenes, optionally substituted with 1-3 R.

[0177] In one embodiment of R1, the 5-membered monocyclic heteroarenes are selected from:

[0178] the above radicals are optionally substituted with 1-3 R.

[0179] In another embodiment of R1, the divalent radical of the 5-membered monocyclic heteroarene is selected from:

[0180] wherein * indicates attachment to L A , and indicates the remaining attachment to the compound of formula (A) or formula (I), and the foregoing radicals are optionally substituted with 1-3 R;

[0181] In another embodiment of R1, the divalent radical of the 5-membered monocyclic heteroarene is of the structure shown in formula (II):

[0182] wherein

[0183] Y1is N or CH;

[0184] Y2is N or CH;

[0185] wherein * indicates attachment to L A , and indicates the remaining attachment to the compound of formula (A) or formula (I);

[0186] Formula (II) is optionally substituted with 1-3 R.

[0187] In another embodiment, the present application relates to a compound of formula (A) or formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a divalent radical selected from 6-membered monocyclic heteroarenes, which are optionally substituted with 1-3 R.

[0188] In one embodiment of R1, the 6-membered monocyclic heteroarene is selected from:

[0189] which are optionally substituted with 1-3 R.

[0190] In another embodiment of R1, the divalent radical of the 6-membered monocyclic heteroarene is selected from:

[0191] wherein * indicates attachment to L A , and indicates the remaining attachment to the compound of formula (A) or formula (I), and the foregoing radicals are optionally substituted with 1-3 R.

[0192] In another embodiment of R1, the divalent radical of the 6-membered monocyclic heteroarene is of the structure shown in formula (III):

[0193] wherein

[0194] Y3is CH or N;

[0195] Y4is CH or N;

[0196] Y5is CH or N;

[0197] * indicates attachment to L A , indicates the remaining other end attachment to the compound of Formula (A) or Formula (I), Formula (III) is optionally substituted with 1-3 R.

[0198] In another embodiment of R1, the divalent radical of the 6-membered monocyclic heteroarene is of the structure of Formula (III A ):

[0199] wherein,

[0200] Y3is CH or N;

[0201] * indicates attachment to L A , indicates the remaining other end attachment to the compound of Formula (A) or Formula (I), Formula (III A ) is optionally substituted with 1-3 R.

[0202] In another embodiment, the present application relates to a compound of Formula (A) or Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a divalent radical of a 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle, optionally substituted with one or more R.

[0203] In another embodiment of R1, the divalent radical of the 6-membered monocyclic heteroarene is of the structure of Formula (III B ):

[0204] wherein, * indicates attachment to L A , indicates the remaining other end attachment to the compound of Formula (A) or Formula (I), Formula (III B ) is optionally substituted with 1-3 R.

[0205] In one embodiment of R1, the 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle is selected from:

[0206] the foregoing groups are optionally substituted with 1-6 R.

[0207] In another embodiment of R1, the divalent radical of a 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle is selected from:

[0208] wherein * indicates attachment to L A , indicates the remaining attachment to the compound of formula (A) or formula (I), and the above radical is optionally 1-4 R substituted.

[0209] In another embodiment, the present application is directed to a compound of formula (A) or formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1is a radical of formula (IV):

[0210] wherein,

[0211] * indicates attachment to L A , indicates the remaining attachment to the compound of formula (A) or formula (I), and formula (IV) is optionally 1-4 R substituted.

[0212] In another embodiment, the present application is directed to a compound of formula (A) or formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a bond.

[0213] In another embodiment, the present application is directed to a compound of formula (A) or formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a divalent linking group of formula (V’): A1 i A2 j A3 k

[0214] wherein,

[0215] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j and k is other than 0;

[0216] L A1 , L A2 and L A3 are each independently a bond, or selected from the group consisting of C 3-7 ​​​​​​cycloalkane, 4- to 7-membered heterocycle, 5- or 6-membered aryl or heteroaryl bivalent radical, wherein the bivalent radical is optionally substituted with 1-6 R L substituted;

[0217] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NR L -, -C(O)-, -C(O)NR L -, -NR L C(O)-, -C(O)NR L (CR L R L’ ) p -, -C(O)(CR L R L’ ) p -, -NR L C(O)(CR L R L’ ) p -, -(CR L R L’ ) p -, -(CR L R L’ CR L R L’ O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0218] each R L and R L’ is independently selected from H, D, halogen, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or

[0219] R L and R L’ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl;

[0220] represents the connection to U; # represents the connection to the other remaining end in the compound of formula (V’).

[0221] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein, LA is a divalent linking group of formula (V'): #-S0-(L A1 ) i -S1-(L A2 ) j -S2-(L A3 ) k -S3-■(V')

[0222] wherein,

[0223] i is 0 or 1, j is 0 or 1, k is 0 or 1; provided that at least one of i, j and k is not 0;

[0224] L A1 , L A2 and L A3 are each independently a bond, or a divalent group selected from C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein said divalent group is optionally substituted with 1-6 groups selected from D, halo, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0225] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein, p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0226] # indicates attachment to R1; indicates attachment to U.

[0227] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a divalent linking group of formula (V'): A ) #-(L A1 ) i -(L A2 ) j -(L A3 ) k -■(V') A )

[0228] wherein # indicates attachment to R1; and ■ indicates attachment to U.

[0229] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a divalent linking group represented by formula (V B ) A1 ) i A2 ) j A3 ) k B )

[0230] wherein # indicates attachment to R1; and ■ indicates attachment to U.

[0231] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a divalent linking group represented by formula (V C ) A1 ) i (L A2 ) j -S2-(L A3 ) k -S3-■(V C )

[0232] wherein (L A1 ) i and (L A2 ) j share one atom and / or one chemical bond;

[0233] # indicates attachment to R1; and ■ indicates attachment to U.

[0234] In one embodiment of L A , (L A1 ) i and (L A2 ) j share one atom and / or one chemical bond, non-limiting examples of which are:

[0235] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.​​​

[0236] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a bivalent linking group represented by formula (V D ) -S0-(L A1 ) i -S1-(L A2 ) j (L A3 ) k -S3-■(V D )

[0237] wherein (L A2 ) j and (L A3 ) k share one atom and / or one chemical bond;

[0238] # indicates attachment to R1; indicates attachment to U.

[0239] In one embodiment of L A , (L A2 ) j and (L A3 ) k share one atom and / or one chemical bond, non-limiting examples of which are:

[0240] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0241] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A1 , L A2 and L A3 one or two of which are a chemical bond, and the remaining each independently a bivalent group selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein the bivalent groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0242] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0243] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0244] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0245] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0246] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0247] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0248] In another embodiment, the present application relates to a compound of formula (A) or a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0249] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0250] In one embodiment, the present application relates to a compound of Formula (B), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0251] wherein,

[0252] Ring A is phenyl or 5- or 6-membered heteroaryl;

[0253] X1is N, CD, or CH;

[0254] X2is N or CR2;

[0255] R1is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, or 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl, C 1- 6haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl are optionally substituted with one or more R;

[0256] R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0257] R5is halogen;

[0258] R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to complete deuteration;

[0259] R s and R t are independently H, D, halogen, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 1-6 alkyl, C

[0260] m is 0, 1, 2, or 3;

[0261] n is 0, 1, 2, 3, or 4;

[0262] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 haloalkyl, C

[0263] L B is a divalent linking group;

[0264] U is a group that binds to an E3 ubiquitin ligase.

[0265] In another embodiment, the present application relates to a compound of Formula (B), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is phenyl or 6-membered heteroaryl.

[0266] In another embodiment, the present application relates to a compound of Formula (B), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring A is

[0267] In another embodiment, the present application relates to a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0268] wherein,

[0269] X1is N, CD, or CH;

[0270] R1is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl, optionally substituted with one or more R; 1-6 alkyl, C 1- 6haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl, optionally substituted with one or more R;

[0271] R3and R4are independently H, D, halogen, C1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0272] R5is halogen;

[0273] R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 6haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0274] R s and R t are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to complete deuteration;

[0275] m is 0, 1, 2 or 3;

[0276] n is 0, 1, 2, 3 or 4;

[0277] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0278] L B is a bivalent linking group;

[0279] U is a group that binds to an E3 ubiquitin ligase.

[0280] In another embodiment, the present application relates to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1is N.

[0281] In another embodiment, the present application relates to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1’is H, halogen, C 1-3alkyl, or 5- or 6-membered monocyclic aryl or heteroaryl. In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H, F, CHF2, CF3, CH3, CH(CH3)(CF3), pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl.

[0282] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H.

[0283] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R3 and R4 are both H.

[0284] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R5 is F.

[0285] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R6 is CH3 or CD3.

[0286] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein m is 0.

[0287] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 0.

[0288] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1, R t is F, CH3 or CD3.

[0289] In another embodiment, the present application relates to a compound of Formula (B) or a compound of Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein LB The divalent linker shown in formula (VI): #-S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI)

[0290] in,

[0291] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j, and k is not 0;

[0292] L B1 L B2 and L B3 Each is an independent chemical bond, or selected from C 3-7 Cycloalkanes, 4- to 7-membered heterocycles, 5- or 6-membered aryl or heteroaryl divalent groups, wherein the divalent group is optionally surrounded by 1-6 R... L replace;

[0293] S0, S1, S2, and S3 are each an independent chemical bond, -O-, -S-, -NR. L -,-C(O)-,-C(O)NR L -,-NR L C(O)-,-C(O)NR L (CR L R L’ ) p -,-C(O)(CR L R L’ ) p -,-NR L C(O)(CR L R L’ ) p -,-(CR L R L’ ) p -,-(CR L R L’ CR L R L’ O) q -, C 1-6 imide or C 1-6 Alynyl group; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0294] Each R L and R L’ Each is independently selected from H, D, halogens, CN, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or

[0295] R L and R L’ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl;

[0296] ■denotes the connection to U; # denotes the connection to the other remaining end in the compound of formula (V).

[0297] In another embodiment, the present application relates to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a bivalent linking group of formula (VI): # -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI)

[0298] wherein,

[0299] i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0;

[0300] L B1 , L B2 and L B3 are each independently a bond, or a bivalent group selected from C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein said bivalent group is optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0301] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0302] ■ indicates connection to U; # indicates connection to the remaining end of compound (B) or compound (V).

[0303] In another embodiment, the present invention relates to a compound of formula (B) or formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L B For formula (VI) A The divalent linker shown is: #-(L B1 ) i -(L B2 ) j -(L B3 ) k -■(VI A )

[0304] In this context, ■ indicates connection to U; # indicates connection to the remaining end of either compound (B) or compound (V).

[0305] In another embodiment, the present invention relates to a compound of formula (B) or formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L B For formula (VI) B The divalent linker shown is: #-S0-(L B1 ) i -(L B2 ) j -(L B3 ) k -■(VI B )

[0306] In this context, ■ indicates connection to U; # indicates connection to the remaining end of either compound (B) or compound (V).

[0307] In another embodiment, the present invention relates to a compound of formula (B) or formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein L B For formula (VI) C The divalent linker shown is: #-S0-(L B1 ) i (L B2 ) j -S2-(L B3 ) k -S3-■(VI C )

[0308] Among them, (L) B1 )i and (L B2 ) j share one atom and / or one chemical bond;

[0309] represents the remaining connection to U; # represents the remaining connection to the other of the compound of formula (B) or the compound of formula (V).

[0310] In one embodiment of L B , (L B1 ) i and (L B2 ) j share one atom and / or one chemical bond, non-limiting examples of which are:

[0311] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0312] In another embodiment, the present application relates to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a bivalent linking group of formula (VI D ) B1 i B2 j (L B3 ) k D

[0313] wherein (L B2 ) j and (L B3 ) k share one atom and / or one chemical bond;

[0314] represents the remaining connection to U; # represents the remaining connection to the other of the compound of formula (B) or the compound of formula (V).

[0315] In one embodiment of L B , (L B2 ) j and (L B3 ) k share one atom and / or one chemical bond, non-limiting examples of which are:

[0316] ​​​​​wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0317] In another embodiment, the present application is directed to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B1 , L B2 and L B3 one or two of which are a bond and the others are each independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein the divalent radicals are optionally substituted with one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0318] In another embodiment, the present application is directed to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0319] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0320] In another embodiment, the present application is directed to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0321] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0322] In another embodiment, the present application is directed to a compound of formula (B) or a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0323] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0324] In another embodiment, the present application relates to a compound of Formula (B) or Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0325] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0326] In another embodiment, the present application relates to a compound of Formula (B) or Formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0327] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0328] In another embodiment, the present application relates to a compound of Formula (VII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0329] wherein,

[0330] R1is a bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R;

[0331] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein the C 1-6 alkyl and C 1-6 haloalkyl groups are optionally substituted with one or more D, up to complete deuteriation;

[0332] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein the C 1-6 alkyl and C1- 6haloalkyl optionally substituted with one or more D up to complete deuteration;

[0333] n is 0, 1 or 2;

[0334] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0335] L A is a bond or a divalent linking group;

[0336] U is a group that binds to E3 ubiquitin ligase.

[0337] In another embodiment, the present application relates to a compound of Formula (VII A ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0338] wherein,

[0339] Y3is N or CH;

[0340] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D up to complete deuteriation;

[0341] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1- haloalkyl are optionally substituted with one or more D up to complete deuteriation;

[0342] n is 0, 1 or 2;

[0343] L A is a bond or a divalent linking group;

[0344] U is a group that binds to E3 ubiquitin ligase.

[0345] In another embodiment, the present application relates to a compound of Formula (VII B ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0346] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to fully deuterated;

[0347] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to fully deuterated;

[0348] n is 0, 1 or 2;

[0349] L A is a bond or a divalent linking group;

[0350] U is a group that binds to an E3 ubiquitin ligase.

[0351] In another embodiment, the present application relates to a compound of Formula (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0352] wherein,

[0353] R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to fully deuterated;

[0354] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to fully deuterated;

[0355] n is 0, 1 or 2;

[0356] L A is a bond or a divalent linking group;

[0357] U is a group that binds to an E3 ubiquitin ligase.

[0358] In another embodiment, the present application relates to a compound of Formula (VII), (VIIA ), (VII B ), (VII C ), (VII 1-3 ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII t ), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2is H, F, CHF2, CF3, CH3, or CH(CH3)(CF3).

[0359] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII t ), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2is H, F, CHF2, CF3, CH3, or CH(CH3)(CF3).

[0360] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII t ), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2is H.

[0361] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), (VII C ), (VII A ), (VII B ), (VII C ), (VII t ), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 0.

[0362] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), (VII C ), (VII t ), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1, R t is F, CH3, or CD3.

[0363] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), (VII C ), (VII A ), (VII A1 ) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a divalent linking group of formula (V’):i -S1-(L A2 ) j -S2-(L A3 ) k -S3-■(V’)

[0364] wherein,

[0365] i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0;

[0366] L A1 , L A2 and L A3 are each independently a bond, or a divalent radical selected from C 3-7 cycloalkane, 4- to 7-membered heterocycle, 5- or 6-membered aryl or heteroaryl, wherein said divalent radical is optionally substituted with 1-6 R L ;

[0367] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NR L -, -C(O)-, -C(O)NR L -, -NR L C(O)-, -C(O)NR L (CR L R L’ ) p -, -C(O)(CR L R L’ ) p -, -NR L C(O)(CR L R L’ ) p -, -(CR L R L’ ) p -, -(CR L R L’ CR L R L’ O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein, p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0368] each R L and R L’ is independently selected from H, D, halogen, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or

[0369] R L and R L’ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl;

[0370] # indicates attachment to R1; ■ indicates attachment to U.

[0371] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a bivalent linker of formula (V): A1 i A2 j A3 k

[0372] wherein,

[0373] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j and k is not 0;

[0374] L A1 , L A2 and L A3 are each independently a bond, or a bivalent radical selected from C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein said bivalent radical is optionally substituted with 1-6 radicals selected from D, halo, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0375] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 ​​​​​​Alynyl group; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0376] # indicates connection to R1; ■ indicates connection to U.

[0377] In another embodiment, the present invention relates to (VII), (VII) A ), (VII) B ) or (VII) C ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L A For the formula (V') A The divalent linker shown is: #-(L A1 ) i -(L A2 ) j -(L A3 ) k -■(V' A )

[0378] In this context, # indicates that it is connected to R1; ■ indicates that it is connected to U.

[0379] In another embodiment, the present invention relates to (VII), (VII) A ), (VII) B ) or (VII) C ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L A For the formula (V') B The divalent linker shown is: #-S0-(L A1 ) i -(L A2 ) j -(L A3 ) k -■(V' B )

[0380] In this context, # indicates that it is connected to R1; ■ indicates that it is connected to U.

[0381] In another embodiment, the present invention relates to (VII), (VII) A ), (VII) B ) or (VII) C ) compound, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein L A For the formula (V') C The divalent linker shown is: #-S0-(L A1 ) i (LA2 ) j -S2-(L A3 ) k -S3-■(V’ C )

[0382] wherein (L A1 ) i and (L A2 ) j share one atom and / or one chemical bond

[0383] wherein # indicates attachment to R1; and ■ indicates attachment to U.

[0384] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is a bivalent linking group of formula (V’ D ): #-S0-(L A1 ) i -S1-(L A2 ) j (L A3 ) k -S3-■(V’ D )

[0385] wherein (L A2 ) j and (L A3 ) k share one atom and / or one chemical bond

[0386] wherein # indicates attachment to R1; and ■ indicates attachment to U.

[0387] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A1 , L A2 and L A3 one or two of which are a chemical bond, and the others are each independently a bivalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein said bivalent radical is optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0388] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0389] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0390] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0391] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0392] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII C ), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L A is:

[0393] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0394] In another embodiment, the present application relates to a compound of formula (VII), (VII A ), (VII B ), or (VII Ca compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal A is:

[0395] wherein the above groups are optionally substituted with one or more groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0396] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal

[0397] wherein,

[0398] R1’ is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, or 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein the C 1-6 alkyl, C 1- 6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl are optionally substituted with one or more R;

[0399] each R t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6 haloalkyl are optionally substituted with one or more D, up to complete deuteriation;

[0400] n is 0, 1 or 2;

[0401] each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0402] L B is a bivalent linking group;

[0403] U is a group that binds to an E3 ubiquitin ligase.

[0404] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H, F, CHF2, CF3, CH3, CH(CH3)(CF3) phenyl, pyridyl or pyrimidyl. In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H. 1-3 alkyl, or 5- or 6-membered monocyclic aryl or heteroaryl.

[0405] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H, F, CHF2, CF3, CH3, CH(CH3)(CF3) phenyl, pyridyl or pyrimidyl. In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1' is H.

[0406] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 0.

[0407] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1, R t is F, CH3or CD3.

[0408] In another embodiment, the present application relates to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a divalent linking group of Formula (VI): -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI)

[0409] wherein,

[0410] i is 0 or 1, j is 0 or 1, and k is 0 or 1; provided that at least one of i, j and k is other than 0;

[0411] L B1 , L B2 and L B3 are each independently a bond, or selected from the group consisting of C 3-7cycloalkane, 4- to 7-membered heterocycle, 5- or 6-membered aryl or heteroaryl bivalent radical, wherein the bivalent radical is optionally substituted with 1-6 R L substituted;

[0412] S0, S1, S2and S3are each independently a bond, -O-, -S-, -NR L -, -C(O)-, -C(O)NR L -, -NR L C(O)-, -C(O)NR L (CR L R L’ ) p -, -C(O)(CR L R L’ ) p -, -NR L C(O)(CR L R L’ ) p -, -(CR L R L’ ) p -, -(CR L R L’ CR L R L’ O) q -, C 1-6 alkenylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0413] each R L and R L’ is independently selected from H, D, halogen, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or

[0414] R L and R L’ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl;

[0415] represents the connection to U; # represents the connection to the other remaining end in the compound of formula (V).

[0416] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L Bfor a divalent linking group of formula (VI): # -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI)

[0417] wherein,

[0418] i is 0 or 1, j is 0 or 1, k is 0 or 1; provided that at least one of i, j and k is not 0;

[0419] L B1 , L B2 and L B3 are each independently a bond, or a divalent group selected from C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein said divalent group is optionally substituted with 1-6 groups selected from D, halo, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0420] S0, S1, S2and S3are each independently a bond, -0-, -S-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)NH(CH2) p -, -C(O)(CH2) p -, -NHC(O)(CH2) p -, -(CH2) p -, -(CH2CH2O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein, p is 1, 2, 3 or 4; q is 1, 2 or 3;

[0421] represents the connection to U; # represents the connection to the other remaining end in the compound of formula (V).

[0422] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein, L B is a divalent linking group of formula (VI): # -S0-(L A ) B1 ) i -(L B2 ) j -(L B3 ) k -■(VI A )

[0423] wherein ■ indicates attachment to U; and # indicates attachment to the remaining end of the compound of formula (V).

[0424] In another embodiment, the present application is directed to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a divalent linking group represented by formula (VI B ) -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI B )

[0425] wherein ■ indicates attachment to U; and # indicates attachment to the remaining end of the compound of formula (V).

[0426] In another embodiment, the present application is directed to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a divalent linking group represented by formula (VI C ) -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI C )

[0427] wherein (L B1 ) i and (L B2 ) j share one atom and / or one chemical bond;

[0428] wherein ■ indicates attachment to U; and # indicates attachment to the remaining end of the compound of formula (V).

[0429] In another embodiment, the present application is directed to a compound of formula (V), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is a divalent linking group represented by formula (VI D ) -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI D)

[0430] wherein (L B2 ) j and (L B3 ) k share one atom and / or one chemical bond;

[0431] wherein ■ represents the attachment to U; and # represents the attachment to the other remaining end in the compound of formula (V).

[0432] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B1 , L B2 and L B3 are each independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein said divalent radical is optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0433] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0434] wherein the above radicals are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0435] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0436] wherein the above radicals are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

[0437] In another embodiment, the present application relates to a compound of formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0438] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0439] In another embodiment, the present application is directed to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0440] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0441] In another embodiment, the present application is directed to a compound of Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L B is:

[0442] wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

[0443] In another embodiment, the present application is directed to a compound of Formula (A), (B), (I), (V), (VII), (VII A ), (VII B ) or (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0444] wherein,

[0445] represents a single or double bond;

[0446] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0447] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0448] each Q1is independently C(O) or C(R9)2;

[0449] each Q2is independently N or CH;

[0450] each Q3and Q4is independently N or CR9;

[0451] each K1, K2and K3is independently N or CR9;

[0452] K4and K5are each independently N or C;

[0453] H1is N, C or CR9;

[0454] H2and H3are each independently C(O), N, O, S, NR9, CR9or C(R9)2;

[0455] H4and H8are each independently N or CR9;

[0456] H5, H6and H7are each independently C(O), O, S, NR9or C(R9)2;

[0457] each R7is independently H or C 1-6 alkyl;

[0458] each R8is independently D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle;

[0459] each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene;

[0460] each o is independently 0, 1 or 2;

[0461] each h is independently 0, 1, 2, 3 or 4;

[0462] each z is independently 0, 1 or 2;

[0463] each r and s is independently 0, 1, 2 or 3; and r and s are not simultaneously 0;

[0464] each t and u is independently 0, 1, 2 or 3; and t and u are not simultaneously 0.

[0465] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ) or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0466] wherein,

[0467] represents a single or double bond;

[0468] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0469] each W is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0470] each Q1is independently C(O) or C(R9)2;

[0471] each Q2is independently N or CH;

[0472] each Q3and Q4is independently N or CR9;

[0473] each R7is independently H or C 1-6 alkyl;

[0474] each R8is independently D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atom to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocyclic ring;

[0475] each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atom to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocyclic ring, C 6-10 aromatic hydrocarbon or 5- to 10-membered heteroaromatic hydrocarbon;

[0476] each h is independently 0, 1, 2, 3 or 4;

[0477] each k is independently 0, 1, 2, 3 or 4;

[0478] each z is independently 0, 1 or 2;

[0479] each r and s is independently 1, 2, or 3;

[0480] each t and u is independently 1, 2, or 3.

[0481] In another embodiment, the present application is directed to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0482] wherein,

[0483] Q3is N or CR9;

[0484] each R9is independently H, D, or halogen;

[0485] each k is independently 0 or 1.

[0486] In another embodiment, the present application is directed to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0487] wherein,

[0488] Q3is N or CR9;

[0489] each R9is independently H, D, or halogen;

[0490] each k is independently 0 or 1.

[0491] In another embodiment, the present application is directed to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0492] wherein,

[0493] Q3 is N or CR9;

[0494] each R9 is independently H, D, or halogen;

[0495] each k is independently 0 or 1.

[0496] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0497] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0498] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ), or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein U is:

[0499] wherein,

[0500] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2;

[0501] each R 10 is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0502] each R 11 is independently H, Cl, CN, ethynyl, phenyl,

[0503] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ) or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0504] wherein,

[0505] each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O) or CH2;

[0506] each R 10 is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH,

[0507] each R 11 is independently H, Cl, CN, ethynyl, phenyl,

[0508] each R 12 is independently -CH3,

[0509] each R 13 is independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3.

[0510] In another embodiment, the present application relates to a compound of Formula (A), Formula (B), Formula (I), Formula (V), (VII), (VII A ), (VII B ) or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0511] In another embodiment, the present application relates to a compound of Formula (I), Formula (V), (VII), (VII A ), (VII B ) or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0512] In another embodiment, the present application relates to a compound of Formula (I), Formula (V), (VII A ), (VII B ) or Formula (VIII), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein U is:

[0513] In another embodiment, the present application relates to a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, selected from any one of the following compounds:

[0514] The compounds of the present application can include one or more asymmetric centers and can thus occur as various stereoisomers, for example, enantiomeric and / or diastereomeric forms. For example, the compounds of the present application can be individual enantiomers, diastereomers or geometric isomers (such as cis- and trans-forms), or can be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0515] "tautomer" refers to one functional group in certain compounds changing its structure to become another functional group isomer, and can quickly convert to each other, becoming two isomers in dynamic equilibrium, and the two isomers are called tautomers.

[0516] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they occur, either as reactants or as precipitates or crystals from the solvent. These complexes are known as "solvates". When the solvent is water, the complex is known as a "hydrate". The present application encompasses all solvates of the compounds of the present application.

[0517] The term "solvate" refers to a form of a compound or salt thereof in combination with a solvent, typically formed from a solvolysis reaction. This physical association can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the solid state form of the compound. "Solvate" includes both solution-phase solvates and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0518] The term "hydrate" refers to a compound in combination with water. Typically, the ratio of the number of water molecules to the number of molecules of the compound contained in a hydrate of the compound is specified. Thus, a hydrate of a compound can be represented, for example, by the general formula R xH20, where R is the compound, and x is a number greater than zero. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than zero and less than 1, for example, hemihydrates (R 0.5H20)), and polyhydrates (x is a number greater than 1, for example, dihydrates (R 2H20) and hexahydrates (R 6H20)).

[0519] The compounds of the present application can be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present application can exist in one or more crystalline forms. Accordingly, the present application includes within its scope all amorphous or crystalline forms of the compounds of the present application. The term "polymorph" refers to crystalline forms of a compound (or salts, hydrates or solvates thereof) that have the same elemental composition but different crystal packing arrangements. All polymorphs have the same X-ray diffraction pattern. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, the rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate over another. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0520] The present application also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be suitably substituted into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application also embraces compounds of the present application that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labelled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, can be used in 3 H and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e. 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labelled compounds of Formula (I) of the present application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and

[0521] In addition, prodrugs are also encompassed by the present application. The term "prodrug" as employed herein denotes a compound which is converted into its active form, e.g. by hydrolytic cleavage in the blood, after its administration to a patient. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each incorporated herein by reference.

[0522] A prodrug is any covalently bonded compound which, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that their solubility characteristics are improved when the prodrug is administered to a patient. Prodrugs include, for example, compounds of the application in which hydroxy, amino, or mercapto groups are bonded to any group which, when administered to a patient, cleaves to form a hydroxy, amino, or mercapto group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the hydroxy, mercapto, and amino functional groups of the compounds of Formula (I). In addition, in the case of carboxylic acids (-COOH), esters can be used, such as methyl ester, ethyl ester, and the like. The ester itself can be active and / or can be hydrolyzed under in vivo conditions of the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those that break down easily in the human body to release the parent acid or salt thereof.

[0523] Pharmaceutical compositions, formulations, and kits

[0524] In another aspect, the present application provides pharmaceutical compositions comprising a compound of the present application (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0525] A pharmaceutically acceptable excipient for use in the present application refers to a nontoxic carrier, adjuvant or vehicle with which the compound is administered. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0526] The present application also includes kits (e.g., pharmaceutical packs). The kits provided can include a compound of the present application, other therapeutic agents, and first and second containers (e.g., vials, ampules, bottles, syringes, and / or dispersable packs or other suitable containers) containing the compound of the present application, other therapeutic agents. In some embodiments, the kits provided can also optionally include a third container comprising a pharmaceutically-acceptable excipient that can be used to dilute or suspend the compound of the present application and / or other therapeutic agents. In some embodiments, the combination of the compound of the present application and other therapeutic agents provided in the first and second containers form a single unit dosage form.

[0527] The pharmaceutical compositions provided by the present application also include other therapeutic agents. In some embodiments, the other therapeutic agents include: mitotic inhibitors, tubulin inhibitors, alkylating agents, antimetabolites, DNA intercalators, topoisomerase inhibitors, biological response modifiers, immune checkpoint inhibitors, CD20 mAb, or BCL2 inhibitors. In some embodiments, the other therapeutic agents include: vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, cisplatin, carboplatin, cyclophosphamide, 5-fluorouracil, tegafur, methotrexate, cytarabine, hydroxyurea, doxorubicin, mitomycin, bleomycin, enocitabine, camptothecin, interferon, adalimumab, nivolumab, ipilimumab, atezolizumab, rituximab, ibritumomab tiuxetan, or venetoclax.

[0528] The pharmaceutical compositions provided by the present application can be administered by a variety of routes including, but not limited to: oral administration, parenteral administration, inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0529] Generally, an effective amount of a compound provided herein is administered. The amount of a compound actually administered can be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0530] When used to prevent a condition described herein, a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice and under the supervision of a doctor, at a dosage level as described above. Subjects at risk of developing a particular condition include, generally, those who have a family history of the condition, or those who, as a result of genetic testing or screening, are determined to be particularly susceptible to developing the condition.

[0531] A pharmaceutical composition provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound, or a pharmaceutical composition thereof, over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window, over an extended period of time.

[0532] Various methods of administration can be used to further deliver a pharmaceutical composition of the application. For example, in some embodiments, a pharmaceutical composition can be administered as a bolus, e.g., to rapidly increase the concentration of a compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient, e.g., an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus delivered directly to the vein, e.g., by IV infusion, can deliver more rapidly, such that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, a pharmaceutical composition can be administered as a continuous infusion, e.g., by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. In addition, in other embodiments, a bolus dose of a pharmaceutical composition can be administered first, followed by a continuous infusion.

[0533] Oral compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage form, each unit containing a predetermined amount of the active ingredient(s) considered as a dosage to produce the desired therapeutic effect, in association with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured, disposable syringes or injectable liquids in sealed containers, foils or ampules, or tablets or capsules in blister or strain packs, or the like, for retail or wholesale distribution. In such compositions, the compound(s) is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various carriers or excipients and processing aids useful in forming the desired dosing form.

[0534] For oral dosage form, a representative regimen comprises one to five oral doses per day, especially two to four oral doses per day, typically three oral doses per day. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of the compound of the application, with preferred doses providing from about 0.1 to about 10 mg / kg, especially from about 1 to about 5 mg / kg, per dose.

[0535] To provide blood levels similar to or lower than those achieved using injectable doses, transdermal doses are typically selected in amounts from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0536] Injectable doses range from about 0.1 mg / kg / hr to at least 10 mg / kg / hr for from about 1 to about 120 hours, especially 24 to 96 hours. To achieve adequate steady state levels, a preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dose should not exceed about 2 g / day for a 40 to 80 kg human patient.

[0537] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous carrier with buffers, suspending agents, and dispensing agents, colorants, flavorants, and the like. Solid forms can include, for example, any of the following ingredients, or compounds of a similar nature: binders such as, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as, for example, starch or lactose, disintegrating agents, such as, for example, alginic acid, Primogel, or cornstarch; lubricants, such as, for example, magnesium stearate; glidants, such as, for example, colloidal silicon dioxide; sweetening agents, such as, for example, sucrose or saccharin; or flavoring agents, such as, for example, peppermint, methyl salicylate, or orange flavoring.

[0538] Injectable compositions typically are based upon injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, in such compositions the active compound is typically the minor component, often from about 0.05 to 10% by weight, with the remainder being the injectable excipient or the like.

[0539] Transdermal compositions typically are formulated to contain the active ingredient in a topical ointment or cream. When formulated in an ointment, the active ingredient typically is combined with a petrolatum or a water miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are known in the art and typically include additional components to enhance penetration of the active ingredient or formulation into or through the skin. All such known transdermal formulations and components are included within the scope of the present application.

[0540] The compounds of the present application can also be administered by transdermal devices. Such transdermal devices are known in the art and are described in, for example, U.S. Patent Nos. 5,239,33O; 5,223,262; 5,001,139; 4,992,429; 4,879,240; 4,830,408; 4,780,170; 4,664,235; 4,547,360; 4,447,233; 4,447,234; 4,372,587; 4,201,807; 4,180,606; 3,996,887; and 3,970,210.

[0541] The above ingredients for compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques can be found in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0542] The compounds of the present application can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0543] The present application also relates to pharmaceutically acceptable formulations of the compounds of the present application. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moieties, including but not limited to methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. 5,376,645. In some embodiments, the formulation includes a hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0544] Indications

[0545] In another aspect, the present application provides the use of a compound of the present application (including all individual embodiments and generic subsets disclosed herein), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopically enriched variant, hydrate or solvate thereof, and a pharmaceutical composition or kit of the present application, as a medicament.

[0546] In another aspect, a compound of the present application (including all individual embodiments and generic subsets disclosed herein), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopically enriched variant, hydrate or solvate thereof, and a pharmaceutical composition or kit of the present application, can be used to induce BTK inhibition and / or degradation in a cell, e.g., a compound of the present application can induce BTK inhibition and / or degradation in a cell by contacting the cell. In some embodiments, a compound of the present application is contacted with a cell in vitro. In some embodiments, a compound of the present application is contacted with a cell in vivo.

[0547] In other aspects, a compound of the present application (including all individual embodiments and generic subsets disclosed herein), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopically enriched variant, hydrate or solvate thereof, and a pharmaceutical composition or kit of the present application, can be used to treat and / or prevent a disease caused by BTK, e.g., a disease and disorder associated with BTK, e.g., a proliferative disease, e.g., a tumor, including a hematological tumor and a solid tumor, and an inflammatory disorder, an autoimmune disease.

[0548] In some embodiments of any of the methods or uses described herein, the tumor (e.g., a BTK-associated tumor) is a hematological tumor. In some embodiments of any of the methods or uses described herein, the tumor (e.g., a BTK-associated tumor) is a solid tumor. In some embodiments of any of the methods or uses described herein, the tumor (e.g., a BTK-associated tumor) is a B-cell malignancy. In some embodiments of any of the methods or uses described herein, the tumor (e.g., a BTK-associated cancer) is Hodgkin’s lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma), Burkitt’s lymphoma, Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, plasma cell myeloma, plasmacytoma, bone cancer, bone metastasis, breast cancer, gastro-esophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, head and neck cancer, or a gliocyte tumor.

[0549] In some embodiments, the hematological tumor is selected from leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, myeloma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), acute myeloid leukemia with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma), Burkitt's lymphoma, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma. Other examples of hematological tumors include myelodysplastic disorders (MPD), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological tumor is mantle cell lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, or marginal zone lymphoma.

[0550] In some embodiments, the solid tumor is selected from bone cancer, bone metastasis, breast cancer, gastro-esophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, or head and neck cancer.

[0551] In some embodiments, the immune disease is selected from arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodynia, asthma, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0552] In some embodiments, the inflammatory disease is selected from arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, bronchitis, fasciitis, fibrositis, inflammatory enteritis, purulent inflammation, myelitis, myocarditis, myositis, and pneumopathy.

[0553] In some embodiments, the autoimmune disease is selected from the group consisting of lupus, Sjogren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, anti-phospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia.

[0554] In some embodiments, the heteroimmune disease is selected from the group consisting of graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0555] The compounds of the present application exhibit potent and selective BTK inhibition and / or degradation. For example, the compounds of the present application exhibit nanomolar (nM) potency against wild-type BTK, and BTK kinases encoded by BTK genes comprising BTK kinase inhibitor (BTKi) resistance mutations, including single mutations (e.g., E108K, Y133E, R134E, P385A, T387A, V416L, A428D, M437R, T474A, T474I, T474M, T474S, C481F, C481G, C481R, C481S, C481T, C481W, C481Y, L512M, E513G, F517L, L528W, L547P, or Y551F) and double mutations (Y133E-R134E, P385A-T387A, T474A-C481S, T474I-C481S, T474I-L528, T474M-C481S, T474M-C481T, T474M-L512M, T474M-E513G, T474M-F517L, T474M-L547P, T474S-C481S, C481S-L528W, or C481F-Y551F). In some embodiments, the compounds of the present application are particularly potent against BTK with the single mutations T474I, C481S, or L528W. In some embodiments, the compounds of the present application are particularly potent against BTK with the double mutations T474I-C481S, T474I-L528W, or C481S-L528W.

[0556] Examples

[0557] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. The experimental procedures in the following examples, unless otherwise indicated, were generally performed in accordance with conventional procedures or as recommended by the manufacturer. Unless otherwise indicated, parts and percentages are by weight.

[0558] Generally, in the preparation scheme, each reaction is carried out in an inert solvent at a temperature in the range of room temperature to reflux temperature (e.g., 0 °C to 100 °C, preferably 0 °C to 80 °C). The reaction time is generally in the range of 0.1 to 60 hours, preferably 0.5 to 24 hours.

[0559] The abbreviations used herein have the following meanings:

[0560] Synthesis of Related Intermediate Compounds

[0561] Preparation of Intermediate A-1, Potassium (5-fluoro-2-methoxybenzoyl)amino)methyl trifluoroborate

[0562] The following synthetic route was used

[0563] Step 1. Synthesis of 5-fluoro-2-methoxybenzoyl chloride

[0564] To a 100 mL three-necked flask, equipped with magnetic stirring, was added 5-fluoro-2-methoxybenzoic acid (26 g, 150 mmol) and anhydrous dichloromethane (300 mL), the solution was stirred to clear, cooled in an ice-water bath, and oxalyl chloride (38 g, 300 mmol) and anhydrous N,N-dimethylformamide (1.1 g, 15 mmol) were added dropwise under a nitrogen atmosphere. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature overnight. The solvent and unreacted oxalyl chloride were removed by evaporation under reduced pressure and used as is.

[0565] Step 2. Synthesis of Intermediate A-1

[0566] To a 1000 mL three necked flask equipped with magnetic stirring, was added bromomethylboronic acid pinacol ester (36.3 g, 165 mmol) and anhydrous tetrahydrofuran (300 mL), cooled to -78°C under nitrogen atmosphere, added dropwise a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (165 mL, 1 M), stirred for 30 minutes at -78°C, allowed to warm to room temperature and stirred for 30 minutes, added anhydrous methanol (21.1 g, 660 mmol), stirred for 1 hour at room temperature, filtered off the insoluble solid, evaporated the solvent of the filtrate at a temperature not exceeding 30°C, added anhydrous tetrahydrofuran (200 mL) and evaporated the solvent, repeated twice, dissolved the residue in anhydrous tetrahydrofuran (200 mL), added dropwise a solution of 5-fluoro-2-methoxybenzoyl chloride in tetrahydrofuran (200 mL), after the dropwise addition was completed, stirred the reaction mixture at room temperature overnight under nitrogen atmosphere. Evaporated the solvent, dissolved the residue in methanol (300 mL), added potassium hydrogen fluoride aqueous solution (64 g, 825 mmol, 200 mL), stirred the reaction mixture at room temperature overnight. Evaporated the solvent under reduced pressure, distilled off water twice by azeotropic distillation with toluene (100 mL), washed the residue with methyl tert-butyl ether, filtered off, washed the filter cake with hot methanol / acetone (1 / 3, 1000 mL), concentrated the filtrate to dryness, slushed with methyl tert-butyl ether, allowed the solid to precipitate, filtered off, dried the filter cake at 50°C under vacuum to give a white solid 31 g, yield 70.7%.

[0567] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.75 (br s, 1H), 7.65-7.62 (m, 1H), 7.30-7.25 (m, 1H), 7.17-7.14 (m, 1H), 3.87 (s, 3H), 2.13-2.10 (m, 2H).

[0568] Preparation of intermediate A-2 (Z)-3-amino-3-(4-bromophenyl)acrylonitrile

[0569] The following synthetic route was used

[0570] Into a 1000 mL three-necked flask equipped with magnetic stirring, was added 4-bromobenzonitrile (50 g, 274.7 mmol) and anhydrous tetrahydrofuran (500 mL), the solution was stirred, vacuumed and replaced by nitrogen for 3 times, the temperature was dropped to -78 °C, lithium diisopropylamide (206 mL, 412.0 mmol) was added dropwise, after reaction at -78 °C for 4 hours, anhydrous acetonitrile (17.3 g, 412.0 mmL) was added dropwise, after dropwise addition, the reaction was stirred at room temperature for 12 hours under nitrogen atmosphere. The reaction was quenched by adding water (500 mL), extracted by ethyl acetate (500 mL x 2), the combined organic phase was washed by saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 42.6 g of white solid, with a yield of 70.0%. LC-MS (APCI): m / z = 223.0 (M+1) + .

[0571] Preparation of intermediate A-3 compound (4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)boronic acid

[0572] The following synthetic route was used

[0573] Into a 2000 mL three-necked flask equipped with magnetic stirring and condenser, (4-(aminomethyl)phenyl)boronic acid hydrochloride (30.00 g, 161.53 mmol), 5-fluoro-2-methoxybenzoic acid (18.20 g, 161.53 mol) and tetrahydrofuran (300 mL) were sequentially added, the mixture was stirred and dispersed, N,N-diisopropylethylamine (55.00 g, 646.14 mmol) was added, 1-propylphosphonic anhydride (187 mL, 323.06 mmol, 50% ethyl acetate solution) was added dropwise under nitrogen atmosphere, the reaction was stirred overnight after the temperature was raised to 70 °C. The reaction was cooled to room temperature, slowly poured into ice water (4000 mL), stirred for 1 hour, filtered and dried to obtain 39.42 g of white solid. Yield 81.0%. LC-MS (APCI): m / z = 304.1 (M+1) + .

[0574] Preparation of intermediate A-4 compound 6-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl formate

[0575] The following synthetic route was used

[0576] Into a 500 mL single neck flask equipped with magnetic stirring and condenser, was added 2-bromo-5-iodopyridine (15.0 g, 53.2 mmol), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (18 g, 18.5 mmol), 1,4-dioxane (100 mL) and water (25 mL) sequentially, the solution was stirred to clear, then potassium phosphate tribasic (22 g, 133 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.8 g, 5.32 mmol) were added, the flask was evacuated and purged with nitrogen for 3 times, the temperature was slowly increased to 100 °C under nitrogen atmosphere, the reaction was stirred at 100 °C for 12 h. The reaction was cooled to room temperature, the insoluble solid was filtered off, washed with ethyl acetate (20 mL), the organic solvent was removed under reduced pressure, ethyl acetate (150 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness and purified by silica gel column to give white solid 15.1 g in 83.8% yield. LC-MS (APCI): m / z = 339.0 (M+1) + .

[0577] Preparation of intermediate A-5 compound tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate

[0578] The following synthetic route was used

[0579] Into a 500 mL three neck flask equipped with magnetic stirring and condenser, was added 1-(tert-butoxycarbonyl)piperazine (20.00 g, 106.38 mmol), 2-bromo-5-iodopyridine (36.24 g, 127.66 mmol), tris(dibenzylideneacetone)dipalladium (2.43 g, 2.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.08 g, 5.32 mmol), sodium tert-butoxide (30.64 g, 319.14 mmol) and toluene (200 mL) sequentially, the flask was evacuated and purged with nitrogen for 3 times, the mixture was stirred to disperse, the reaction was stirred at 60 °C overnight. The reaction was cooled to room temperature, saturated brine (200 mL) was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL x 2), the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column to give white solid 30.50 g in 84.1% yield. LC-MS (APCI): m / z = 342.1 (M+1) + .

[0580] Preparation of intermediate A-6 compound tert-butyl 4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate

[0581] The following synthetic route was employed

[0582] Step 1 Synthesis of compound methyl (6-bromopyridin-3-yl)methanesulfonate

[0583] Into a vessel was added 6-bromo-3-hydroxymethylpyridine (5.0 g, 26.88 mmol), triethylamine (8.15 g, 80.64 mmol) and dichloromethane (60 mL) successively, the solution was stirred and clarified, methylsulfonyl chloride (6.16 g, 53.76 mmol) was added dropwise under ice-water bath, after addition, the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was quenched by adding water (50 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil which was used directly in the next step.

[0584] Step 2 Synthesis of intermediate A-6

[0585] Into a vessel was added methyl (6-bromopyridin-3-yl)methanesulfonate (about 26.88 mmol) obtained in the previous step, acetonitrile (60 mL), l-(tert-butoxycarbonyl)piperazine (3.22 g, 32.26 mmol) and N,N-diisopropylethylamine (10.4 g, 80.64 mmol) successively, the solution was stirred and clarified, the temperature was raised to 70 °C, and the reaction was stirred for 2 hours. The temperature was cooled to room temperature, the solvent was removed by evaporation under reduced pressure, water (50 mL) and ethyl acetate (50 mL) were added, stirred for 2 minutes, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and then the sample was passed through a column to give white solid 4.3 g with a yield of 45.1%. LC-MS (APCI): m / z = 356.1 (M+1) + .

[0586] Preparation of intermediate A-7 compound tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate

[0587] The following synthetic route was employed

[0588] Into a vessel was added N-tert-butoxycarbonyl-4-hydroxypiperidine (4.0 g, 20 mmol), triethylamine (4.0 g, 39.5 mmol) and dichloromethane (40 mL) successively, the solution was cooled to 0 °C under ice bath, methylsulfonyl chloride (3.0 g, 26.2 mmol) was added dropwise, after completion of the addition, the temperature was naturally raised to room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (100 mL x 3), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated and used directly in the subsequent reaction.

[0589] Preparation of intermediate B-1 compound N-(4-(3-amino-7-iodo-lH-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0590] The following synthetic route was employed

[0591] Synthesis of Step 1 compound N-(4-(3-cyano-4-methoxypyridin-2-yl)benzyl)-5- fluoro-2-methoxybenzamide

[0592] Into a 500 mL single neck flask, equipped with magnetic stirring and condenser, was added 2-chloro-4-methoxynicotinonitrile (20.00 g, 118.64 mmol), intermediate A-3 (37.74 g, 125 mol), tetrakis(triphenylphosphine)palladium (4.11 g, 3.5 mmol), potassium carbonate (41.0 g, 297.51 mmol), 1,4-dioxane (200 mL) and water (40 mL), vacuumed and nitrogen purged 3 times, stirred to warm to 80 °C under nitrogen atmosphere, and reacted overnight. Cooled to room temperature, filtered off insoluble solid, washed with 1,4-dioxane (20 mL), and the filtrate was slowly poured into stirring ice water (2000 mL), stirred for 1 hour, filtered, and dried to give white solid 37.62 g. Yield 81.1%. LC-MS (APCI): m / z = 392.1 (M+1) + .

[0593] Synthesis of Step 2 compound N-(4-(3-cyano-4-hydroxypyridin-2-yl)benzyl)-5-fluoro- 2-methoxybenzamide

[0594] Into a 1000 mL single neck flask, equipped with magnetic stirring and condenser, was added N-(4-(3-cyano-4-methoxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (37.62 g, 96.21 mmol) and N,N-dimethylformamide (300 mL), stirred to dissolve, added p-toluenesulfonic acid monohydrate (91.51 g, 481.05 mmol) and lithium chloride (20.39 g, 481.05 mmol), warmed to 150 °C under nitrogen atmosphere, and reacted for 0.5 hour. Cooled to room temperature, slowly poured into ice water (1800 mL), stirred for 1.5 hours, filtered, and dried to give white solid 31.63 g, yield 87.2%. LC-MS (APCI): m / z = 378.3 (M+1) + .

[0595] Synthesis of Step 3 compound N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)benzyl)-5- fluoro-2-methoxybenzamide

[0596] Into a 500 mL single neck flask, equipped with magnetic stirring, was added N-(4-(3-cyano-4-hydroxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (31.63 g, 83.90 mmol) and acetonitrile (300 mL), stirred to dispersion, added N-iodosuccinimide (19.82 g, 88.09 mmol), heated to 65 °C under nitrogen atmosphere, maintained for 2 h, cooled to room temperature with stirring, a large amount of solid precipitated, filtered, washed with acetonitrile (50 mL), obtained 34.05 g of yellow white solid, yield 80.7%. LC-MS (APCI): m / z = 504.3 (M+1) + .

[0597] Synthesis of compound N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0598] Into a 250 mL single neck flask, equipped with magnetic stirring and condenser, was added N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (34.05 g, 67.69 mmol) and phosphorus oxychloride (120 mL), heated to 80 °C under nitrogen atmosphere, maintained for 2 h with stirring. Cooled to room temperature, solvent was evaporated under reduced pressure, added toluene, concentrated to dryness under reduced pressure, added ethyl acetate (200 mL), added saturated aqueous sodium bicarbonate solution (100 mL) with stirring, separated the organic phase, aqueous phase was extracted with ethyl acetate (50 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, recrystallized from ethyl acetate and n-heptane, obtained 12.94 g of yellow solid, yield 36.7%. LC-MS (APCI): m / z = 521.8 (M+1) + .

[0599] Synthesis of intermediate B-1

[0600] Into a 250 mL single neck flask, equipped with magnetic stirring, was added N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (12.94 g, 1.26 mmol), hydrazine hydrate (0.378 g, 7.56 mmol) and N,N-dimethylformamide (120 mL), vacuumed and replaced with nitrogen 3 times, heated to 60 °C, maintained for overnight with stirring. Cooled to room temperature, poured slowly into stirring ice water (1000 mL), a large amount of solid precipitated, filtered, washed with water (20 mL), dried in oven, obtained 10.42 g of yellow solid powder, yield 81.1%. LC-MS (APCI): m / z = 518.1 (M+1) + .

[0601] Preparation of intermediate B-2 compound tert-butyl 6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H- pyrazolo[4,3-c]pyridine-7-yl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0602] The following synthetic route was employed

[0603] Step 1 synthesis of compound tert-butyl 6-iodo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate

[0604] Into a 500 mL single necked flask, equipped with magnetic stirring and condenser, was added intermediate A-4 (15.1 g, 44.7 mmol), sodium iodide (13.2 g, 89.4 mmol), cuprous iodide (2.55 g, 13.4 mmol) and 1,4-dioxane (100 mL) sequentially, N,N'-dimethylethylenediamine (1.5 g, 17.9 mmol) was added with stirring, vacuumed and replaced with nitrogen for 3 times, heated to 100 °C under nitrogen atmosphere, and kept the temperature for 48 hours. Cooled to room temperature, filtered off the insoluble solid, evaporated the organic solvent under reduced pressure, added ethyl acetate (100 mL) and brine (80 mL, 10%), separated the organic phase, the aqueous phase was extracted with ethyl acetate (50 mL x 2), combined the organic phase, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column, yellow solid 13.2 g, yield 76.7%. LC-MS (APCI): m / z = 387.0 (M+1) + .

[0605] Step 2 synthesis of intermediate B-2

[0606] Into a 500 mL single neck flask equipped with magnetic stirring and condenser, was added 6-iodo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (13.2 g, 34.1 mmol), intermediate B-1 (7.6 g, 14.8 mmol), bis(pinacolato)diboron (15.2 g, 59.2 mmol), n-butanol (100 mL) and water (20 mL) sequentially, the solution was stirred until clear, then cesium fluoride (8.8 g, 59.2 mmol), palladium acetate (0.66 g, 2.9 mmol) and n-butyl bis(1-adamantyl)phosphine (2.0 g, 5.9 mmol) were added, the flask was evacuated and backfilled with nitrogen 3 times, then the temperature was raised to 120 °C under nitrogen atmosphere, the reaction was stirred at 120 °C for 12 h. The reaction was cooled to room temperature, the organic solvent was removed under reduced pressure, ethyl acetate (100 mL) and brine (80 mL, 10%) were added, the organic phase was separated, extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, the residue was purified by silica gel column to give 3.3 g of yellow solid, yield 14.8%. LC-MS (APCI): m / z = 650.2 (M+1) + .

[0607] Preparation of intermediate B-3 compound 4-(4-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0608] The following synthetic route 1 was used

[0609] Step 1 synthesis of compound 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0610] Into a vessel was added crude intermediate A-7, 3-iodo-1H-4-amino-pyrazolo[3,4-d]pyrimidine (4.0 g, 16.6 mmol), cesium carbonate (10.8 g, 33.2 mmol) and N,N-dimethylformamide (80 mL) sequentially, the solution was stirred until clear, the reaction was heated to 100 °C overnight. The reaction was cooled to room temperature, 200 mL of water was added, extracted with ethyl acetate (200 mL x 3), the organic phase was washed with 500 mL of saturated brine twice, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column to give 5.2 g of yellowish solid, yield 70%. ESI-MS: 444 [M + ].

[0611] Step 2 synthesis of intermediate B-3

[0612] To the vessel was added tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate (2.4 g, 5.4 mmol), intermediate A-3 (1.8 g, 5.94 mmol), tetrakis(triphenylphosphine)palladium (1.25 g, 1.08 mmol), potassium carbonate (2.24 g, 16.2 mmol), ethylene glycol dimethyl ether (30 mL), and water (6 mL), the solution was stirred, purged with nitrogen three times, and warmed to 110 °C overnight. The solution was cooled to room temperature, water (100 mL) was added, and the solution was extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to give 2.8 g of a brown solid in 90.3% yield. ESI-MS: 576 [M+1]. + +1]。

[0613] or the following synthetic route ②

[0614] Step 1 Synthesis of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1-carboxylate

[0615] To a 50 mL two-necked flask equipped with magnetic stirring, was added 3-iodo-1H- 4-amino-pyrazolo[3,4-d]pyrimidine (1 g, 3.65 mmol), N-tert-butoxycarbonyl-4- hydroxypiperidine (0.88 g, 4.37 mmol) and anhydrous tetrahydrofuran (18 mL) at 0 °C, the solution was stirred, and triphenylphosphine (2.87 g, 3.81 mmol) was added, the solution was purged with nitrogen three times, and diisopropyl azodicarboxylate (1.5 g, 7.43 mmol) was added, the solution was stirred at room temperature overnight, TLC, LC-MS showed that the reaction was complete, water was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3) and water (50 mL), the organic phase was separated, washed with water (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and the product was obtained by column chromatography using petroleum ether / ethyl acetate as eluent, which was 500 mg in 30.9% yield. LC-MS (APCI): m / z = 445.1 (M+1) + .

[0616] Step 2 Synthesis of intermediate B-3

[0617] To a 50 mL single neck flask equipped with magnetic stirring was added tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate (500 mg, 1.13 mmol), Intermediate A-3 (341 mg, 1.13 mmol), 1,4- dioxane (8 mL) and water (2 mL), the solution was stirred clear, then sodium carbonate (358 mg, 33.78 mmol) and tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol) were added sequentially, the flask was evacuated and backfilled with nitrogen three times, the reaction was stirred at 100 °C overnight. TLC showed the reaction was complete, the reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column to give 416 mg, 64.1% yield. LC-MS (APCI): m / z = 576.3 (M+1) + .

[0618] Preparation of compound N-(4-(3-amino-7-(1',2',3',6'-tetrahydro-[3,4'- bipyridinyl]-6-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0619] The following synthetic route was used

[0620] To a 100 mL single neck flask equipped with magnetic stirring was added Intermediate B-2 (500 mg, 0.77 mmol) and dichloromethane (10 mL), the solution was stirred clear, hydrogen chloride ethyl acetate solution (4 mL, 4M) was added, the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere, concentrated to dryness under reduced pressure to give white solid 500 mg, 100% yield. LC-MS (APCI): m / z = 550.2 (M+1) + .

[0621] Preparation of compound N-(4-(3-amino-7-(5-(piperidin-4-yl)pyridin-2-yl)-1H- pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0622] The following synthetic route was used

[0623] Step 1 Synthesis of compound tert-butyl 4-(6-(3-amino-4-(4-((5-fluoro-2- methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperidine- 1-carboxylate

[0624] To a 100 mL stainless steel autoclave equipped with magnetic stirring, was added intermediate B-2 (2.8 g, 4.31 mmol), ammonium formate (2.0 g, 31.7 mmol), ethylene glycol monomethyl ether (30 mL) and wet palladium on carbon (280 mg, 10%), hydrogen was bubbled for 30 seconds, sealed, placed in an oil bath, warmed to 100 °C and stirred overnight. Cooled to room temperature, carefully opened, diluted with ethyl acetate (50 mL), filtered to remove insoluble solids, the filter cake was washed with ethyl acetate (20 mL), the filtrate was concentrated to dryness and the residue was purified by silica gel column to give 2.6 g of yellow solid, 92.8% yield. LC-MS (APCI): m / z = 652.3 (M+1) + .

[0625] Synthesis of intermediate P-2

[0626] To a 100 mL single neck flask equipped with magnetic stirring was added tert-butyl 4-(6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3- c]pyridin-7-yl)pyridin-3-yl)piperidine-1-carboxylate (2.6 g, 3.9 mmol) and dichloromethane (20 mL), the solution was stirred clear, hydrogen chloride in ethyl acetate solution (20 mL, 4M) was added and the reaction was stirred at room temperature under a nitrogen atmosphere for 2 hours, concentrated to dryness under reduced pressure to give 2.6 g of white solid, 100% yield. LC-MS (APCI): m / z = 552.3 (M+1) + .

[0627] Synthesis of intermediate P-3 compound N-(4-(3-amino-7-(5-(1-(azetidin-3-yl)piperidin-4- yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0628] The following synthetic route was employed

[0629] Synthesis of intermediate P-3 compound N-(4-(3-amino-7-(5-(1-(azetidin-3-yl)piperidin-4- yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0630] To a 100 mL single neck flask equipped with magnetic stirring was added Intermediate P-2 (2.2 g, 4.0 mmol), 1-tert-butoxycarbonyl-3-azetidinone (2.0 g, 11.7 mmol) and dichloromethane (20 mL) successively. The solution was stirred and clarified, and glacial acetic acid (600 mg, 10 mmol) and sodium triacetoxyborohydride (2.0 g, 9.4 mmol) were added. The reaction was stirred at room temperature under a nitrogen atmosphere for 12 hours. Dichloromethane (30 mL) was added to dilute the reaction, and aqueous sodium bicarbonate solution (50 mL, 10%) was added. The mixture was stirred for 5 minutes, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.8 g of a yellow solid, with a yield of 64.3%. LC-MS (APCI): m / z = 707.3 (M+1) + .

[0631] Synthesis of Intermediate P-3 in Step 2

[0632] To a 100 mL single neck flask equipped with magnetic stirring was added 3-(4-(6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (1.8 g, 2.5 mmol) and dichloromethane (20 mL). The solution was stirred and clarified, and hydrogen chloride ethyl acetate solution (20 mL, 4M) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 2 hours, and was concentrated to dryness under reduced pressure to obtain 1.8 g of a white solid, with a yield of 100%. LC-MS (APCI): m / z = 607.3 (M+1) + .

[0633] Preparation of Compound N-(4-(7-(5-(1-([1,3'-azetidinium]-3-yl)piperidin-4-yl)pyridin-2-yl)-3-amino-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide from Intermediate P-4

[0634] The preparation method described for Intermediate P-3 was used, with Intermediate P-3 replacing Intermediate P-2 as the raw material, to obtain the product.

[0635] Preparation of Compound N-(4-(3-amino-7-(5-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide from Intermediate P-5

[0636] The following synthetic route was used

[0637] Step 1 Synthesis of compound tert-butyl 4-(6-iodopyridin-3-yl)piperazine-1-carboxylate

[0638] Into a 500 mL three-necked flask, equipped with magnetic stirring and condenser, was added sequentially intermediate A-5 (20.00 g, 58.56 mmol), cuprous iodide (1.12 g, 5.86 mmol), sodium iodide (17.58 g, 117.28 mmol), N,N'-dimethylethylenediamine (1.03 g, 11.72 mmol) and 1,4-dioxane (200 mL), vacuumed and purged with nitrogen for 3 times, stirred to disperse, stirred at 100 °C overnight. Cooled to room temperature, quenched with saturated brine (200 mL), separated the organic phase, the aqueous phase was extracted with ethyl acetate (200 mL x 2), combined the organic phase, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give a white solid 17.60 g, yield 77.1%. LC-MS (APCI): m / z = 390.1 (M+1) + .

[0639] Step 2 Synthesis of compound tert-butyl 4-(6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperazine-1-carboxylate

[0640] Into a 250 mL three-necked flask, equipped with magnetic stirring and condenser, was added sequentially intermediate B-1 (7.80 g, 15.08 mmol), tert-butyl 4-(6-iodopyridin-3-yl)piperazine-1-carboxylate (17.60 g, 45.24 mmol), n-butyl bis(1-adamantyl)phosphine (2.16 g, 6.04 mmol), palladium acetate (678.02 mg, 3.02 mmol), bis(pinacolato)diboron (15.32 g, 60.32 mmol) and cesium fluoride (9.16 g, 60.32 mmol), vacuumed and purged with nitrogen for 3 times, added n-butanol (100 mL) and water (20 mL), stirred to disperse, stirred at 120 °C overnight. Cooled to room temperature, quenched with saturated brine (100 mL), separated the organic phase, the aqueous phase was extracted with ethyl acetate (100 mL x 2), combined the organic phase, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give a yellow solid 2.66 g, yield 27.1%. LC-MS (APCI): m / z = 653.3 (M+1) + .

[0641] Step 3 Synthesis of intermediate P-5

[0642] Into a 100 mL single necked flask equipped with magnetic stirring was added 4-(6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H- pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.66 g, 4.08 mmol), dichloromethane (30 mL) and hydrogen chloride ethyl acetate solution (20 mL, 4M) successively, stirred to disperse, stirred at room temperature for 1 hour. Concentrated to get yellow solid 2.64 g, yield 99.9%. LC-MS (APCI): m / z = 553.3 (M+1) + .

[0643] Preparation of intermediate P-6 compound N-(4-(3-amino-7-(5-(4-([1,3'-azabicyclo[3.1.0]hexane]-3-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0644] Prepared according to the procedure described for intermediate P-3 using intermediate P-5 (2.40 g, 4.08 mmol) in place of intermediate P-2 as starting material to give yellow solid 1.36 g. LC-MS (APCI): m / z = 608.3 (M+1) + .

[0645] Preparation of intermediate P-7 compound N-(4-(7-(5-(4-([1,3'-azabicyclo[3.1.0]hexane]-3-yl)piperazin-1-yl)pyridin-2-yl)-3-amino-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0646] Prepared according to the procedure described for intermediate P-3 using intermediate P-6 (1.12 g, 1.65 mmol) in place of intermediate P-2 as starting material to give yellow solid 442.3 mg. LC-MS (APCI): m / z = 663.4 (M+1) + .

[0647] Preparation of intermediate P-8 compound N-(4-(3-amino-7-(5-(piperazin-1-ylmethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0648] Prepared according to the procedure described for Intermediate P-5 using Intermediate A-6 (2.0 g, 5.602 mmol) instead of Intermediate A-5 as starting material to give 400 mg as a yellow solid. LC-MS (APCI): m / z = 567.3 (M+1) + .

[0649] Preparation of Intermediate P-9, compound N-(4-(3-amino-7-(5-((4-(azetidin-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0650] Prepared according to the procedure described for Intermediate P-3 using Intermediate P-8 (2.0 g, 3.54 mmol) instead of Intermediate P-2 as starting material to give 1.0 g as a yellow solid. LC-MS (APCI): m / z = 622.3 (M+1) + .

[0651] Preparation of Intermediate P-10, compound N-(4-(7-(5-((4-([1,3'-azetidin]-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-3-amino-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0652] Prepared according to the procedure described for Intermediate P-3 using Intermediate P-9 (1.0 g, 1.61 mmol) instead of Intermediate P-2 as starting material to give a yellow solid. LC-MS (APCI): m / z = 677.4 (M+1) + .

[0653] Preparation of Intermediate P-11, compound N-(4-(3-amino-6-(piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0654] Using the following synthetic route

[0655] Step 1 Synthesis of compound 4-(3-ethoxy-3-oxopropionyl)piperidine-1-carboxylate benzyl ester

[0656] To a vessel was added 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10 g, 38 mmol), N,N'-carbonyldiimidazole (7.4 g, 45.6 mmol) and anhydrous tetrahydrofuran (200 mL) sequentially, the solution was stirred and warmed to 70 °C for 1 h, then cooled to room temperature, monomethyl malonate potassium salt (5.93 g, 38 mmol) and anhydrous magnesium chloride (3.62 g, 38 mmol) were added, the reaction was stirred at 70 °C overnight. After the reaction was cooled, hydrochloric acid solution (1 N) was added to quench the reaction. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 10.5 g of a clear oil, yield 82%. ESI-MS: 334 [M + +1].

[0657] Synthesis of compound 4-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)benzyl piperidine-1-carboxylate

[0658] To a vessel was added 4-(3-ethoxy-3-oxopropionyl)benzyl piperidine-1-carboxylate (1.5 g, 4.5 mmol), intermediate A-2 (500 mg, 2.25 mmol) and N-methyl pyrrolidone (15 mL) sequentially, the solution was stirred and subjected to microwave reaction at 250 °C for 10 min. After the reaction was cooled to room temperature, water (100 mL) was added and the solution was extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 700 mg of a light brown solid, yield 63%. Five batches of the microwave reaction were performed and 3.6 g of the product was obtained. ESI-MS: 494 [M + +2].

[0659] Synthesis of compound 4-(6-(4-bromophenyl)-4-chloro-5-cyanopyridin-2-yl)benzyl piperidine-1-carboxylate

[0660] To a vessel was added 4-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)benzyl piperidine-1-carboxylate (3.9 g, 7.91 mmol) and phosphorus oxychloride (30 mL) sequentially, the solution was stirred and heated to 80 °C for 2 h, the reaction was concentrated, quenched with warm water, the solution was adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with ethyl acetate (200 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give 2.5 g of a brown solid, yield 61%. ESI-MS: 510 [M + ].

[0661] Synthesis of compound 4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic acid benzyl ester

[0662] To the vessel was added 4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic acid benzyl ester (1.5 g, 2.5 mmol) and N,N-dimethylformamide (25 mL), stirred to dissolve, then hydrazine hydrate (1.25 g, 24.51 mmol) was added, and the reaction was heated to 110 °C for 1.5 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to give 1.5 g of a yellow solid in 60% yield. ESI-MS: 609 [M + ]。

[0663] Synthesis of compound 4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic acid benzyl ester

[0664] To the vessel was added 4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic acid benzyl ester (1.5 g, 2.5 mmol) and N,N-dimethylformamide (25 mL), stirred to dissolve, then hydrazine hydrate (1.25 g, 24.51 mmol) was added, and the reaction was heated to 110 °C for 1.5 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to give 1.5 g of a yellow solid in 60% yield. ESI-MS: 609 [M + +1]。

[0665] Synthesis of intermediate P-11

[0666] 4-(3-amino-4-(4-(((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)piperidin-1-carboxylic acid benzyl ester (510 mg, 0.84 mmol) and methanol / ethyl acetate (v / v: 1 / 1, 20 mL) were added sequentially to a container and stirred until dissolved. Palladium on carbon (500 mg) was then added, and the mixture was purged three times with hydrogen. The reaction was carried out overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the residue was washed with methanol / ethyl acetate. The filtrate was concentrated and separated by silica gel column chromatography to give 350 mg of a white solid, yield 87%. ESI-MS: 475 [M + +1].

[0667] Preparation of intermediate P-12 compound N-(4-(6-(1-([1,3'-adiazonylbutane]-3-yl)piperidin-4-yl)-3-amino-1H-pyrazolo[4,3-c]pyridin-4-ylbenzyl)-5-fluoro-2-methoxybenzamide hydrochloride

[0668] The following synthetic route was adopted.

[0669] Step 1: Synthesis of compound 3-(4-(3-amino-4-(4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)piperidin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0670] Intermediate P-11 (200 mg, 0.42 mmol), N-tert-butoxycarbonyl-3-azacyclobutanone (108 mg, 0.63 mmol), sodium triacetoxyborohydride (267 mg, 1.26 mmol), acetic acid (76 mg, 1.26 mmol), and dichloromethane (10 mL) were added sequentially to a container. The mixture was stirred until dissolved and allowed to stand overnight at room temperature. The solution was diluted with water and extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain 215 mg of a pale yellow solid (80% yield). ESI-MS: 630 [M + +1].

[0671] Step 2: Synthesis of compound N-(4-(3-amino-6-(1-(azacyclobutan-3-yl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide hydrochloride

[0672] To a vessel was added 3-(4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)piperidin-1-yl)-[1,3'-azetidin]-1'-carboxylic acid tert-butyl ester and dichloromethane (10 mL), the solution was stirred clear, hydrogen chloride ethyl acetate solution (5 mL, 4 M) was added, stirred at room temperature for 1 hour, concentrated to dryness to give a white solid, which was used directly in the subsequent reaction. ESI-MS: 585 [M + +1].

[0673] Synthesis of compound 3-(4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)piperidin-1-yl)-[1,3'-azetidin]-1'-carboxylic acid tert-butyl ester

[0674] To a vessel was added N-(4-(3-amino-6-(1-(azetidin-3-yl)piperidin-4-yl)-1H-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide hydrochloride, N-tert-butoxycarbonyl-3- azetidinone (108 mg, 0.63 mmol), sodium triacetoxyborohydride (267 mg, 1.26 mmol), acetic acid (76 mg, 1.26 mmol) and dichloromethane (10 mL), the solution was stirred clear, stirred at room temperature overnight, diluted with water, extracted with dichloromethane (50 mL x 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, separated on a silica gel column to give a light yellow solid 150 mg in 64% yield. ESI-MS: 685 [M + +1].

[0675] Synthesis of intermediate P-12

[0676] To a vessel was added 3-(4-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H- pyrazolo[4,3-c]pyridin-6-yl)piperidin-1-yl)-[1,3'-azetidin]-1'-carboxylic acid tert-butyl ester and dichloromethane (10 mL), the solution was stirred clear, hydrogen chloride ethyl acetate solution (5 mL, 4 M) was added, stirred at room temperature for 1 hour, concentrated to dryness to give a white solid, which was used directly in the subsequent reaction. ESI-MS: 585 [M + +1].

[0677] Preparation of intermediate P-13 compound N-(4-(3-amino-7-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0678] The following synthetic route was employed

[0679] Step 1 Synthesis of compound 3-bromo-l-(2,2-diethoxyethyl)-lH-pyrazole

[0680] To a vessel was added 3-bromopyrazole (1.0 g, 6.8 mmol), bromoacetaldehyde diethyl acetal (1.41 g, 7.14 mmol), cesium carbonate (3.48 g, 10.7 mmol) and acetonitrile (20 mL) sequentially, stirred to dissolve, warmed to 80 °C and allowed to react overnight. The reaction was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate twice and the filtrate was concentrated and separated on a silica gel column to give 1.7 g of a colorless, clear oil in 95% yield. LC-MS (APCI): m / z = 263.1 (M+1) + .

[0681] Step 2 Synthesis of compound 3-bromo-l-(2,2-diethoxyethyl)-lH-pyrazole-5- carbaldehyde

[0682] To a vessel was added 3-bromo-l-(2,2-diethoxyethyl)-lH-pyrazole (1.7 g, 6.48 mmol) and anhydrous tetrahydrofuran (30 mL) sequentially, stirred to dissolve, cooled to -78 °C and lithium diisopropylamide (5 mL, 10 mmol, 2 M) was added slowly dropwise. The reaction was allowed to react at -78 °C for 1 hour and N,N-dimethylformamide (850 mg, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and this solution was added slowly dropwise to the above reaction mixture at -78 °C. The reaction was allowed to react at -78 °C for 1.5 hours. The reaction was quenched by the addition of saturated ammonium chloride solution and diluted with water at room temperature. The organic phase was extracted with methyl tert-butyl ether (100 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated on a silica gel column to give 1.57 g of a light yellow oil in 83% yield. LC-MS (APCI): m / z = 291.1 (M+1) + .

[0683] Step 3 Synthesis of compound 3-bromo-l-(2-oxoethyl)-lH-pyrazole-5- carbaldehyde

[0684] To a vessel was added 3-bromo-l-(2,2-diethoxyethyl)-lH-pyrazole-5-carboxaldehyde (1.57 g, 5.4 mmol), trifluoroacetic acid (6 mL), tetrahydrofuran (3 mL), and water (3 mL) sequentially, the solution was stirred and heated to 40 °C for 4 h. The reaction was cooled to room temperature and concentrated. The residue was azeotropically distilled with toluene (10 mL x 3) to remove water three times. The residue was used directly in the next step without further purification. LC-MS (APCI): m / z = 191.1 (M+l) + .

[0685] Synthesis of compound 5-benzyl-2-bromo-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine

[0686] To a vessel was added 3-bromo-l-(2,2-diethoxyethyl)-lH-pyrazole-5-carboxaldehyde (1.57 g, 5.4 mmol), trifluoroacetic acid (6 mL), tetrahydrofuran (3 mL), and water (3 mL) sequentially, the solution was stirred and heated to 40 °C for 4 h. The reaction was cooled to room temperature and concentrated. The residue was azeotropically distilled with toluene (10 mL x 3) to remove water three times. The residue was used directly in the next step without further purification. LC-MS (APCI): m / z = 191.1 (M+l) + .

[0687] Synthesis of compound N-(4-(3-amino-7-(5-benzyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-2-yl)-lH-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0688] To a vessel was added 5-benzyl-2-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (475 mg, 1.63 mmol), intermediate B-l (450 mg, 0.87 mmol), n-butyl bis(l-adamantyl)phosphine (129 mg, 0.36 mmol), bis(pinacolato)diboron (555 mg, 2.19 mmol), palladium acetate (42 mg, 0.18 mmol), cesium fluoride (540 mg, 3.6 mmol), water (3 mL), and n-butanol (15 mL) sequentially. The reaction vessel was purged with nitrogen three times and heated to 120 °C under nitrogen atmosphere. The reaction was stirred at reflux overnight. The reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column to give 110 mg of yellow solid in 21.0% yield. LC-MS (APCI): m / z = 603.1 (M+l) + .

[0689] Synthesis of intermediate P-13

[0690] To the vessel was added N-(4-(3-amino-7-(5-benzyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-2-yl)-lH-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (110 mg, 0.18 mmol) and methanol (10 mL) sequentially, the solution was stirred clear, palladium on carbon (100 mg, 10%) was added, the hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to give 80 mg of a colorless transparent solid in 86.9% yield. LC-MS (APCI): m / z = 513.1 (M + 1) + .

[0691] Preparation of intermediate C-3 compound (S)-5-(4-formylpiperidin-l-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide

[0692] The following synthetic route was employed

[0693] Step 1 Synthesis of compound methyl 5-(4-(dimethoxymethyl)piperidin-l-yl)picolinate

[0694] To a 100 mL single necked flask equipped with magnetic stirring was added methyl 5-fluoropicolinate (5.00 g, 32.23 mmol), 4-(dimethoxymethyl)piperidine (5.13 g, 32.23 mmol), K2CO3(13.36 g, 96.69 mmol) and DMF (50 mL) sequentially, the reaction was stirred at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated to give 9.48 g of yellow oil. No purification was needed, and the material was used directly in the next step. LC-MS (APCI): m / z = 295.0 (M + 1) + .

[0695] Step 2 Synthesis of compound 5-(4-(dimethoxymethyl)piperidin-l-yl)picolinic acid

[0696] To a 250 mL single necked flask equipped with magnetic stirring was added methyl 5-(4- (dimethoxymethyl)piperidin-l-yl)picolinate (9.48 g, 32.23 mmol), LiOH-H2O (8.14 g, 193.38 mmol), THF (100 mL) and H2O (100 mL) sequentially, the reaction was stirred at room temperature for 4 hours. The THF was removed by rotary evaporation under reduced pressure, and the aqueous phase was added with citric acid (12.41 g). The solid was isolated by stirring at room temperature for 10 minutes, and was filtered to give 8.92 g of white solid in 98.8% yield over two steps. LC-MS (APCI): m / z = 281.0 (M + 1) + .

[0697] Step 3 Synthesis of compound (S)-5-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6- dioxopiperidin-3-yl)picolinamide

[0698] Into a 250 mL three-necked flask equipped with magnetic stirring, was added 5-(4- (dimethoxymethyl)piperidin-l-yl)picolinic acid (8.92 g, 31.84 mmol), (S)-3-aminopiperidine- 2,6-dione hydrochloride (6.29 g, 38.21 mmol), HATU (15.74 g, 41.39 mmol) and DMF (90 mL) sequentially. The mixture was stirred at 0 °C for 10 min, DIPEA (13.70 mL, 95.52 mmol) was added dropwise slowly, and the reaction was stirred at room temperature overnight. H2O (90 mL) was added to the reaction mixture, which was stirred at room temperature for 10 min. The solid was collected by filtration to give white solid 7.97 g in 64.2% yield. LC-MS (APCI): m / z = 391.0 (M+l)+.

[0699] Step 4 Synthesis of compound C-3

[0700] Into a 50 mL single-necked flask equipped with magnetic stirring, was added (S)-5-(4- (dimethoxymethyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (1.00 g, 2.56 mmol) and HCl / EA (20 mL) sequentially. The reaction was stirred for 1 h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was added to saturated NaHC03 aqueous solution (20 mL). The mixture was extracted with DCM (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give white solid 0.77 g in 87.4% yield. LC-MS (APCI): m / z = 345.0 (M+l)+. + .

[0701] Preparation of intermediate C-4 compound (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4- formylpiperidin-l-yl)benzamide

[0702] The following synthetic route was employed

[0703] Step 1 Synthesis of compound methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluorobenzoate

[0704] Into a 250 mL flask equipped with magnetic stirring, was placed 2-fluoro-4- bromobenzoic acid methyl ester (4 g, 17.16 mmol), 4-(dimethoxymethyl)piperidine (4 g, 25.12 mmol) and 1,4-dioxane (40 mL), the solution was stirred, then Cs2CO3(11.2 g, 34.36 mmol), BINAP (1.3 g, 2.09 mmol) and Pd(OAc)2(1.3 g, 1.78 mmol) were added, the flask was flushed with nitrogen three times, then heated to 110 °C for 3 h. The reaction was cooled to room temperature, diluted with ethyl acetate (60 mL), the insoluble solid was filtered off, washed with ethyl acetate, the filtrate was concentrated, then the sample was passed through a column to give 3.6 g of yellow oil, yield 67.67%. LC-MS (APCI): m / z = 312.2 (M+1) + .

[0705] Synthesis of compound 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid methyl ester

[0706] Into a 100 mL flask equipped with magnetic stirring, was placed compound 4-(4- (dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid methyl ester (3.6 g, 11.61 mmol), THF (20 mL) and H2O (20 mL), the solution was stirred, then lithium hydroxide monohydrate (2.44 g, 58.10 mmol) was added, the reaction was stirred at room temperature for 6 h, the organic solvent was removed under reduced pressure, then dilute hydrochloric acid (3 M) was slowly added dropwise under ice water bath, the pH was adjusted to 2, a large amount of white solid was precipitated, which was filtered, washed with water, and dried to give 2.4 g of white solid, yield 69.60%. LC-MS (APCI): m / z = 298.1 (M+1) +

[0707] Synthesis of compound (S)-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide

[0708] Into a 50 mL flask equipped with magnetic stirring, was placed compound 4-(4- (dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid (2.4 g, 8.08 mmol), DMF (30 mL) and DIPEA (3.12 g, 24.18 mmol), the solution was stirred, then the flask was flushed with nitrogen three times, cooled to 0 °C, then HATU (3.99 g, 10.50 mmol) and (S)-3-aminopiperidine-2,6-dione hydrochloride (1.59 g, 11.59 mmol) were added, the reaction was carried out at 0 °C for 3 h. Water (20 mL) was added to quench the reaction, a large amount of solid was precipitated, which was filtered, washed with water, and dried to give 3.3 g of gray solid, yield 100%. LC-MS (APCI): m / z = 408.2 (M+1) +

[0709] Synthesis of compound C-4, step 4

[0710] To a 100 ml single necked flask equipped with magnetic stirring was added (S)-4-(4- (dimethoxymethyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (3.3 g, 8.10 mmol), acetone (30 mL) and water (30 mL), the solution was stirred clear, PPTS (4.0 g, 16.21 mmol) was added, the reaction was heated to 65 °C under nitrogen atmosphere and stirred overnight. It was cooled to room temperature, the organic solvents were evaporated under reduced pressure, the residue was extracted with EA (30 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give a yellow solid 1.56 g in 53.30% yield. LC-MS (APCI): m / z = 362.1 (M+1) + .

[0711] Preparation of intermediate C-5 compound 2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[0712] The following synthetic route was used

[0713] Synthesis of compound 2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid tert-butyl ester, step 1

[0714] To a 50 mL three necked flask equipped with magnetic stirring was added 1-(6-bromo-5-fluoro- 1-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (2.00 g, 5.86 mmol), tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (2.52 g, 11.72 mmol), Pd-PEPPSI-IHpt(Cl) (284.86 mg, 0.29 mmol), Cs2CO3(4.77 g, 14.65 mmol) and 1,4-dioxane (20 mL), it was evacuated and replaced with nitrogen 3 times, the reaction was stirred at 105 °C overnight. It was cooled to room temperature, saturated brine (20 mL) was added to quench the reaction, the aqueous phase was extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give a white solid 0.97 g in 34.8% yield. LC-MS (APCI): m / z = 476.1 (M+1) + .

[0715] Synthesis of compound C-5, Step 2

[0716] Into a 50 mL single neck flask equipped with magnetic stirring was added tert-butyl 2-(l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-4- hydroxypiperidin-4-yl)acetate (0.97 g, 2.04 mmol) and HCl / 1,4-dioxane (4 M, 20 mL) sequentially. The reaction was stirred at room temperature overnight. Concentration afforded a white solid 0.83 g in 89.3% yield. LC-MS (APCI): m / z = 420.2 (M+l) + .

[0717] Preparation of intermediate compound 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0718] The following synthetic route was employed

[0719] Synthesis of compound tert-butyl 2-(l-(2-fluoro-4-nitrophenyl)-4- hydroxypiperidin-4-yl)acetate, Step 1

[0720] Into a 50 mL single neck flask equipped with magnetic stirring was added 3,4- difluoronitrobenzene (2.00 g, 12.57 mmol), tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (2.71 g, 12.57 mmol) and DMF (20 mL) sequentially. The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (80 mL) and filtered. The filtrate was concentrated to afford a yellow oil 4.45 g which was used in the next step without purification. LC-MS (APCI): m / z = 355.0 (M+l) + .

[0721] Synthesis of compound tert-butyl 2-(l-(2-fluoro-4-nitrophenyl)-4- hydroxypiperidin-4-yl)acetate, Step 1

[0722] Into a 50 mL single neck flask equipped with magnetic stirring was added tert-butyl 2-(l-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (4.45 g, 12.57 mmol) and MeOH (100 mL) sequentially. Pd / C (10%, 1.00 g) was added and the reaction was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction was filtered and the filtrate was concentrated to afford a colorless oil 4.00 g which was used in the next step without purification. LC-MS (APCI): m / z = 325.0 (M+l) +.

[0723] Synthesis of compound tert-butyl 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetate

[0724] Into a 100 mL single necked flask equipped with magnetic stirring was added tert-butyl 2-(l-(2-fluoro-4-aminophenyl)-4-hydroxypiperidin-4-yl)acetate (4.00 g, 12.34 mmol), 3-bromopiperidine-2,6-dione (4.74 g, 24.68 mmol) and DMF (40 mL) sequentially. The solution was stirred clear and NaHC03(2.07 g, 24.68 mmol) was added. The reaction was stirred at 65 °C overnight. It was cooled to room temperature, filtered and the filtrate was concentrated over a silica gel column to give a white solid 5.29 g in 98.4% yield over three steps. LC-MS (APCI): m / z = 436.0 (M+1) + .

[0725] Synthesis of compound C-6

[0726] Into a 50 mL single necked flask equipped with magnetic stirring was added tert-butyl 2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4- hydroxypiperidin-4-yl)acetate (1.00 g, 2.30 mmol) and HC1 / 1,4-dioxane (4 M, 20 mL) sequentially. The reaction was stirred overnight. It was concentrated to give a white solid 0.91 g in 95.2% yield. LC-MS (APCI): m / z = 380.0 (M+1) + .

[0727] Synthesis of example compounds

[0728] Preparation of example 1 compound N-(4-(3-amino-7-(l'-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-l',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-6-yl)-lH- pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-1)

[0729] The following synthetic route was employed

[0730] To a 10 mL microwave tube equipped with magnetic stirring was added successively intermediate P-1 (200 mg, 0.36 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (120 mg, 0.43 mmol) and N,N-dimethylformamide (5 mL), the solution was stirred, N,N-diisopropylethylamine (100 mg, 0.77 mmol) was added, the tube was sealed, placed in a microwave reactor and heated to 110 °C, the reaction was stirred for 2 hours. It was cooled to room temperature, saturated brine (8 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 80 mg of a white solid, 27.3% yield. LC-MS (APCI): m / z = 806.2 (M+1) + .

[0731] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.43 (s, 1H), 11.08 (br s, 1H), 9.00 (s, 1H), 8.91-8.87 (m, 2H), 8.24 (d, J = 8.8 Hz, 1H), 8.07-8.04 (m, 1H), 7.72-7.70 (m, 2H), 7.54-7.50 (m, 3H), 7.40 (d, J = 1.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.19-7.17 (m, 1H), 6.52 (s, 1H), 5.09-5.05 (m, 1H), 4.81 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 4.18 (s, 2H), 3.89 (s, 3H), 3.81 (t, J = 4.8 Hz, 2H), 2.88-2.85 (m, 1H), 2.75 (s, 2H), 2.60-2.49 (m, 2H), 2.02-1.99 (m, 1H).

[0732] Example 2 Preparation of (E)-N-(4-(3-amino-7-(1'-(4-(4-methoxyphenyl)-4-oxobut-2- enoyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-6-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)- 5-fluoro-2-methoxybenzamide (E-2)

[0733] The following synthetic route was used

[0734] To a 100 mL single necked flask equipped with magnetic stirring was added sequentially intermediate P-1 (200 mg, 0.36 mmol), (E)-4-(4-methoxyphenyl)-4-oxo-2-butenic acid (100 mg, 0.48 mmol) and N,N-dimethylformamide (10 mL), the solution was stirred clear, N,N-diisopropylethylamine (80 mg, 0.62 mmol), 1-hydroxybenzotriazole (80 mg, 0.59 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (90 mg, 0.47 mmol) were added, vacuumed and nitrogen purged for 3 times, the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Saturated brine (20 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25 mL x 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 50 mg of white solid with a yield of 18.6%. LC-MS (APCI): m / z = 738.2 (M+1) + .

[0735] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.41 (s, 1H), 8.98 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.67 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.56 - 7.48 (m, 4H), 7.39 - 7.34 (m, 1H), 7.23 - 7.19 (m, 1H), 7.11 (d, J = 9.2 Hz, 2H), 6.52 (s, 1H), 4.81 (s, 2H), 4.67 (d, J = 12.8 Hz, 1H), 4.62 (d, J = 4.8 Hz, 2H), 4.17 (t, J = 12.8 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.33 - 3.31 (m, 1H), 3.05 - 2.99 (m, 1H), 2.88 - 2.82 (m, 1H), 1.99 - 1.91 (m, 2H).

[0736] Preparation of compound N-(4-(3-amino-7-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-3) of Example 3

[0737] Prepared according to the procedure described in Example 1 using intermediate P-2 (200 mg, 0.36 mmol) instead of intermediate P-1 as starting material to give 80 mg of white solid in 27.3% yield. LC-MS (APCI): m / z = 808.2 (M+1) + .

[0738] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.40 (br s, 1H), 11.25 (br s, 1H), 8.96 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.72-7.69 (m, 3H), 7.55-7.51 (m, 3H), 7.42 (d, J = 2.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.21-7.18 (m, 1H), 5.11-5.06 (m, 1H), 4.81 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.25 (d, J = 12.8 Hz, 2H), 3.91 (s, 3H), 3.13 (t, J = 13.6 Hz, 2H), 3.11-3.02 (m, 2H), 2.90-2.88 (m, 1H), 2.61-2.55 (m, 2H), 2.04-1.95 (m, 4H), 1.81-1.79 (m, 2H).

[0739] Preparation of compound (E)-N-(4-(3-amino-7-(5-(1-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperidin-4-yl)pyridin-2-yl))-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-4) according to the procedure described in Example 2 using intermediate P-2 (200 mg, 0.36 mmol) instead of intermediate P-1 as starting material to give 50 mg of white solid in 18.6% yield. LC-MS (APCI): m / z = 740.2 (M+1)

[0740] Prepared according to the procedure described in Example 1 using intermediate P-2 (200 mg, 0.36 mmol) instead of intermediate P-1 as starting material to give 80 mg of white solid in 27.3% yield. LC-MS (APCI): m / z = 808.2 (M+1) + .

[0741] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.40 (s, 1H), 8.97 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.57-7.53 (m, 3H), 7.39-7.34 (m, 1H), 7.23-7.19 (m, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 5.10-5.06 (m, 1H), 4.82 (s, 2H), 4.630 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 7.8 Hz, 2H), 3.92 (s, 3H), 3.91-3.88 (m, 1H), 3.39-3.35 (m, 1H), 3.03-3.00 (m, 2H), 2.90-2.87 (m, 1H), 2.72-2.68 (m, 1H), 2.62-2.55 (m, 2H), 2.05-1.98 (m, 4H), 1.91-1.88 (m, 2H), 1.82-1.76 (m, 2H).

[0742] Preparation of compound N-(4-(3-amino-7-(5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-5) according to the procedure described in example 1, using intermediate P-3 (200 mg, 0.33 mmol) instead of intermediate P-1 as starting material.

[0743] Preparation of compound N-(4-(3-amino-7-(5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-5) according to the procedure described in example 1, using intermediate P-3 (200 mg, 0.33 mmol) instead of intermediate P-1 as starting material. + .

[0744] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.40 (s, 1H), 8.97 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.89-7.87 (m, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56-7.48 (m, 4H), 7.38-7.33 (m, 1H), 7.23-7.19 (m, 1H), 7.11 (d, J = 9.2 Hz, 2H), 4.82 (s, 2H), 4.70-4.66 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.17 (d, J = 7.8 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.33-3.28 (m, 1H), 3.05-3.00 (m, 2H), 2.90-2.87 (m, 1H), 1.95-1.91 (m, 2H), 1.76-1.63 (m, 2H).

[0745] Preparation of compound (E)-N-(4-(3-amino-7-(5-(1-(1-(4-(4-methoxyphenyl)-4- oxobut-2-enoyl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4- yl)benzyl)-5-fluoro-2-methoxybenzamide (E-6)

[0746] The preparation method according to Example 2 was used to prepare white solid 50 mg, yield 19.1% using intermediate P-3 (200 mg, 0.33 mmol) instead of intermediate P-1 as raw material. LC-MS (APCI): m / z = 795.3 (M+1) + .

[0747] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.39 (s, 1H), 8.96 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.76 (d, J = 15.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.57-7.53 (m, 3H), 7.39-7.34 (m, 1H), 7.23-7.19 (m, 1H), 7.11 (d, J = 2.0 Hz, 2H), 6.97 (d, J = 15.2 Hz, 1H), 4.82 (s, 2H), 4.630 (d, J = 6.0 Hz, 2H), 4.41 (t, J = 8.0 Hz, 1H), 4.23-4.20 (m, 1H), 4.09-4.04 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.24-3.20 (m, 1H), 3.02-2.96 (m, 2H), 2.70-2.67 (m, 1H), 2.03-1.98 (m, 3H), 1.89-1.86 (m, 2H), 1.80-1.74 (m, 2H).

[0748] Preparation of compound N-(4-(3-amino-7-(5-(1-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-azabicyclo[3.1.0]hexan]-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-7) according to the procedure described in example 1, using intermediate P-4 (303 mg, 0.5 mmol) instead of intermediate P-1 as starting material.

[0749] Preparation according to the procedure described in example 1, using intermediate P-4 (303 mg, 0.5 mmol) instead of intermediate P-1 as starting material, afforded 50 mg of a white solid. LC-MS (APCI): m / z = 918.3 (M+1) + .

[0750] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.41 (s, 1H), 8.97 (s, 1H), 8.92 (t, J = 6.0 Hz, 1H), 8.69 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.89-7.87 (m, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56-7.48 (m, 4H), 7.38-7.33 (m, 1H), 7.23-7.19 (m, 1H), 7.11 (d, J = 9.2 Hz, 2H), 4.82 (s, 2H), 4.70-4.66 (m, 1H), 4.62 (d, J = 6.0 Hz, 4H), 4.17 (d, J = 7.8 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.33-3.28 (m, 3H), 3.05-3.00 (m, 2H), 2.90-2.87 (m, 2H), 1.95-1.91 (m, 2H), 1.76-1.63 (m, 2H).

[0751] Preparation of compound (E)-N-(4-(3-amino-7-(5-(1-(1'-(4-(4-methoxyphenyl)-4- oxobut-2-enoyl)-[1,3'-azetidinyl]-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-8)

[0752] Prepared according to the procedure described in example 2, using intermediate P-4 (200 mg, 0.3 mmol) instead of intermediate P-1 as starting material, to give 40 mg of white solid in 15.6% yield. LC-MS (APCI): m / z = 850.3 (M+1) + .

[0753] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.39 (s, 1H), 8.97 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.10-8.04 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 15.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.56-7.52 (m, 3H), 7.41 (d, J = 8.8 Hz, 1H), 7.38-7.33 (m, 2H), 7.28-7.25 (m, 1H), 7.22-7.19 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 15.2 Hz, 1H), 4.82 (s, 2H), 4.63 (d, J = 6.0 Hz, 2H), 4.35-4.32 (m, 1H), 4.23-4.20 (m, 1H), 4.03-4.00 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.24-3.20 (m, 1H), 3.02-2.96 (m, 5H), 2.70-2.67 (m, 1H), 2.03-1.98 (m, 5H), 1.50-1.39 (m, 4H).

[0754] Preparation of compound N-(4-(3-amino-7-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-9) according to the procedure described in example 1, using intermediate P-5 (120 mg, 0.20 mmol) instead of intermediate P-1 as starting material.

[0755] Preparation according to the procedure described in example 1, using intermediate P-5 (120 mg, 0.20 mmol) instead of intermediate P-1 as starting material. 40.00 mg of yellow solid was obtained in 24.7% yield. LC-MS (APCI): m / z = 809.3 (M+1) + .

[0756] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.30 (s, 1H), 11.10 (s, 1H), 8.92-8.88 (m, 2H), 8.50 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.75-7.70 (m, 3H), 7.59-7.51 (m, 4H), 7.44 (s, 1H), 7.38-7.33 (m, 2H), 7.22-7.19 (m, 1H), 5.11-5.07 (m, 1H), 4.78 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.70-3.68 (m, 4H), 3.52-3.49 (m, 4H), 2.90-2.88 (m, 2H), 2.03-1.99 (m, 2H).

[0757] Preparation of compound (E)-N-(4-(3-amino-7-(5-(4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-10)

[0758] Prepared according to the procedure described in example 2 using intermediate P-5 (100.00 mg, 0.17 mmol) instead of intermediate P-1 as starting material to give 24.00 mg of yellow solid in 19.1% yield. LC-MS (APCI): m / z = 741.3 (M+1) + .

[0759] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.30 (s, 1H), 11.10 (s, 1H), 8.92-8.88 (m, 2H), 8.50 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.75-7.70 (m, 3H), 7.59-7.51 (m, 4H), 7.44 (s, 1H), 7.38-7.33 (m, 2H), 7.22-7.19 (m, 1H), 5.11-5.07 (m, 1H), 4.78 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.70-3.68 (m, 4H), 3.52-3.49 (m, 4H), 2.90-2.88 (m, 2H), 2.03-1.99 (m, 2H).

[0760] Preparation of compound (E)-N-(4-(3-amino-7-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-1H- pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-11)

[0761] Prepared according to the procedure described in example 1 using intermediate P-6 (100 mg, 0.15 mmol) instead of intermediate P-1 as starting material to give 33.00 mg of yellow solid in 25.5% yield. LC-MS (APCI): m / z = 864.3 (M+1) + .

[0762] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.28 (s, 1H), 11.08 (br s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.87 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.72-7.67 (m, 3H), 7.56-7.51 (m, 4H), 7.38-7.33 (m, 1H), 7.22-7.19 (m, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.71-6.68 (m, 1H), 5.10-5.05 (m, 1H), 4.78 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 8.0 Hz, 2H), 3.97-3.92 (m, 2H), 3.90 (s, 3H), 3.46-3.42 (m, 1H), 3.36-3.33 (m, 4H), 2.93-2.84 (m, 1H), 2.60-2.54 (m, 5H), 2.03-1.99 (m, 2H).

[0763] Preparation of compound (E)-N-(4-(3-amino-7-(5-(4-(1-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-12)

[0764] Prepared according to the procedure described in Example 2 using intermediate P-6 (100.00 mg, 0.15 mmol) instead of intermediate P-1 as starting material to give 15.00 mg of yellow solid in 12.6% yield. LC-MS (APCI): m / z = 796.3 (M+1) + .

[0765] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.27 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.87 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.08-8.05 (m, 2H), 7.84 (d, J = 15.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.56-7.51 (m, 4H), 7.37-7.34 (m, 1H), 7.22-7.19 (m, 1H), 7.11 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 15.6 Hz, 1H), 4.78 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.42 (t, J = 8.0 Hz, 1H), 4.28-4.24 (m, 1H), 4.10-4.05 (m, 1H), 3.92 (s, 4H), 3.88 (s, 3H), 3.38-3.35 (m, 4H), 2.57-2.55 (m, 4H), 2.02-1.98 (m, 2H).

[0766] Example 13 Preparation of compound N-(4-(3-amino-7-(5-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-azabicyclo[3.1.0]hexan]-3-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-13)

[0767] Prepared according to the procedure described in Example 1 using intermediate P-7 (100 mg, 0.14 mmol) instead of intermediate P-1 as starting material to give 31.00 mg of yellow solid in 24.1% yield. LC-MS (APCI): m / z = 919.4 (M+1) + .

[0768] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.28 (s, 1H), 11.08 (br s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.87 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.72-7.67 (m, 3H), 7.56-7.51 (m, 4H), 7.38-7.33 (m, 1H), 7.22-7.19 (m, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.71-6.68 (m, 1H), 5.10-5.05 (m, 1H), 4.78 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 8.0 Hz, 2H), 3.97-3.92 (m, 2H), 3.90 (s, 3H), 3.46-3.42 (m, 1H), 3.36-3.33 (m, 4H), 2.93-2.84 (m, 1H), 2.60-2.54 (m, 5H), 2.03-1.99 (m, 2H).

[0769] Example 14 Preparation of compound (E)-N-(4-(3-amino-7-(5-(4-(1'-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)-[1,3'-azetidinyl]-3-yl)piperazin-1-yl)pyridin-2-yl)-1H- pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-14)

[0770] Prepared according to the procedure described in Example 2 using intermediate P-7 (200.00 mg, 0.27 mmol) instead of intermediate P-1 as starting material to give 27.00 mg of a yellow solid in 11.8% yield. LC-MS (APCI): m / z = 851.4 (M+1) + .

[0771] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.27 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.86 (s, 1H), 8.09-8.03 (m, 3H), 7.78 (d, J = 15.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.55-7.49 (m, 4H), 7.38-7.33 (m, 1H), 7.22-7.19 (m, 1H), 7.09 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 15.6 Hz, 1H), 4.77 (s, 2H), 4.61 (d, J = 6.0 Hz, 2H), 4.33 (t, J = 8.0 Hz, 2H), 4.11-4.07 (m, 1H), 4.02-3.97 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.72-3.69 (m, 2H), 3.51-3.46 (m, 1H), 3.41-3.35 (m, 4H), 3.00-2.97 (m, 3H), 2.57-2.55 (m, 4H), 2.02-1.98 (m, 2H).

[0772] Preparation of compound N-(4-(3-amino-7-(5-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-15)

[0773] The following synthetic route was used

[0774] To a 10 mL microwave tube equipped with magnetic stirring was added sequentially intermediate P-8 (200 mg, 0.33 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (93 mg, 0.338 mmol), N,N'-dimethylethylenediamine (116 mg, 90.1 mmol) and dimethyl sulfoxide (4 mL), stirred and dispersed, reacted at 110 °C in the microwave for 1.5 hours. Cooled to room temperature, quenched with saturated brine (5 mL), separated the organic phase, the aqueous phase was extracted with ethyl acetate (5 mL x 2), the combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 65 mg of yellow solid with a yield of 23.9%. LC-MS (APCI): m / z = 823.3 (M+1) + .

[0775] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.45 (br s, 1H), 11.09 (s, 1H), 9.00 (s, 1H), 8.92 (t, J = 6.4 Hz, 1H), 8.73 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.56-7.52 (m, 3H), 7.38-7.33 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.22-7.18 (m, 1H), 5.10-5.05 (m, 1H), 4.83 (br s, 2H), 4.62 (d, J = 6.4 Hz, 2H), 3.92 (s, 3H), 3.66 (s, 2H), 3.49 (br s, 4H), 2.92-2.84 (m, 1H), 2.60-2.53 (m, 5H), 2.03-1.99 (m, 1H), 0.85-0.82 (m, 1H).

[0776] Example 16 Preparation of compound (E)-N-(4-(3-amino-7-(5-((4-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-16)

[0777] Prepared according to the procedure described in Example 2 using intermediate P-8 (200.00 mg, 0.33 mmol) instead of intermediate P-1 as starting material to give 40.00 mg of a yellow solid in 16.0% yield. LC-MS (APCI): m / z = 755.2 (M+1) + .

[0778] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.42 (br s, 1H), 8.97 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 10.2 Hz, 2H), 7.87-7.85 (m, 1H), 7.76 (d, J = 14.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.53-7.50 (m, 3H), 7.39 (d, J = 14.8 Hz, 1H), 7.34-7.32 (m, 1H), 7.20-7.16 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.81 (br s, 2H), 4.60 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.64-3.60 (m, 6H), 3.45-3.39 (m, 4H).

[0779] Preparation of compound N-(4-(3-amino-7-(5-((4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-17)

[0780] The process was prepared according to the description of example 15, using intermediate P-9 (205 mg, 0.33 mmol) instead of intermediate P-8 as raw material, to obtain 90 mg of yellow solid, yield 31.1%. LC-MS (APCI): m / z = 878.3 (M+1) + .

[0781] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.43 (br s, 1H), 11.08 (s, 1H), 8.98 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.55-7.52 (m, 3H), 7.37-7.32 (m, 1H), 7.21-7.17 (m, 1H), 6.77 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.07-5.03 (m, 1H), 4.81 (br s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.05 (t, J = 8.0 Hz, 2H), 3.91 (s, 3H), 3.85-3.82 (m, 2H), 3.59 (s, 2H), 3.16 (d, J = 5.2 Hz, 1H), 2.90-2.85 (m, 1H), 2.62-2.53 (m, 5H), 2.49-2.26 (m, 5H).

[0782] Preparation of compound (E)-N-(4-(3-amino-7-(5-((4-(1-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)azetidin-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-18)

[0783] Prepared according to the procedure described in example 2 using intermediate P-9 (100.00 mg, 0.161 mmol) instead of intermediate P-1 as starting material to give 21.00 mg of yellow solid in 16.2% yield. LC-MS (APCI): m / z = 810.3 (M+1) + .

[0784] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.41 (br s, 1H), 8.96 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.66 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 10.2 Hz, 2H), 7.84-7.82 (m, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.53-7.50 (m, 3H), 7.36-7.31 (m, 1H), 7.20-7.16 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 15.6 Hz, 1H), 6.65-6.63 (m, 1H), 4.78 (br s, 2H), 4.60 (d, J = 6.0 Hz, 2H), 4.33 (t, J = 8.0 Hz, 1H), 4.16-4.12 (m, 1H), 4.00-3.96 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82-3.76 (m, 2H), 3.19-3.3.15 (m, 4H), 2.39-2.33 (m, 4H).

[0785] Example 19 Preparation of compound N-(4-(3-amino-7-(5-((4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-azabicyclo[3.1.0]hexan]-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-19)

[0786] The process was prepared according to the description of example 15, using intermediate P-10 (150 mg, 0.222 mmol) instead of intermediate P-8 as starting material, to give 65 mg of yellow solid in 31.4% yield. LC-MS (APCI): m / z = 933.4 (M+1) + .

[0787] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.42 (br s, 1H), 11.07 (s, 1H), 8.98 (s, 1H), 8.91 (t, J = 6.4 Hz, 1H), 8.67 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.56-7.52 (m, 3H), 7.35-7.33 (m, 1H), 7.22-7.18 (m, 1H), 6.78 (s, 1H), 6.64 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 5.08-5.03 (m, 1H), 4.81 (br s, 2H), 4.62 (d, J = 6.4 Hz, 2H), 4.46-4.44 (m, 1H), 4.04-4.00 (m, 2H), 3.91 (s, 3H), 3.80-3.76 (m, 2H), 3.65-3.58 (m, 3H), 3.39-3.35 (m, 4H), 3.95-3.91 (m, 4H), 2.60-2.54 (m, 2H), 2.48-2.43 (m, 3H), 2.33-2.29 (m, 3H).

[0788] Example 20 Preparation of compound (E)-N-(4-(3-amino-7-(5-((4-(1'-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-20)

[0789] The procedure described in example 2 was followed using intermediate P-10 (150 mg, 0.222 mmol) instead of intermediate P-1 as starting material to afford 20 mg of yellow solid in 10.4% yield. LC-MS (APCI): m / z = 865.4 (M+1) + .

[0790] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.42 (br s, 1H), 8.97 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 10.2 Hz, 2H), 7.84-7.82 (m, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.53-7.50 (m, 3H), 7.36-7.31 (m, 1H), 7.20-7.16 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 15.6 Hz, 1H), 6.65-6.63 (m, 1H), 4.78 (br s, 2H), 4.61-4.59 (m, 4H), 4.33 (t, J = 8.0 Hz, 1H), 4.16-4.12 (m, 2H), 4.00-3.96 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82-3.76 (m, 2H), 3.19-3.3.15 (m, 5H), 2.39-2.33 (m, 4H).

[0791] Example 21 Preparation of compound (E)-N-(4-(3-amino-7-(5-(4-(4-methoxyphenyl)-4- oxobut-2-enoyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-lH-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-21)

[0792] The process described in example 2 was followed using intermediate P-13 (61 mg, 0.12 mmol) instead of intermediate P-l as starting material to afford 10 mg of yellow solid in 11.9% yield. LC-MS (APCI): m / z = 701.2 (M+l) + .

[0793] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.25 (br s, 1H), 8.97 (t, J = 6.0 Hz, 1H), 8.76 (br s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.55-7.52 (m, 1H), 7.40-7.35 (m, 2H), 7.24-7.20 (m, 1H), 7.13 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 4.66 (d, J = 6.0 Hz, 2H), 4.52-4.49 (m, 4H), 3.92 (s, 3H), 3.90 (s, 3H), 3.74-3.71 (m, 2H).

[0794] Preparation of compound (E)-N-(4-(3-amino-6-(1-(4-(4-methoxyphenyl)-4-oxobut-2-enoyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-22)

[0795] The following synthetic route was used

[0796] Into a 25 mL three-necked flask, equipped with magnetic stirring, was added sequentially intermediate P-11 (57 mg, 0.12 mmol), (E)-4-(4-methoxyphenyl)-4-oxo-2-butenic acid (37 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (31 mg, 0.16 mmol), 1-hydroxybenzotriazole (22 mg, 0.16 mmol) and N,N-dimethylformamide (4 mL), stirred and dispersed, cooled to 0 °C, N,N-diisopropylethylamine (46.4 mg, 0.36 mmol) was added dropwise slowly, stirred at room temperature for 4 hours. The reaction was quenched by adding saturated brine (5 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 15 mg of yellow solid, in 18.9% yield. LC-MS (APCI): m / z = 663.3 (M+1) + .

[0797] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.05 (s, 1H), 8.88 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 15.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.55-7.46 (m, 4H), 7.38-7.34 (m, 1H), 7.22-7.18 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 4.68 (br s, 2H), 4.64-4.59 (m, 3H), 4.13 (d, J = 12.8 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.33-3.26 (m, 1H), 3.08-3.00 (m, 1H), 2.87-2.80 (m, 1H), 1.99 (d, J = 12.8 Hz, 2H), 1.85-1.67 (m, 2H).

[0798] Example 23 Preparation of compound N-(4-(3-amino-6-(1-(1'-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)-[1,3'-azabicyclo[3.1.0]hexan]-3-yl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide

[0799] The following synthetic route was employed

[0800] To a vessel was added sequentially intermediate P-12 (150 mg, 0.24 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (67 mg, 0.24 mmol), triethylamine (49 mg, 0.48 mmol) and dimethyl sulfoxide (5 mL), stirred and dispersed, reacted at 120 °C overnight. Cooled to room temperature, diluted with water, a light yellow solid precipitated, filtered, the filter cake was dissolved in dichloromethane / methanol and separated on a silica gel column to give a bright yellow solid 50 mg, yield 25%. ESI-MS: 841 [M + +1].

[0801] 1H NMR (400 MHz, DMSO-d6) d (ppm): 11.99 (s, 1H), 11.08 (s, 1H), 8.46 (s, 1H), 7.88 (t, J = 6.0 Hz, 1H), 7.66-7.63 (m, 2H), 7.62-7.58 (m, 1H), 7.55-7.48 (m, 3H), 7.37-4.32 (m, 1H), 7.21-7.18 (m, 1H), 7.00 (s, 1H), 6.79-6.75 (m, 1H), 6.66-6.62 (m, 1H), 4.65 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H), 4.05-4.00 (m, 2H), 3.90 (s, 3H), 3.80-3.76 (m, 1H), 3.64-3.60 (m, 1H), 2.93-2.82 (m, 2H), 2.83-2.80 (m, 2H), 2.69-2.67 (m, 1H), 2.26-2.23 (m, 1H), 1.91-1.74 (m, 6H).

[0802] Preparation of compound N-(4-(3-amino-7-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)pyridin-2-yl)-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-24)

[0803] The following synthetic route was used:

[0804] wherein N-(4-(3-amino-7-bromo-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide was prepared according to the method described in Example 4 of PCT / CN2024 / 103173.

[0805] Preparation of compound (E)-N-(4-(3-amino-7-(5-(1-(4-(4-methoxyphenyl)-4-oxobutan-2-enoyl)piperidin-4-yl)pyridin-2-yl)-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-25)

[0806] The following synthetic route was used:

[0807] Preparation of Example 26 compound N-(4-(3-amino-7-(5-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-26)

[0808] The following synthetic route was employed:

[0809] Preparation of Example 27 compound N-(4-(3-amino-7-(5-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-27)

[0810] The following synthetic route was employed:

[0811] Preparation of Example 28 compound N-(4-(3-amino-6-(1-(1'-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)-[1,3'-azetidinyl]-3-yl)piperidin-4-yl)-7-(pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-28)

[0812] The following synthetic route was employed:

[0813] Preparation of Example 29 compound N-(4-(3-amino-7-(5-(1-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-29)

[0814] The following route was employed for the synthesis:

[0815] To a 10 mL microwave tube equipped with magnetic stirring was added P-2 (100.0 mg, 0.18 mmol), DMSO (3 mL) and DIPEA (123.4 mg, 0.91 mmol) sequentially. The solution was stirred and clear, 5-fluoro-2-(l-methyl-2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (105.2 mg, 0.36 mmol) was added. The solution was heated to 120 °C for 1.5 hours. The solution was concentrated by rotary evaporation. 42.3 mg, 28.0% yield was obtained. LC-MS (APCI): m / z = 822.31 (M+l) + .

[0816] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.39 (br s, 1H), 8.96 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.72-7.69 (m, 3H), 7.55-7.51 (m, 3H), 7.42 (d, J = 2.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.21-7.18 (m, 1H), 5.18-5.13 (m, 1H), 4.81 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.25 (d, J = 12.8 Hz, 2H), 3.91 (s, 3H), 3.14 (t, J = 13.6 Hz, 2H), 3.03 (s, 3H), 3.00-2.93 (m, 2H), 2.80-2.68 (m, 2H), 2.04-1.95 (m, 4H), 1.81-1.79 (m, 2H).

[0817] Preparation of compound N-(4-(3-amino-7-(5-(l-(l-(2-(l-methyl-2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-lH-pyrazolo[4,3- c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-30)

[0818] The synthesis was performed using the following route:

[0819] To a 10 mL microwave tube equipped with magnetic stirring was added P-3 (100.0 mg, 0.16 mmol), DMSO (3 mL) and DIPEA (112.0 mg, 0.82 mmol) sequentially. The solution was stirred and clear, 5-fluoro-2-(l-methyl-2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (95.7 mg, 0.33 mmol) was added. The solution was heated to 120 °C for 1.5 h. The solution was concentrated by rotary evaporation. 40.3 mg, 28.1% yield was obtained. LC-MS (APCI): m / z = 877.3 (M+l) + .

[0820] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.39 (s, 1H), 8.96 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.89-7.87 (m, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56-7.48 (m, 4H), 7.38-7.33 (m, 1H), 7.22-7.18 (m, 1H), 6.82 (s, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.16-5.11 (m, 1H), 4.81 (s, 2H), 4.63 (d, J = 6.4 Hz, 2H), 4.17 (t, J = 7.8 Hz, 2H), 3.92-3.90 (m, 5H), 3.03-2.91 (m, 6H), 2.90-2.87 (m, 1H), 2.78-2.71 (m, 2H), 2.04-1.97 (m, 3H), 1.90-1.87 (m, 2H), 1.76-1.63 (m, 2H).

[0821] Example 31 Preparation of compound N-(4-(3-amino-7-(5-(l-(l'-(2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,3'-biazetidin]-3-yl)piperidin-4-yl)pyridin-2-yl)-lH-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-31)

[0822] The synthesis was performed using the following route:

[0823] To a 10 mL microwave tube equipped with magnetic stirring was added P-4 (100.0 mg, 0.15 mmol), DMSO (3 mL) and DIPEA (102.0 mg, 0.75 mmol) sequentially. The solution was stirred and clear, then 5-fluoro-2-(l-methyl-2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (88.0 mg, 0.30 mmol) was added. The solution was heated to 120 °C for 1.5 h. The solution was concentrated by rotary evaporation. 35.0 mg, 25.0% yield was obtained. LC-MS (APCI): m / z = 932.1 (M+l) + .

[0824] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.66 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.55 - 7.51 (m, 3H), 7.37 - 7.32 (m, 1H), 7.21 - 7.18 (m, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, J = 1.6 Hz, 1H), 5.14 - 5.10 (m, 1H), 4.80 (s, 2H), 4.62 (d, J = 6.4 Hz, 2H), 4.05 (t, J = 7.8 Hz, 2H), 3.91 (s, 3H), 3.83 - 3.79 (m, 2H), 3.66 - 3.64 (m, 1H), 3.43 - 3.36 (m, 4H), 3.01 (s, 3H), 2.95 - 2.91 (m, 3H), 2.90 - 2.87 (m, 2H), 2.77 - 2.72 (m, 1H), 2.67 - 2.55 (m, 2H), 2.04 - 1.97 (m, 5H), 1.90 - 1.87 (m, 2H), 1.76 - 1.63 (m, 2H).

[0825] Example 32: Preparation of compound N-(4-(3-amino-7-(5-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)pyridin-2-yl)-lH-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-32)

[0826] The synthesis was performed using the following route:

[0827] To a 100 mL flask equipped with magnetic stirring was added P-2 (100.0 mg, 0.18 mmol), C-1 (80.4 mg, 0.23 mmol) and MeOH (5 mL) sequentially. The solution was stirred to dissolve, CH3COOH (10 mg, 0.18 mmol) was added, and NaBH3CN (45.7 mg, 0.72 mmol) was added under ice water bath. After the addition was completed, the ice water bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NaHC03solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 51.0 mg of white solid with a yield of 32.1%. LC-MS (APCI): m / z = 878.0 (M+1) + .

[0828] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (br s, 1H), 11.06 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 3H), 7.37-7.33 (m, 2H), 7.21-7.18 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 5.08-5.04 (m, 1H), 4.80 (s, 2H), 4.62 (d, J = 6.8 Hz, 2H), 4.16 (t, J = 8.0 Hz, 2H), 3.91 (s, 3H), 3.73-3.70 (m, 2H), 3.07-3.00 (m, 3H), 2.87-2.85 (m, 1H), 2.66-2.61 (m, 3H), 2.56-2.52 (m, 2H), 2.15-2.10 (m, 2H), 2.02-1.97 (m, 2H), 1.85-1.73 (m, 4H).

[0829] Example 33 Preparation of compound N-(4-(3-amino-7-(5-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-33)

[0830] The synthesis was carried out using the following route:

[0831] Into a 100 mL flask equipped with magnetic stirring, was added P-2 (100.0 mg, 0.18 mmol), C-2 (87.0 mg, 0.23 mmol) and MeOH (5 mL) successively. The solution was stirred to dissolve, CH3COOH (10 mg, 0.18 mmol) was added, and NaBH3CN (45.7 mg, 0.72 mmol) was added under ice water bath. After the addition was completed, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column to give 40.5 mg of white solid, with a yield of 24.6%. LC-MS (APCI): m / z = 905.00 (M+1) + .

[0832] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (br s, 1H), 11.06 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.84 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 3H), 7.37-7.33 (m, 2H), 7.22-7.13 (m, 2H), 5.08-5.04 (m, 1H), 4.80 (s, 2H), 4.62 (d, J = 6.8 Hz, 2H), 4.05 (d, J = 12.0 Hz, 2H), 3.91 (s, 3H), 3.92-3.88 (m, 5H), 3.01-2.93 (m, 4H), 2.66-2.54 (m, 4H), 2.23-2.20 (m, 1H), 2.06-1.97 (m, 4H), 1.85-1.73 (m, 7H).

[0833] Preparation of compound (S)-5-(4-((4-(6-(3-amino-4-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-lH-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperidin-l-yl)methyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (E-34)

[0834] The synthesis was carried out using the following route:

[0835] To a 100 mL flask equipped with magnetic stirring was added P-2 (100.0 mg, 0.18 mmol), C-3 (81.2 mg, 0.23 mmol) and MeOH (5 mL) successively, the solution was stirred to dissolve, CH3COOH (10 mg, 0.18 mmol) was added, NaBH3CN (45.7 mg, 0.72 mmol) was added under ice water bath, after addition, the ice bath was removed, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column to give 35.1 mg of white solid, with a yield of 23.4%. LC-MS (APCI): m / z = 880.1 (M+l) + .

[0836] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (br s, 1H), 10.83 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.70-8.66 (m, 2H), 8.31 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55-7.51 (m, 3H), 7.42-7.32 (m, 2H), 7.21-7.18 (m, 1H), 4.79 (s, 2H), 4.75-4.72 (m, 1H), 4.62 (d, J = 6.8 Hz, 2H), 3.97-3.91 (m, 6H), 3.01-2.98 (m, 2H), 2.91-2.79 (m, 4H), 2.66-2.61 (m, 1H), 2.22-2.20 (m, 3H), 2.06-1.97 (m, 4H), 1.85-1.73 (m, 8H).

[0837] Example 35 Preparation of compound (S)-4-(4-((4-(6-(3-amino-4-(4-((5-fluoro-2- methoxybenzamido)methyl)phenyl)-lH-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperidin- 1-yl)methyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (E-35)

[0838] The synthesis was carried out using the following route:

[0839] To a 100 mL flask equipped with magnetic stirring was added P-2 (100.0 mg, 0.18 mmol), C-4 (85.1 mg, 0.23 mmol) and MeOH (5 mL) successively, the solution was stirred to dissolve, CH3COOH (10 mg, 0.18 mmol) was added, NaBH3CN (45.7 mg, 0.72 mmol) was added under ice water bath, after addition, the ice bath was removed, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column to give 32.0 mg of white solid, with a yield of 19.7%. LC-MS (APCI): m / z = 897.3 (M+l) + .

[0840] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (br s, 1H), 10.83 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.66 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.64-7.60 (m, 1H), 7.55-7.51 (m, 3H), 7.35-7.32 (m, 1H), 7.21-7.18 (m, 1H), 6.82-6.73 (m, 2H), 4.79 (s, 2H), 4.75-4.72 (m, 1H), 4.62 (d, J = 6.8 Hz, 2H), 3.92-3.87 (m, 5H), 3.01-2.98 (m, 2H), 2.87-2.65 (m, 4H), 2.20-2.18 (m, 2H), 2.08-1.97 (m, 6H), 1.82-1.73 (m, 8H).

[0841] Example 36 Preparation of compound N-(4-(3-amino-7-(5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-ylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-36)

[0842] The synthesis was carried out using the following route:

[0843] Into a 100 mL flask equipped with magnetic stirring, was added P-2 (100.0 mg, 0.18 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (71.1 mg, 0.23 mmol) and MeOH (5 mL) successively. The solution was stirred to dissolve, CH3COOH (10 mg, 0.18 mmol) was added, and NaBH3CN (45.7 mg, 0.72 mmol) was added under ice water bath. After the addition was completed, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a white solid 40.5 mg in 26.6% yield. LC-MS (APCI): m / z = 837.3 (M+1) + .

[0844] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.37 (br s, 1H), 10.25 (br s, 1H), 8.95 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.66 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.55-7.51 (m, 3H), 7.37-7.32 (m, 1H), 7.21-7.18 (m, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.80 (s, 2H), 4.62 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.69 (t, J = 6.8 Hz, 4H), 3.00 (d, J = 10.4 Hz, 2H), 2.69-2.63 (m, 5H), 2.21 (d, J = 7.2 Hz, 2H), 2.06-1.97 (m, 3H), 1.84-1.73 (m, 8H).

[0845] Example 37 Preparation of compound N-(4-(3-amino-7-(5-(1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-37)

[0846] The synthesis was carried out using the following route:

[0847] To a 100 mL flask equipped with magnetic stirring was added C-5 (98.8 mg, 0.23 mmol), DIPEA (64 mg, 0.47 mmol) and anhydrous CH3CN (3 mL) successively. The solution was stirred and cooled in an ice-water bath. TSTU (106.4 mg, 0.35 mmol) was added. After the addition was completed, the ice-water bath was removed and the reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere. P-2 (100.0 mg, 0.18 mmol) and a solution of DIPEA (98.7 mg, 0.72 mmol) in DMF (2 mL) were added successively. The reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous NaCl solution (20 mL). The reaction was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and washed with saturated aqueous NaCl solution (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 20.3 mg of white solid. Yield: 11.8%. LC-MS (APCI): m / z = 953.3 (M+1) + .

[0848] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.40 (br s, 1H), 10.52 (br s, 1H), 8.97 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.56-7.52 (m, 3H), 7.38-7.33 (m, 1H), 7.22-7.13 (m, 1H), 5.08 (s, 1H), 4.80 (s, 2H), 4.73-4.68 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.26-4.19 (m, 1H), 3.95 (s, 3H), 3.92-3.88 (m, 5H), 3.20-3.17 (m, 3H), 3.11-3.02 (m, 2H), 2.90-2.88 (m, 1H), 2.74 (t, J = 9.6 Hz, 2H), 2.63 (s, 2H), 1.99-1.84 (m, 5H), 1.78-1.72 (m, 3H), 1.62-1.58 (m, 1H).

[0849] Example 38 Preparation of compound N-(4-(3-amino-7-(5-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-38)

[0850] The synthesis was performed using the following route:

[0851] To a 100 mL flask equipped with magnetic stirring was added C-6 (89.4 mg, 0.23 mmol), DIPEA (64.1 mg, 0.47 mmol) and anhydrous CH3CN (3 mL) successively. TSTU (106.2 mg, 0.35 mmol) was added under ice-water bath. After the addition was completed, the ice-water bath was removed and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Then P-2 (100.0 mg, 0.18 mmol) and DIPEA (98.7 mg, 0.72 mmol) in DMF (2 mL) was added. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous NaCl solution (20 mL). The reaction mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated aqueous NaCl solution (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 22.5 mg of white solid as a product. Yield: 13.6%. LC-MS (APCI): m / z = 913.4 (M+1) +

[0852] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 12.38 (br s, 1H), 10.77 (br s, 1H), 8.97 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.56-7.52 (m, 3H), 7.38-7.33 (m, 1H), 7.22-7.13 (m, 2H), 6.88-6.83 (m, 1H), 6.65-6.62 (m, 1H), 6.51-6.47 (m, 1H), 4.97 (s, 1H), 4.80 (s, 2H), 4.73-4.68 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.26-4.19 (m, 1H), 3.91 (s, 3H), 3.20-3.17 (m, 5H), 2.96-2.84 (m, 6H), 2.72-2.64 (m, 4H), 2.58-2.54 (m, 3H), 2.11-2.06 (m, 2H), 1.91-1.85 (m, 3H), 1.79-1.66 (m, 6H).

[0853] Example 39 Preparation of compound N-(4-(3-amino-7-(5-(1-(1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methoxybenzamide (E-39)

[0854] The synthesis was performed using the following route:

[0855] To a 100 mL flask equipped with magnetic stirring was added C-5 (98.8 mg, 0.23 mmol), DIPEA (64.1 mg, 0.47 mmol) and CH3CN (2 mL) successively. The solution was stirred and cooled in an ice water bath. TSTU (106.4 mg, 0.34 mmol) was added dropwise. After the addition was completed, the ice water bath was removed and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. P-3 (100.0 mg, 0.16 mmol) and DIPEA (89.7 mg, 0.66 mmol) in DMF (2 mL) were added dropwise. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous NaCl solution (20 mL). The reaction was extracted with ethyl acetate (15 mL x 3). The organic layers were combined and washed with saturated aqueous NaCl solution (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give 15.3 mg of white solid. Yield: 9.2%. LC-MS (APCI): m / z = 1008.4 (M+1) +

[0856] 1H NMR (400 MHz, DMSO-d6) d (ppm): 12.38 (br s, 1H), 10.52 (br s, 1H), 8.95 (s, 1H), 8.90 (t, J = 6.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55-7.51 (m, 3H), 7.37-7.33 (m, 2H), 7.21-7.18 (m, 1H), 7.12 (d, J = 7.2 Hz, 1H), 4.87 (s, 1H), 4.80 (s, 2H), 4.62 (d, J = 6.8 Hz, 2H), 4.24 (t, J = 8.0 Hz, 2H), 4.10-4.05 (m, 1H), 3.94-3.87 (m, 9H), 3.74-3.70 (m, 2H), 3.18-3.14 (m, 3H), 3.07-3.00 (m, 2H), 2.98-2.92 (m, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.69-2.65 (m, 1H), 2.28 (s, 2H), 2.02-1.97 (m, 2H), 1.87-1.82 (m, 4H), 1.76-1.69 (m, 5H).

[0857] Example 40 Preparation of compound (S)-5-(4-((3-(4-(6-(3-amino-4-(4-((5-fluoro-2- methoxybenzamido)methyl)phenyl)-lH-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3- yl)piperidin-l-yl)azetidin-l-yl)methyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3- yl)picolinamide (E-40)

[0858] The synthesis was performed using the following route:

[0859] Into a 100 mL flask equipped with magnetic stirring was added P-3 (100.0 mg, 0.16 mmol), C-3 (73.7 mg, 0.21 mmol) and MeOH (5 mL) sequentially. The solution was stirred to dissolve, CH3COOH (10.0 mg, 0.16 mmol) was added, and NaBH3CN (41.5 mg, 0.66 mmol) was added under ice water bath. After the addition was completed, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NaHC03solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a white solid 36.5 mg in 23.7% yield. LC-MS (APCI): m / z = 935.3 (M+1) +

[0860] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 12.36 (br s, 1H), 10.83 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.70-8.66 (m, 2H), 8.29 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55-7.51 (m, 3H), 7.40-7.32 (m, 2H), 7.21-7.18 (m, 1H), 4.79-4.70 (m, 3H), 4.62 (d, J = 6.8 Hz, 2H), 3.93-3.90 (m, 5H), 3.50-3.41 (m, 2H), 2.92-2.64 (m, 11H), 2.38-2.32 (m, 2H), 2.19-2.15 (m, 1H), 2.02-1.70 (m, 12H), 1.60-1.50 (m, 2H).

[0861] Example 41 Preparation of compound (S)-4-(4-((3-(4-(6-(3-amino-4-(4-((5-fluoro-2- methoxybenzamido)methyl)phenyl)-lH-pyrazolo[4,3-c]pyridin-7-yl)pyridin-3-yl)piperidin- 1-yl)azetidin-l-yl)methyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (E-41)

[0862] The synthesis was performed using the following route:

[0863] Into a 100 mL flask equipped with magnetic stirring, P-3 (100 mg, 0.16 mmol), C-4 (77.4 mg, 0.21 mmol) and MeOH (5 mL) were added successively. The solution was stirred to dissolve, CH3COOH (10.0 mg, 0.16 mmol) was added, and NaBH3CN (41.5 mg, 0.66 mmol) was added under ice water bath. After addition, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NaHC03solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a white solid 38.6 mg in 24.5% yield. LC-MS (APCI): m / z = 952.40 (M+1) +

[0864] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 12.36 (br s, 1H), 10.83 (br s, 1H), 8.95 (s, 1H), 8.89 (t, J = 6.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.01-7.97 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.63-7.59 (m, 1H), 7.55-7.51 (m, 2H), 7.37-7.32 (m, 1H), 7.21-7.18 (m, 1H), 6.80-6.74 (m, 2H), 4.79 (s, 2H), 4.73-4.69 (m, 1H), 4.62 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.88-3.84 (m, 2H), 3.30-3.22 (m, 6H), 2.92-2.64 (m, 6H), 2.67-2.61 (m, 2H), 2.40-2.30 (m, 4H), 2.13-2.07 (m, 2H), 2.02-1.92 (m, 2H), 1.89-1.78 (m, 4H), 1.74-1.66 (m, 4H), 1.57-1.50 (m, 2H).

[0865] Biological activity test

[0866] 1. Detection of intracellular degradation activity of BTK-PROTAC

[0867] NanoLuc Binary Technology Technology is to use Luciferase is recombinantly expressed as two peptide segments, HiBiT and LgBiT, which have high binding affinity in living cells to reconstitute functional NanoBiT luciferase in the presence of substrate Endurazine TM Live Cell Substrates(Promega N2571) then produces a bright luminescent signal, the intensity of which is proportional to the amount of labeled target protein. Therefore, it can be used to detect the changes in the amount of target protein in living cells in real time.

[0868] In this experiment, Promega's technology was used. The HiBiT tag was knocked into the endogenous BTK target protein in Ramos cells or TMD-8 cells by CRISPR gene editing method, and then the LgBiT plasmid was stably transfected into the cell line, and on this basis, the gene editing of the point of interest mutation was carried out. The sgRNA and donor DNA for gene editing were designed by ourselves and synthesized by IDT company, and the LgBiT plasmid was purchased from Promega(N2681).

[0869] The degradation activity detection steps are as follows:

[0870] a) Add the compound to the 384-well plate with a gradient concentration by D300e, and add the well with 0.5% DMSO as a control.

[0871] b) Collect cells in logarithmic growth phase, prepare cell suspension and count, calculate cell concentration.

[0872] c) After diluting the cell suspension to the required concentration, add Endurazine substrate (substrate: cell suspension = 1:200) to the diluted cells, mix gently and put into a culture dish, and pre-incubate in a 37°C, 5% CO2 incubator for 2h.

[0873] d) Add the pre-incubated cells to the middle wells of the 384-well plate with added compound at 50μL per well, the first column without cells only with culture medium as a blank control, and the remaining edge wells with PBS. Place the 384-well plate in a 37°C, 5% CO2 incubator for culture.

[0874] e) Read the plate in Biotek cytation3.0 enzyme label instrument at the corresponding detection time point, and after detection, continue to culture in the incubator, and export all data.

[0875] The following nonlinear fitting formula is used to obtain the DC of the compound 50 (Half-degradation concentration): Y=Bottom+(Top-Bottom) / (1+10^((LogDC50 - X) * HillSlope) X: compound concentration log value Y: BTK retention rate (BTK%)

[0876] The DT of the compound was obtained using the following non-linear fitting formula 50 (Half-life): Y = Bottom + (Top-Bottom) / (1 + ((X^HillSlope) / (DT 50 ^HillSlope))) X: time (Time: h) Y: BTK retention rate (BTK%)

[0877] The BTK retention rate (BTK%) was calculated according to the following formula:

[0878] BTK% = (Lum test drug - Lum vehicle control) / (Lum cell control - Lum vehicle control) x 100%.

[0879] The results of the representative examples on the degradation of BTK protein are summarized in Table 1, Table 3 (DC 50 ) and Table 2, Table 4 (Dmax) below. Among them, A represents 0 < DC 50 ≤ 50 nM, B represents 50 nM < DC 50 ≤ 500 nM, C represents DC 50 > 500 nM; ++ represents Dmax ≥ 70%, + represents 0 < Dmax < 70%.

[0880] Table 1

[0881] Table 2

[0882] Table 3

[0883] Table 4

[0884] 2. Test of growth inhibition activity of cells

[0885] In this experiment, the luminescence method cell viability detection kit provided by Promega Company was used, which is a homogeneous method for cell viability detection. The cell viability of cultured cells (TMD-8 cells: human diffuse large B lymphoma cell line, OCI-Ly10 cells: human diffuse large B lymphoma cells) was determined by quantifying ATP. The specific experimental steps are as follows:

[0886] a) Collect cells in the logarithmic growth phase, prepare cell suspension and count, and calculate the cell concentration.

[0887] b) After diluting the cell suspension to the desired concentration, add it to the middle wells of a 96-well plate, and add PBS to the edge wells. Add culture solution to the wells without cells as a blank control.

[0888] c) In addition to the cell plate for compound analysis, another 96-well plate is prepared as a T0 plate, 3-6 blank wells and 3-6 cell wells are added, and the next day, CTG is used to detect cell viability, which is used as the T0 viability value of the cells.

[0889] d) Place the cell plate in a 37°C, 5% CO2 incubator overnight.

[0890] e) The next day, add each concentration of compound in gradient dilution, and place the cell plate in a 37°C, 5% CO2 incubator for 72 h. Add 0.5% DMSO to the wells without compound as a positive control for cell growth.

[0891] f) Add CTG reagent (Cell Titer-Glo kit) according to the manufacturer's instructions to detect cell viability values.

[0892] g) Read the plate with a Biotek cytation3.0 enzyme labeler and export the data.

[0893] h) Calculate the IC50 using GraphPad Prism 7.0 software.

[0894] The following nonlinear fitting formula is used to obtain the IC 50 (Half maximal inhibitory concentration): Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope)) X: Compound concentration log value Y: Inhibition rate (% inhibition)

[0895] The formula for calculating the cell inhibition rate (% inhibition) is:

[0896] % Inhibition = 1 - (Lum test drug - Lum vehicle control) / (Lum cell control - Lum vehicle control) x 100%.

[0897] The results of the representative examples on the in vitro proliferation inhibition of tumor cells are summarized in Table 3 below. Among them, A represents 0 < IC 50 ≤ 5 nM, B represents IC 50 > 5 nM.

[0898] Table 3

[0899] 3. BTK protein phosphorylation detection

[0900] This experiment aims to simply, quickly and directly detect the endogenous level of BTK in cells, the specific experimental steps are as follows:

[0901] Adherent cells (NIH / 3T3 BTK WT and NIH / 3T3 BTK C481S) operation steps

[0902] Day 1:

[0903] 1. Plate NIH / 3T3 BTK WT cells 7.5k / well, NIH / 3T3 BTK C481S cells 10k / well in 96-well plates respectively, 37℃, 5% CO2 culture overnight.

[0904] Day 2:

[0905] 1. Prepare 3-fold final concentration gradient of compound dilutions, take 50uL and add to 100uL cell culture. 0.5% DMSO as cell growth positive control.

[0906] 2. 37℃, 5% CO2 culture for 0.5h.

[0907] 3. Add final concentration of 1mM Na3VO4, 37℃, 5% CO2 culture for 2h.

[0908] 4. During the culture, prepare the following reagents:

[0909] 1x Lysis buffer with added lysis buffer: 3vol ddH2O + 1vol 4x Lysis buffer + 100x Blocking reagent

[0910] p-BTK(Y223)cryptate-antibody and p-BTK(Y223)d2-antibody working solution: add 1 volume of each frozen antibody (-20℃) to 19 volumes of detection buffer (4℃).

[0911] 5. After incubation, remove the culture medium, add 50uL 1x Lysis buffer with added lysis buffer, room temperature, 500rpm, for 30min.

[0912] 6. Mix the lysate, transfer 16uL to a 384-well plate, 1x Lysis buffer with added lysis buffer as a blank control.

[0913] 7. Add 4uL of pre-mixed two antibody working solution (cryptate Ab:d2 Ab=1:1), seal the plate.

[0914] 8. Incubate overnight at room temperature.

[0915] Day 3:

[0916] Read the plate at 665 nm and 620 nm with Biotek cytation3.0 microplate reader and calculate the 665 / 620 nm ratio per well.

[0917] Data analysis:

[0918] Calculate IC50 with GraphPad Prism7.0 software 50 .

[0919] The phosphorylation BTK Y223 IC50 of the compounds was obtained using the following non-linear fit equation 50 (Half maximal phosphorylation inhibition concentration): Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)) X: compound concentration log value Y: inhibition rate (%inhibition)

[0920] The inhibition rate (%) of cell phosphorylation was calculated using the following formula: Inhi. (%) = 1-(each concentration well-blank well) / (positive control well-blank well)

[0921] Suspension cell (Ramos) operation steps

[0922] Day 1:

[0923] 1. Plate 2.5k / well Ramos cells containing BTK WT or BTK C481S or BTK T474I in 96-well plates, 25μL / well, respectively, add each concentration gradient of compound using Tecan D300e, 37℃, 5% CO2 incubate for 2h.

[0924] 2. Add 8.33uL of 20mM Na3VO4 to make the final concentration 5mM, 37℃, 5% CO2 incubate for 3h.

[0925] 3. During the incubation period, prepare the following reagents:

[0926] 4x Lysis buffer has been added: 24vol 4x Lysis buffer + 1vol 25x Blocking reagent.

[0927] p-BTK(Y223) cryptate-antibody and p-BTK(Y223) d2-antibody working solution: Add 1 volume of each frozen antibody (-20℃) to 38 volumes of detection buffer (4℃) and mix well.

[0928] 4. After incubation, directly add 11.1 uL 4x pre-mixed lysis buffer, 800 rpm, room temperature, shake for 30 min.

[0929] 5. Mix the lysis solution, transfer 16 uL to a 384-well plate, and 1x pre-mixed lysis buffer as a blank control.

[0930] 6. Add 4 uL of pre-mixed two antibody working solution (cryptate Ab:d2 Ab = 1:1), seal the plate.

[0931] 7. Incubate overnight at room temperature.

[0932] Day 2:

[0933] Read the plate at 665 nm and 620 nm using a Biotek cytation 3.0 enzyme labeler, and calculate the 665 / 620 nm ratio per well.

[0934] Data analysis:

[0935] Calculate IC 50 using GraphPad Prism 7.0 software.

[0936] The following non-linear fitting formula is used to obtain the phosphorylation BTK Y223 IC 50 (half phosphorylation inhibition concentration) of the compound: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)) X: compound concentration log value Y: inhibition rate (% inhibition)

[0937] The formula for calculating the cell phosphorylation inhibition rate Inhibition (% inhibition) is: Inhi. (%) = 1 - (each concentration well-blank well) / (positive control well-blank well)

[0938] The experimental results show that the compound of the present application has strong activity on wild-type BTK kinase and drug-resistant mutant BTK C481S, BTK T474I kinase.

[0939] 4. Metabolic stability evaluation

[0940] Metabolic stability is generally used to describe the speed and degree of compound metabolism, and is one of the main factors affecting pharmacokinetic properties. Many compounds are substrates of CYP450 enzymes and other drug metabolism enzymes, and liver microsomes are a system rich in CYP450. The purpose of this experiment is to study the in vitro metabolic stability by incubating the compound of the present application with human and SD rat liver microsomes and detecting the remaining proportion of the compound using LC-MS / MS.

[0941] ① Solution preparation

[0942] Phosphate buffer (PBS): Mix 150 mL of KH2PO4 (0.5 M) solution and 700 mL of K2HPO4 (0.5 M) solution, and adjust the pH of the mixture to 7.4 with K2HPO4 (0.5 M) solution to obtain 5-fold concentrated PBS, which is stored at 4°C. Before use, dilute 5-fold with ultrapure water, and add 3.3 mM magnesium chloride to obtain phosphate buffer PBS (100 mM).

[0943] NADPH regenerating system solution: prepare a NADPH solution containing 6.5 mM NADP, 16.5 mM G-6-P, and 3 U / mL G-6-PD in 5 mL of PBS.

[0944] Internal standard termination solution: prepare 50 ng / mL propranolol hydrochloride and 200 ng / mL tolbutamide as internal standard working solution with acetonitrile.

[0945] Human liver microsomal solution: mix 0.31 mL of human liver microsomes (25 mg / mL) with 0.961 mL of PBS (pH 7.4) to obtain a human liver microsomal dilution solution with a protein concentration of 0.625 mg / mL.

[0946] SD rat liver microsomal solution: mix 0.31 mL of SD rat liver microsomes (25 mg / mL) with 0.961 mL of PBS (pH 7.4) to obtain a SD rat liver microsomal dilution solution with a protein concentration of 0.625 mg / mL.

[0947] Sample working solution: prepare the powder of the compound of the present application, the powder of positive control dextromethorphan, and the powder of omeprazole to 10 mM with DMSO as a sample stock solution. Then dilute with 70% acetonitrile-water to obtain a 0.25 mM sample working solution.

[0948] ② Sample incubation

[0949] Add 398 μL of human liver microsomal dilution solution to a 96-well incubation plate (N = 2), and add 2 μL of 0.25 mM of the compound to be tested, dextromethorphan, respectively, and mix well.

[0950] Add 398 μL of SD rat liver microsomal dilution solution to a 96-well incubation plate (N = 2), and add 2 μL of 0.25 mM of the compound to be tested, omeprazole, respectively, and mix well.

[0951] Add 300 μL of pre-cooled termination solution to each well of a 96-well deep well plate, and place it on ice as a termination plate.

[0952] Put 96-well incubation plate and NADPH regeneration system into a 37℃ water bath box, shake at 100 r / min, pre-incubate for 5 min. Take 80 μL of incubation solution from each well of the incubation plate and add to the termination plate, mix, supplement with 20 μL of NADPH regeneration system solution, and take as the 0 min sample. Add 80 μL of NADPH regeneration system solution to each well of the incubation plate, start the reaction, and start timing. The concentration of the test compound in the reaction is 1 μM, and the protein concentration is 0.5 mg / mL.

[0953] At 10, 30, 90 min of the reaction, respectively, take 100 μL of the reaction solution, add to the termination plate, vortex for 3 min to terminate the reaction.

[0954] Centrifuge the termination plate at 5000 rpm at 4℃ for 15 min. Take 200 μL of supernatant to a 96-well plate into which 200 μL of ultrapure water has been added in advance, mix, and use LC-MS / MS to analyze the sample, and take 10 μL of sample.

[0955] ③Sample analysis method

[0956] In this experiment, the peak area of the test compound, dextromethorphan, omeprazole and the internal standard is detected by LC-MS / MS system, and the peak area ratio of the compound to the internal standard is calculated.

[0957] ④Data processing

[0958] The peak area of the sample and the internal standard is obtained by the mass spectrometer and the Analyst software, and the residual amount (R%) of the compound is plotted against time by using the single exponential degradation model of the Graphpad prism 7.0 software to obtain the substrate elimination rate constant K

[0959] Ct / C0=exp(-K*t)

[0960] And the half-life T is calculated according to the following formula 1 / 2 And the intrinsic clearance CL int Where V / M is equal to 1 / C (protein).

[0961] The experimental results show that the compound of the present application has excellent metabolic stability.

[0962] 5.Rat pharmacokinetic experiment

[0963] 6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210 g, are divided into 2 groups, 3 in each group, and a single dose of compound is administered intravenously or orally (10 mg / kg orally), and the pharmacokinetic differences are compared.

[0964] The rats are fed with standard feed and given water. The rats are fasted for 16 hours before the experiment. The drug is dissolved in PEG400 and dimethyl sulfoxide. The blood samples are collected from the eye sockets. The time points for blood collection are 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after the administration.

[0965] The rats are anesthetized by inhaling ether, and 300 μL of blood samples are collected from the eye sockets into test tubes. There are 30 μL of 1% heparin saline solution in the test tubes. Before use, the test tubes are dried at 60°C overnight. After the blood samples are collected at the last time point, the rats are anesthetized by ether and sacrificed.

[0966] After the blood samples are collected, the test tubes are gently inverted for at least 5 times to ensure mixing, and then placed on ice. The blood samples are centrifuged at 5000 rpm for 5 minutes at 4°C to separate the plasma from the red blood cells. 100 μL of the plasma is pipetted into a clean plastic centrifuge tube, and the name of the compound and the time point are marked. The plasma is stored at -80°C before analysis. The concentration of the compound of the present application in the plasma is determined by LC-MS / MS. The pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.

[0967] The experimental results show that the compound of the present application has better pharmacokinetic properties in animals, and thus has better pharmacodynamics and therapeutic effect.

[0968] The above is a further detailed description of the present application in combination with specific preferred embodiments, and the specific implementation of the present application should not be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application, and all of them should be considered as falling within the protection scope of the present application.

Claims

1. A compound of Formula (I): ###0001### (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. wherein X1is N, CD or CH; X2is N or CR2; R1is a chemical bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R; R2is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more groups selected from D, halogen, -(CH2) t -OH, oxo, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy; t is 0, 1 or 2; R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to full deuteriation; R5is halogen; R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to per-deuteration; R s and R t independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to perdeuteration; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; L A is a chemical bond or a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

2. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X1is N.

3. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X2is CR2.

4. The compound of claim 3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H, halogen or C1-5alkyl optionally substituted with 1-5 halogens 1-3 alkyl.

5. The compound of claim 4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H, F, CHF2, CF3, CH3or CH(CH3)(CF3).

6. The compound of claim 5, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H.

7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R3and R4are both H.

8. The compound of any one of claims 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R5is F.

9. The compound of any one of claims 1-8, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R6is CH3or CD3.

10. The compound of any one of claims 1-9, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, m is 0.

11. The compound of any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0.

12. The compound according to any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 1, R t is F, CH3or CD3.

13. The compound of any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a chemical bond.

14. The compound of any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a divalent radical selected from 5-membered monocyclic heteroarene optionally substituted with 1-3 R.

15. The compound of claim 14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, 5-membered monocyclic heteroarenes are selected from the group consisting of: the above radicals are optionally substituted with 1-3 R.

16. The compound of claim 14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, The divalent radical of the 5-membered monocyclic heteroarenes is of the formula (II): wherein Y1is N or CH; Y2is N or CH; * denotes a connection to L A connected, represents the remaining other end connected to the compound of formula (I); formula (II) is optionally substituted with 1-3 R.

17. The compound of any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a divalent radical selected from 6-membered monocyclic heteroarene optionally substituted with 1-3 R.

18. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, 6-membered monocyclic heteroarenes are selected from the group consisting of: the above radicals are optionally substituted with 1-3 R.

19. The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, The divalent radical of the 6-membered monocyclic heteroarene is of the formula (III): wherein Y3is CH or N; Y4is CH or N; Y5is CH or N; * denotes a connection to L A connected, represents the remaining other end connected to the compound of formula (I); formula (III) is optionally substituted with 1-3 R.

20. The compound of claim 19, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, The divalent radical of the 6-membered monocyclic heteroarene is of the structure shown in formula (III) A ) : wherein Y3is CH or N; * denotes a connection to L A connected, represents the remaining other end connected to the compound of formula (I); Formula (III A ) is optionally substituted with 1-3 R.

21. The compound of claim 20, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, The divalent radical of the 6-membered monocyclic heteroarene is of the structure shown in formula (III) B ) : wherein * indicates the attachment to L A ​ represents the other end of the bond to the compound of formula (A) or the compound of formula (I), formula (III B ) is optionally substituted with 1-3 R.

22. The compound according to any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a divalent radical of 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle optionally substituted with 1-6 R.

23. The compound of claim 22, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, 9- to 13-membered bicyclic or tricyclic heteroarenes or heterocycles are selected from: the above radicals are optionally substituted with 1-4 R.

24. The compound of claim 22, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is a structure represented by formula (IV): wherein * denotes a connection to L A connected, represents the remaining other end connected to the compound of formula (I); formula (IV) is optionally substituted with 1-4 R.

25. The compound of any one of claims 1-24, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a chemical bond.

26. The compound of any one of claims 1-24, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V'): -S0-(L A1 ) i -S1-(L A2 ) j -S2-(L A3 ) k -S3-■(V') wherein i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0; L A1 , L A2 and L A3 are each independently a chemical bond, or a divalent radical selected from C 3-7 cycloalkane, 4- to 7-membered heterocycle, 5- or 6-membered aryl or heteroaryl, wherein the divalent radical is optionally substituted with 1-6 R L ; S0, S1, S2and S3are each independently a bond, -0-, -S-, -NR L -, -C(O)-, -C(O)NR L -, -NR L C(O)-, -C(O)NR L (CR L R L’ ) p -, -C(O)(CR L R L’ ) p -, -NR L C(O)(CR L R L’ ) p -, -(CR L R L’ ) p -, -(CR L R L’ CR L R L’ O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3; each R is independently selected from H, D, halogen, CN, OH, C L and R L’ are each independently selected from H, D, halogen, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or R L and R L’ together with the carbon atom to which they are attached form a 3- to 6- membered cycloalkyl, 3- to 7- membered heterocycloalkyl; represents the connection to R1; represents the connection to U.

27. The compound of any one of claims 1-24, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V'): -S0-(L A1 ) i -S1-(L A2 ) j -S2-(L A3 ) k -S3-■(V’) wherein i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0; L A1 , L A2 and L A3 are each independently a chemical bond, or a divalent radical selected from the group consisting of C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein the divalent radical is optionally substituted with 1-6 radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl; S0, S1, S2and S3are each independently a bond, -0-, -S-, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)NH(CH2) p -, -C(0)(CH2) p -, -NHC(0)(CH2) p -, -(CH2) p -, -(CH2CH20) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3; represents the connection to R1; represents the connection to U.

28. The compound of claim 26 or 27, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V A ) as shown below: A1 ) i -(L A2 ) j -(L A3 ) k -■(V A ).

29. The compound of claim 26 or 27, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V B ) shown below: -S0-(L A1 ) i -(L A2 ) j -(L A3 ) k -■(V B ).

30. The compound of claim 26 or 27, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V C ) : -S0-(L A1 ) i (L A2 ) j -S2-(L A3 ) k -S3-■(V C ) wherein (L A1 ) i and (L A2 ) j share one atom and / or one chemical bond.

31. The compound of claim 26 or 27, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is a divalent linking group of formula (V D ) : -S0-(L A1 ) i -S1-(L A2 ) j (L A3 ) k -S3-■(V D ) wherein (L A2 ) j and (L A3 ) k share one atom and / or one chemical bond.

32. The compound of any one of claims 26-31, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A1 , L A2 and L A3 are each independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein said divalent radical is optionally substituted with 1-6 radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

33. The compound of any one of claims 26-31, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

34. The compound according to any one of claims 26-31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

35. The compound according to any one of claims 26-31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L A To: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

36. A compound of Formula (V): ###00023### (V) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. wherein X1is N, CD or CH; R1' is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl, C 1- 6haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl optionally substituted with one or more R; R3and R4are independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to full deuteriation; R5is halogen; R6is C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to per-deuteration; R s and R t independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D, up to perdeuteration; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; L B is a divalent linking group; U is a group that binds to E3 ubiquitin ligase.

37. The compound of claim 36, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, X1is N.

38. The compound of claim 36 or 37, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1' is H, a halogen, and C, which can be substituted with 1-5 halogens. 1-3 Alkyl, or 5- or 6-membered monocyclic aryl or heteroaryl.

39. The compound of any one of claims 36-38, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is H, F, CHF2, CF3, CH3, CH(CH3)(CF3), pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl.

40. The compound of claim 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is H.

41. The compound of any one of claims 36-40, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R3and R4are both H.

42. The compound of any one of claims 36-41, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R5is F.

43. The compound of any one of claims 36-42, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R6is CH3or CD3.

44. The compound of any one of claims 36-43, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, m is 0.

45. The compound of any one of claims 36-44, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0.

46. The compound according to any one of claims 36-45, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 1, R t is F, CH3or CD3.

47. The compound according to any one of claims 36-46, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI): -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI) wherein i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0; L B1 , L B2 and L B3 are each independently a chemical bond, or a divalent radical selected from C 3-7 cycloalkane, 4- to 7-membered heterocycle, 5- or 6-membered aryl or heteroaryl, wherein the divalent radical is optionally substituted with 1-6 R L ; S0, S1, S2and S3are each independently a bond, -0-, -S-, -NR L -, -C(O)-, -C(O)NR L -, -NR L C(O)-, -C(O)NR L (CR L R L’ ) p -, -C(O)(CR L R L’ ) p -, -NR L C(O)(CR L R L’ ) p -, -(CR L R L’ ) p -, -(CR L R L’ CR L R L’ O) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3; each R is independently selected from H, D, halogen, CN, OH, C L and R L’ each independently selected from H, D, halogen, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- or 10-membered aryl or 5- to 10-membered heteroaryl, or R L and R L’ together with the carbon atom to which they are attached form a 3- to 6- membered cycloalkyl, 3- to 7- membered heterocycloalkyl; represents the connection to U; represents the remaining other end connected to the compound of formula (V).

48. The compound according to any one of claims 36-46, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI): -S0-(L B1 ) i -S1-(L B2 ) j -S2-(L B3 ) k -S3-■(VI) wherein i is 0 or 1, j is 0 or 1, k is 0 or 1; with the proviso that at least one of i, j and k is not 0; L B1 , L B2 and L B3 are each independently a chemical bond, or a divalent radical selected from the group consisting of C 3-7 cycloalkane or 4- to 7-membered heterocycle, wherein the divalent radical is optionally substituted with 1-6 radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl; S0, S1, S2and S3are each independently a bond, -0-, -S-, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -C(0)NH(CH2) p -, -C(0)(CH2) p -, -NHC(0)(CH2) p -, -(CH2) p -, -(CH2CH20) q -, C 1-6 alkylene or C 1-6 alkynylene; wherein p is 1, 2, 3 or 4; q is 1, 2 or 3; represents the connection to U; represents the remaining other end connected to the compound of formula (V).

49. The compound of claim 47 or 48, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI A ) as shown below: B1 ) i -(L B2 ) j -(L B3 ) k -■(VI A ).

50. The compound of claim 47 or 48, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI B ) is a divalent linking group of formula (VI B1 ) i is a divalent linking group of formula (VI B2 ) j is a divalent linking group of formula (VI B3 ) k is a divalent linking group of formula (VI B ).

51. The compound of claim 47 or 48, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI C ) -S0-(L B1 ) i (L B2 ) j -S2-(L B3 ) k -S3-■(VI C ) wherein (L B1 ) i and (L B2 ) j share one atom and / or one chemical bond.

52. The compound of claim 47 or 48, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is a divalent linking group of formula (VI D ) -S0-(L B1 ) i -S1-(L B2 ) j (L B3 ) k -S3-■(VI D ) wherein (L B2 ) j and (L B3 ) k share one atom and / or one chemical bond.

53. The compound of any one of claims 47-52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B1 , L B2 and L B3 are each independently a divalent radical selected from 4- to 7-membered heterocyclic rings containing 1 or 2 N atoms; wherein said divalent radical is optionally substituted with 1-6 radicals selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl.

54. The compound of any one of claims 47-52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

55. The compound according to any one of claims 47-52, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

56. The compound according to any one of claims 47-52, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, L B is: wherein the above groups are optionally substituted with 1-6 groups selected from D, halogen, OH, CN, C 1-3 alkyl and C 1-3 haloalkyl groups.

57. A compound of Formula (VII): ###0030### (VII) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof. wherein R1is a chemical bond, or a divalent radical selected from 5- or 6-membered monocyclic arene or heteroarene or 9- to 13-membered bicyclic or tricyclic heteroarene or heterocycle; wherein the above divalent radicals are optionally substituted with one or more R; R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to per-deuteration; each R is independently H, D, halogen, C t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to perdeuteration; n is 0, 1, or 2; each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; L A is a chemical bond or a divalent linking group; U is a group that binds to an E3 ubiquitin ligase.

58. The compound of claim 57, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (VII) A ) : wherein, Y3is N or CH; R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to per-deuteration; each R is independently H, D, halogen, C t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to perdeuteration; n is 0, 1, or 2; L A is a chemical bond or a divalent linking group; U is a group that binds to an E3 ubiquitin ligase.

59. The compound of claim 57, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (VII) B ) : wherein, R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl is optionally substituted with one or more D, up to per-deuteration; each R is independently H, D, halogen, C t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to perdeuteration; n is 0, 1, or 2; L A is a chemical bond or a divalent linking group; U is a group that binds to an E3 ubiquitin ligase.

60. The compound of claim 57, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which is a compound of Formula (VII) C ) : wherein, R2is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one or more D, up to per-deuteration; each R is independently H, D, halogen, C t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to perdeuteration; n is 0, 1, or 2; L A is a chemical bond or a divalent linking group; U is a group that binds to an E3 ubiquitin ligase.

61. The compound according to any one of claims 57-60, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H, halogen or C1-5alkyl optionally substituted with 1-5 halogens 1-3 alkyl.

62. The compound of claim 61, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H, F, CHF2, CF3, CH3, or CH(CH3)(CF3).

63. The compound of claim 62, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R2is H.

64. The compound according to any one of claims 57-63, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0.

65. The compound according to any one of claims 57-65, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 1, R t is F, CH3or CD3.

66. A compound of Formula (VIII): ###0030### (VIII) or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof. wherein, R1' is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl; wherein said C 1-6 alkyl, C 1- 6haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5- or 6-membered monocyclic aryl or heteroaryl, and 9- to 13-membered bicyclic or tricyclic heteroaryl or heterocyclyl optionally substituted with one or more R; each R is independently H, D, halogen, C t is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1- 6haloalkyl is optionally substituted with one or more D up to per-deuteration; n is 0, 1, or 2; each R is independently selected from D, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; L B is a divalent linking group; U is a group that binds to an E3 ubiquitin ligase.

67. The compound of claim 66, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1’ is H, halo, C 1-3 alkyl, or 5- or 6-membered monocyclic aryl or heteroaryl.

68. The compound of claim 67, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is H, F, CHF2, CF3, CH3, CH(CH3)(CF3), pyrazolyl, imidazolyl, pyridinyl, or pyrimidinyl.

69. The compound of claim 68, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, R1is H.

70. The compound according to any one of claims 66-69, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 0.

71. The compound according to any one of claims 66-69, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, n is 1, R t is F, CH3or CD3.

72. The compound according to any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, represents a single or double bond; each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each Q3and Q4is independently N or CR9; each K1, K2, and K3is independently N or CR9; K4and K5are each independently N or C; H1is N, C, or CR9; H2and H3are each independently C(O), N, O, S, NR9, CR9, or C(R9)2; H4and H8are each independently N or CR9; H5, H6, and H7are each independently C(O), O, S, NR9, or C(R9)2; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each o is independently 0, 1, or 2; each h is independently 0, 1, 2, 3, or 4; each z is independently 0, 1, or 2; each r and s is independently 0, 1, 2, or 3; and r and s are not simultaneously 0; each t and u is independently 0, 1, 2, or 3; and t and u are not simultaneously 0.

73. The compound of claim 72, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, represents a single or double bond; each V is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each W is independently a chemical bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each Q1is independently C(O) or C(R9)2; each Q2is independently N or CH; each Q3and Q4is independently N or CR9; each R7is independently H or C 1-6 alkyl; each R8is independently D, halo, C 1-6 alkyl or C 1-6 haloalkyl; or two R8together with the atoms to which they are attached form a C 3-7 cycloalkane or 4- to 7-membered heterocycle; each R9is independently H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or two R9together with the atoms to which they are attached form a C 3-7 cycloalkane, 4- to 7-membered heterocycle, C 6-10 arene or 5- to 10-membered heteroarene; each h is independently 0, 1, 2, 3, or 4; each k is independently 0, 1, 2, 3, or 4; each z is independently 0, 1, or 2; each r and s is independently 1, 2, or 3; each t and u is independently 1, 2, or 3.

74. The compound of claim 73, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0 or 1.

75. The compound of claim 73, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0 or 1.

76. The compound of claim 73, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, Q3is N or CR9; each R9is independently H, D, or halogen; each k is independently 0 or 1.

77. The compound of any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is 78. The compound according to any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 10 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, each R is independently H, Cl, CN, ethynyl, phenyl, 11 each independently H, Cl, CN, ethynyl, phenyl, 79. The compound according to any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is: wherein, each V is independently a bond, C(O), NH, O, S, C(O)NH, NHC(O), or CH2; each R is independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, 10 each independently H, CH3, OCH2CH2OH, (OCH2CH2)2OH, each R is independently H, Cl, CN, ethynyl, phenyl, 11 each independently H, Cl, CN, ethynyl, phenyl, each R is independently -CH3, 12 each independently -CH3, Each R 13 Each can be independently -CH3, -CH(CH3)2, -C(CH3)3 or -OCH3.

80. The compound according to any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is:

81. The compound of any one of claims 1-71, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, U is:

82. A compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopic variant, hydrate, or solvate thereof, wherein, The compound is selected from the group consisting of compounds of the following formulae:

83. A pharmaceutical composition comprising a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

84. A unit dosage form comprising the pharmaceutical composition of claim 83.

85. A kit comprising a first container comprising a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, or the pharmaceutical composition of claim 83; and optionally, a second container comprising another therapeutic agent; and optionally, a third container comprising a pharmaceutically acceptable excipient for diluting or suspending the compound and / or another therapeutic agent.

86. The kit of claim 85, wherein, the other therapeutic agent comprises a mitotic inhibitor, a tubulin inhibitor, an alkylating antineoplastic agent, an antimetabolite, a DNA intercalator, a topoisomerase inhibitor, a biological response modifier, an immune checkpoint inhibitor, a CD20 mAb, or a BCL2 inhibitor; preferably, the other therapeutic agent comprises vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, cisplatin, carboplatin, cyclophosphamide, 5-fluorouracil, tegafur, methotrexate, cytarabine, hydroxyurea, doxorubicin, mitomycin, bleomycin, enocitabine, camptothecin, interferon, adalimumab, nivolumab, ipilimumab, atezolizumab, rituximab, ibritumomab, or venetoclax.

87. Use of a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, or the pharmaceutical composition of claim 83, or the unit dosage form of claim 84, or the kit of claim 85 or 86, in the manufacture of a medicament for the treatment and / or prevention of a disease caused by BTK.

88. A method of inducing BTK inhibition and / or degradation in a cell, the method comprising contacting the cell with a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, isotopologue, hydrate, or solvate thereof, or the pharmaceutical composition of claim 83, or the unit dosage form of claim 84, or the kit of claim 85 or 86, the contacting being performed in vitro or in vivo; preferably, the contacting is performed in vitro; preferably, the contacting is performed in vivo.

89. A method of treating and / or preventing a disease caused by BTK in a subject, the method comprising administering to the subject a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopologue, hydrate or solvate thereof, or a pharmaceutical composition of claim 83, or a unit dosage form of claim 84, or a kit of claim 85 or 86.

90. Use of a compound of any one of claims 1-82, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, isotopologue, hydrate or solvate thereof, or a pharmaceutical composition of claim 83, or a unit dosage form of claim 84, or a kit of claim 85 or 86 in the treatment and / or prevention of a disease caused by BTK.

91. The use of claim 87, the method of claim 88 or 89, or the use of claim 90, wherein, the BTK is selected from wild-type BTK or mutant BTK; Preferably, the mutant BTK is a BTK with at least one mutation site; Preferably, the mutant BTK is a single-mutant BTK or a double-mutant BTK; Preferably, the single-mutant BTK is selected from BTK E108K, BTK Y133E, BTK R134E, BTK P385A, BTK T387A, BTK V416L, BTK A428D, BTK M437R, BTK T474A, BTK T474I, BTK T474M, BTK T474S, BTK C481F, BTK C481G, BTK C481R, BTK C481S, BTK C481T, BTK C481W, BTK C481Y, BTK L512M, BTK E513G, BTK F517L, BTK L528W, BTK L547P, or BTK Y551F; Preferably, the single-mutant BTK is selected from BTK T474I, BTK C481S, or BTK L528W; Preferably, the double-mutant BTK is selected from BTK Y133E-R134E, BTK P385A-T387A, BTK T474A-C481S, BTK T474I-C481S, BTK T474I-L528, BTK T474M-C481S, BTK T474M-C481T, BTK T474M-L512M, BTK T474M-E513G, BTK T474M-F517L, BTK T474M-L547P, BTK T474S-C481S, BTK C481S-L528W, or BTK C481F-Y551F; Preferably, the double-mutant BTK is selected from BTK T474I-C481S, BTK T474I-L528W, or BTK C481S-L528W.

92. The use of claim 87, the method of claim 88 or 89, or the use of claim 90, wherein, the disease caused by BTK is selected from an autoimmune disease, an inflammatory disease, or a tumor. Preferably, said autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute post-viral encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, stiff-man syndrome, anti-phospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromuscular disorders, scleroderma, vulvodynia, complications resulting from organ transplants, diabetes, asthma, atopic dermatitis, ulcerative colitis, Crohn's disease or Alzheimer's disease; Preferably, said inflammatory disease is selected from the group consisting of keratitis, rhinitis, stomatitis, parotitis, pharyngitis, angina, tracheitis, bronchitis, pneumonitis, myocarditis, gastritis, gastroenteritis, cholecystitis or appendicitis; Preferably, said tumor is selected from the group consisting of solid tumors or hematological tumors. Preferably, the solid tumor is selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymal tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital tract tumor, penile cancer, prostate cancer, female genital tract tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, or vaginal cancer; preferably, the blood tumor is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), acute myeloid leukemia with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma.

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