1H-pyrazolo [4, 3-c] pyridine compound as well as composition and application thereof

Abstract

The present invention relates to compounds of formula (A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, and pharmaceutical compositions thereof and their use in the treatment and / or prevention of wild and / or mutant BTK kinase mediated diseases. # imgabs0 #

Description

[0001] This application claims priority to Chinese application No. 202310806589.3 filed on July 3, 2023, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medical technology, and in particular relates to highly selective compounds having an inhibitory effect on Bruton's tyrosine kinase (BTK) and its drug-resistant mutations, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Background Art

[0003] Bruton's tyrosine kinase belongs to the Tec family of cytoplasmic tyrosine kinases, which is the second largest family of non-receptor kinases in humans. It is expressed in all cell lineages of the hematopoietic system (except T cells), and it is located in bone marrow, spleen and lymph node tissues. Inactivating mutations in the gene encoding Btk lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (XID) in mice. Both diseases are characterized by major defects in B cell development and function, indicating that Btk plays a vital role in B cell development and function. In addition, constitutive activation of Btk in B cells leads to the accumulation of autoreactive plasma cells. Preclinical studies have shown that Btk-deficient mice are resistant to developing collagen-induced arthritis. In addition, clinical studies on Rituxan (a CD20 antibody that depletes mature B cells) have revealed the key role of B cells in many inflammatory diseases (such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis). Furthermore, aberrant activation of Btk plays an important role in the pathogenesis of B-cell lymphoma, suggesting that inhibition of Btk could be used to treat hematological malignancies.

[0004] The covalent Btk inhibitor ibrutinib is approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), and chronic graft-versus-host disease (cGVHD). Despite its excellent efficacy and general tolerability, adverse events such as bleeding, rash, and diarrhea have been reported.

[0005] These ibrutinib-related adverse reactions are believed to be mainly related to the off-target effects of ibrutinib, which have been shown to be related to the inhibition of EGFR and Tec. Targeting EGFR can induce significant skin toxicity and gastrointestinal adverse reactions because the EGFR signaling cascade involves the biology of the skin and gastrointestinal system. Both Btk and Tec belong to the Tec family kinases. Platelets express Btk and Tec, which serve the downstream of glycoprotein VI (GPVI) signaling. Tec compensates for the absence of Btk in GPVI downstream signaling in murine platelets. The inhibition of Tec kinases by ibrutinib interferes with platelet aggregation and may contribute to the observed bleeding. Therefore, a BTK inhibitor with high Btk inhibition and low EGFR and Tec inhibition is needed to reduce or avoid bleeding, rash and diarrhea.

[0006] Ibrutinib also binds irreversibly to interleukin-2-inducible tyrosine kinase (ITK). ITK plays a key role in FcR-stimulated natural killer NK cell function, primarily through antibody-dependent NK cell-mediated cytotoxicity (ADCC). ADCC is the current standard of care for B-cell malignancies, so it would be desirable to have a Btk inhibitor with high Btk inhibition and low ITK inhibition.

[0007] Covalent (irreversible) BTK inhibitors specifically target the cysteine ​​residue C481 within Btk. Primary and secondary resistance have emerged following treatment with ibrutinib. Mutations within BTK such as C481S, C481Y, C481R, C481F have been shown to clearly interfere with drug binding. It is predicted that the incidence of resistance observed will increase over time with clinical use.

[0008] Non-covalent (reversible) BTK inhibitors do not need to bind to the BTK C481 residue to effectively inhibit wild-type and mutant BTK with C481 residue replaced. However, it has been reported in the literature that non-covalent BTK inhibitors can also produce acquired resistance mutations, such as V416L, A428D, M437R, T474I and L528W mutations.

[0009] Therefore, it is necessary to develop new BTK inhibitors. SUMMARY OF THE INVENTION

[0011] The present invention provides a new 1H-pyrazolo[4,3-c]pyridine compound and a composition comprising the compound and uses thereof, which has better inhibitory activity against BTK, C481 mutant BTK and V416L, A428D, M437R, T474I or L528W mutant BTK kinases, has higher selectivity than EGFR, TEC and ITK kinases, and has better pharmacodynamics and / or pharmacokinetic properties, and can treat diseases or conditions mediated by BTK kinase.

[0012] To this end, the present invention adopts the following technical solutions:

[0013] In one aspect, the present invention relates to a compound of formula (A), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0014]

[0015] in,

[0016] Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0017] X 1 N, CD or CH;

[0018] X 2 N or CR 2 ;

[0019] R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0020] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0021] R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0022] R 3 and R 4 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0023] R 5 is a halogen;

[0024] R 6 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 until fully deuterated;

[0025] R s and R t are independently H, D, halogen, -OR a 、-NR b R c , 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 until fully deuterated;

[0026] m is 0, 1, 2 or 3;

[0027] n is 0, 1, 2, 3 or 4;

[0028] Each R is independently:

[0029] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O)2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0030] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0031] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0032] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0033] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0034] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)ORh 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"';

[0035] Each R'' is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0036] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0037] In another aspect, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0038]

[0039] in,

[0040] X 1 N, CD or CH;

[0041] X 2 N or CR 2 ;

[0042] R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0043] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0044] R 2 H, D, halogen, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0045] R 3 and R 4 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 is optionally substituted with one or more D until fully deuterated;

[0046] R 5 is a halogen;

[0047] R 6 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 until fully deuterated;

[0048] 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 is optionally substituted with one or more D until fully deuterated;

[0049] m is 0, 1, 2 or 3;

[0050] n is 0, 1, 2, 3 or 4;

[0051] Each R is independently:

[0052] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e Rf 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0053] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0054] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0055] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0056] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0057] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0058] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0059] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents.

[0060] In another aspect, the present invention relates to the use of a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing a disease mediated by wild-type and / or mutant BTK kinase; preferably, the mutant BTK kinase is selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G or BTK C481W; preferably, the mutant BTK kinase is BTK C481S; preferably, the mutant BTK kinase is BTK V416L, BTK A428D, BTK M437R, BTK T474I or BTK L528W; preferably, the mutant BTK kinase is BTK T474I or BTK L528W.

[0061] In another aspect, the present invention relates to a method for treating and / or preventing a disease mediated by wild-type and / or mutant BTK kinase in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of the present invention; preferably, the mutant BTK kinase is selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTKC481T, BTK C481G or BTK C481W; preferably, the mutant BTK kinase is BTK C481S; preferably, the mutant BTK kinase is BTK V416L, BTK A428D, BTK M437R, BTK T474I or BTK L528W; preferably, the mutant BTK kinase is BTK T474I or BTK L528W.

[0062] In another aspect, the present invention relates to a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention, for treating and / or preventing diseases mediated by wild-type and / or mutant BTK kinases; preferably, the mutant BTK kinase is selected from BTK C481S, BTKC481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G or BTK C481W; preferably, the mutant BTK kinase is BTK C481S; preferably, the mutant BTK kinase is BTK V416L, BTK A428D, BTK M437R, BTKT474I or BTK L528W; preferably, the mutant BTK kinase is BTK T474I or BTK L528W.

[0063] In a more specific aspect, the BTK-mediated disease of the present invention is selected from: an allergic disease, an autoimmune disease, an inflammatory disease or cancer.

[0064] In a more specific aspect, the BTK-mediated disease of the present invention is a B-cell proliferative disease selected from chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with trilineage myelodysplastic disorder, mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative disease, marginal zone lymphoma or Waldenstrom's macroglobulinemia.

[0065] In a more specific aspect, the BTK-mediated disease of the present invention is multiple myeloma.

[0066] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0067] definition

[0068] Chemical Definition

[0069] Definitions of specific functional groups and chemical terms are described in more detail below.

[0070] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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.

[0071] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4Alkyl groups are particularly preferred; in some embodiments, C 1-3 Alkyl groups are particularly preferred. Examples of the alkyl groups include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 Regardless of whether the alkyl group is preceded by "substituted", each of the alkyl group is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0072] “C 1-6 "Alkylene" refers to the removal of "C 1-6 A divalent group formed by one hydrogen atom in an alkyl group.

[0073] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0074] Therefore, “C 1-6 "Haloalkyl" and "C 1-3 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl" and "C 1-3 "alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 Halogenated alkyl. Exemplary halogenated alkyl groups include, but are not limited to: -CF 3 、-CH 2 F, -CHF 2 、-CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 、-CH 2Cl, -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0075] “C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group having 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 is particularly preferred. Examples of the alkenyl include, but are not limited to, vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-propene-2-yl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadiene (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc. Regardless of whether the alkenyl group is preceded by "substituted", each of the alkenyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined below. In some embodiments, the alkenyl group is unsubstituted C 2-6 In some embodiments, alkenyl is a substituted C 2-6 Alkenyl.

[0076] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 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 Alkynyl is particularly preferred. In some embodiments, the alkynyl does not contain any double bonds. One or more carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of the alkynyl include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), 3-methylbut-1-ynyl (C 5 ), hexynyl (C 6), etc. Regardless of whether the alkynyl group is preceded by "substituted", each of the alkynyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined below. In some embodiments, the alkynyl group is a substituted C 2-6 Alkynyl.

[0077] “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 3-8 Cycloalkyl is preferred, C 3-6 Cycloalkyl is particularly preferred, more preferably C 4-6 Cycloalkyl and C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octyl(C 8 ), cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), etc. Regardless of whether the cycloalkyl group is preceded by "substituted", each of the cycloalkyl group is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0078] "3-12 membered heterocyclyl" refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 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 may be a carbon or nitrogen atom as long as valence permits. In some embodiments, a 3- to 10-membered heterocyclyl is preferred, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 5- to 10-membered heterocyclyl is preferred, which is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 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, especially a 3- to 7-membered monocyclic non-aromatic ring system (also called a 3- to 7-membered monocyclic heterocyclyl); in some embodiments, a 4- to 7-membered heterocyclyl is preferred. Heterocyclyl is particularly preferred, which is a 4 to 7-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3-6-membered heterocyclyl is particularly preferred, which is a 3 to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4-6-membered heterocyclyl is particularly preferred, which is a 4 to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5-6-membered heterocyclyl (e.g., 5-membered heterocyclyl or 6-membered heterocyclyl) is a 5 or 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused, spiro-connected with one or more cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Therefore, the present application also includes "6-12 membered fused bicyclic heterocycle" and "8-10 membered fused bicyclic heterocycle", which means a heterocyclic group in which two rings are fused together by sharing two adjacent atoms, respectively having 6-12 ring atoms and 8-10 ring atoms in total. The present application also includes "7-10 membered spirocyclic heterocycle", which means a heterocyclic group in which two rings are spiro-connected together by sharing one atom, having 7-10 ring atoms in total. Regardless of whether the heterocyclic group is modified with "substituted", each of the heterocyclic groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0079] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, disthiolanyl, and Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, Examples of 6-membered heterocyclic groups that include one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclic groups that include two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithian ... alkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazine (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxepane and thiecanyl. Exemplary C 6 Aryl ring-fused 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzo Oxazolinone, etc. Exemplary 6 Aryl ring-fused 6-membered heterocyclyl (also referred to herein as 6,6-bicyclic heterocyclyl) includes, but is not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0080] “C 6-10 "Aryl" refers to a group having 6-10 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) ("C 6-10 In some embodiments, an aryl group has six ring carbon atoms (“C 6 In some embodiments, an aryl group has ten ring carbon atoms (“C 10 "aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl)"6-10 "Aryl" also includes such ring systems in which the above-mentioned aryl ring is fused with one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by "substituted", each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0081] "5-10 yuan heteroaryl" refers to a group of 4n+2 aromatic ring systems (e.g., 6 or 10 π electrons shared in a cyclic arrangement) of 5 to 10 yuan monocyclic or bicyclic rings with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 yuan heteroaryl (e.g., 5 yuan heteroaryl or 6 yuan heteroaryl) is preferred, which is a group of 5 or 6 yuan monocyclic 4n+2 aromatic ring systems (e.g., 6 π electrons shared in a cyclic arrangement) with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl containing one or more nitrogen atoms, as long as valence permits, the point of attachment can be a carbon or nitrogen atom. Heteroaryl bicyclic systems can include one or more heteroatoms in one or two rings. Heteroaryl also includes a ring system in which the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. Regardless of whether the heteroaryl is preceded by "substituted", each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0082] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, pyridyl. 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, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0083] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb )2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R aa 、-NR bb C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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) 2 R aa 、-OP(=O) 2 R aa ,-P(=O)(R aa ) 2 ,-OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(R bb ) 2 ,-P(=O)(NR bb ) 2 ,-OP(=O)(NR bb ) 2 、-NR bb P(=O)(OR cc ) 2 、-NR bb P(=O)(NR bb ) 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 by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0084] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN (R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bbS(=O) 2 R aa , =NR bb or = NOR cc replace;

[0085] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0086] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(=O)R aa 、-C(=O)N(R cc ) 2 , -CO 2 R aa 、-SO 2 R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(=S)N(R cc ) 2 、-C(=O)SR cc 、-C(=S)SR cc 、-P(=O) 2 R aa ,-P(=O)(R aa ) 2 、-P(=O) 2 N(R cc ) 2 ,-P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bbThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0087] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0088] R dd Each of is independently selected from: halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee 、-OC(=O)R ee 、-OCO 2 R ee 、-C(=O)N(R ff ) 2 、-OC(=O)N(R ff ) 2 、-NR ff C(=O)R ee 、-NR ff CO 2 R 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 SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R 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) 2 R 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 by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0089] R ee Each of R 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 by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0090] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0091] R gg Each of which is independently: halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 - 、-NH 2 (C 1-6 alkyl) + X - 、-NH 3 + 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), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 、-C(=O)N(C 1-6 alkyl) 2 、-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 、-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 、-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)NH 2 、-OC(=NH)N(C 1-6 alkyl) 2 、-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH 2 、-NHC(NH)N(C 1-6 alkyl) 2 、-NHC(=NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 alkyl) 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 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)NH 2 、-C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6Alkyl, -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, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Carbocyclic group, C 6 -C 10 Aryl, C 3 -C 7 Heterocyclic group, C 5 -C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0092] Exemplary substituents on nitrogen atoms 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 , -CO 2 R aa 、-SO 2 R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(=S)N(R cc ) 2 、-C(=O)SR cc 、-C(=S)SR cc、-P(=O) 2 R aa ,-P(=O)(R aa ) 2 、-P(=O) 2 N(R cc ) 2 ,-P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd As mentioned above.

[0093] "Deuterated" or "D-substituted" refers to a compound or group in which one or more hydrogens are replaced by deuterium; deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted. The term "one or more deuterated" and "one or more deuterated" can be used interchangeably.

[0094] A "non-deuterated compound" refers to a compound containing deuterium atoms in a proportion not exceeding the natural deuterium isotope content (0.015%).

[0095] The deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0096] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using conventional methods in the art, such as ion exchange methods, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, if appropriate.

[0097] "Subjects" for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, 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.

[0098] "Disease," "disorder," and "condition" are used interchangeably herein.

[0099] As used herein, and unless otherwise indicated, the terms "treatment," "treating," "treating," "treating," and "treatment" include actions that occur while a subject has a particular disease, disorder, or condition, that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), and also include actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0100] "Combination" and related terms refer to simultaneous or sequential administration of therapeutic agents of the invention. For example, a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. DETAILED DESCRIPTION

[0101] Compound

[0102] Herein, "compounds of the present invention" refers to the compounds of the following formula (I) (including subsets of each formula), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0103] In one embodiment, the present invention relates to a compound of formula (A), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0104]

[0105] in,

[0106] Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0107] X 1 N, CD or CH;

[0108] X 2 N or CR 2 ;

[0109] R 1H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0110] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or Rb and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0111] R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0112] R 3 and R 4 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 is optionally substituted with one or more D until fully deuterated;

[0113] R 5 is a halogen;

[0114] R 6 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 until fully deuterated;

[0115] R s and R t are independently H, D, halogen, -OR a 、-NR b R c , C 1-6 Alkyl or C 1-6haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0116] m is 0, 1, 2 or 3;

[0117] n is 0, 1, 2, 3 or 4;

[0118] Each R is independently:

[0119] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0120] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0121] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0122] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0123] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0124] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"';

[0125] Each R'' is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0126] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0127] In another embodiment, the present invention is directed to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0128]

[0129] in,

[0130] X 1 N, CD or CH;

[0131] X 2 N or CR 2 ;

[0132] R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0133] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0134] R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0135] R 3 and R 4 are independently H, D, halogen, C 1-6 Alkyl or C 1-6haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0136] R 5 is a halogen;

[0137] R 6 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 until fully deuterated;

[0138] 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 is optionally substituted with one or more D until fully deuterated;

[0139] m is 0, 1, 2 or 3;

[0140] n is 0, 1, 2, 3 or 4;

[0141] Each R is independently:

[0142] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0143] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0144] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0145] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0146] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0147] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)Rg 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0148] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0149] Ring A

[0150] In one embodiment, ring A is a benzene ring; in one embodiment, ring A is a 5-6 membered heteroaromatic ring, for example a 6 membered heteroaromatic ring, for example a pyridine ring.

[0151] X 1

[0152] In one embodiment, X 1 is N; in another embodiment, X 1 is CH; in another embodiment, X 1 For CD.

[0153] X 2 and R 2

[0154] In one embodiment, X 2 is N; in another embodiment, X 2 CR 2 .

[0155] In a specific embodiment, X 2 CR 2 , and where R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'; in another specific embodiment, X 2 CR 2 , and where R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R'; in another specific embodiment, X 2 CR 2 , and where R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'; in another specific embodiment, X 2 CR 2 , and where R 2 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'.

[0156] In a more specific embodiment, X 2 CR 2 , and where R 2 H, D, halogen, methyl, -CHF 2 , ethyl, isopropyl,

[0157]

[0158] The above groups are optionally substituted by one or more D, until fully deuterated; preferably H, D, halogen, methyl, -CHF 2 , ethyl, isopropyl,

[0159] The above groups are optionally substituted by one or more D until fully deuterated; preferably H, D, methyl, -CHF 2 , The above groups are optionally substituted by one or more D until fully deuterated; preferably H, D, methyl, -CHF 2 , The above groups are optionally substituted by one or more D, until fully deuterated; preferably H, D, -CHF 2 ,or The above groups are optionally substituted by one or more D, until fully deuterated; preferably H; preferably -CHF 2 ; preferably The above groups are optionally substituted by one or more Ds until fully deuterated.

[0160] R 1

[0161] In one embodiment, R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; in another embodiment, R 1 H, D, halogen, -C(O)NR b R c , C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; in another embodiment, R 1 is H; in another embodiment, R 1 C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; in another embodiment, R 1 is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R. In another embodiment, R 1 is a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more R.

[0162] In a specific embodiment, R 1 for

[0163] 1) H; or

[0164] 2) where Y 1 is N or CR; or

[0165] 3) or

[0166] 4) where Y 2 is O or S; or

[0167] 5) where Y 3 is N, CH or CD; or

[0168] 6) where Y 5 and Y 6 are independently N or C and Y 5 and Y6 At least one of them is N, W 1 , W 2 or W 3 are independently N or CR, represents a single bond or a double bond, provided that Y 3 , Y 4 , Y 5 , Y 6 , W 1 , W 2 and W 3 The bicyclic ring is aromatic; or

[0169] 7) where Y 7 and Y 8 are independently N or C and Y 7 and Y 8 At least one of them is N, Y 9 N, CH or CD, W 4 , W 5 and W 6 are independently N or CR, represents a single bond or a double bond, provided that Y 3 , Y 7 , Y 8 , Y 9 , W 4 , W 5 and W 6 The bicyclic ring is aromatic.

[0170] In another specific embodiment, R 1 for

[0171] 1) H; or

[0172] 2) where Y 1 and Y 2 are independently N or CR; or

[0173] 3) or

[0174] 4) where Y 3 is O or S; or

[0175] 5) Where Z 1 , Z 2 , Z 3 and Z 4 are independently N or CR.

[0176] In a specific embodiment, R 1 For H, D,

[0177] Wherein the above groups are optionally substituted by one or more R;

[0178]

[0179] Wherein the above groups are optionally substituted by one or more R; preferably

[0180] The above groups are optionally substituted by one or more R; preferably H.

[0181] R 3 and R 4

[0182] In one embodiment, R 3 and R 4 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 is optionally substituted with one or more D, up to full deuteration; in another embodiment, R 3 and R 4 are independently H, D or halogen; in another embodiment, R 3 and R 4 are independently H, D or F; in another embodiment, R 3 and R 4 are independently H or D; in another embodiment, R 3 and R 4 is independently H. In another embodiment, R 3 and R 4 Independently D.

[0183] R 5 and R 6

[0184] In one embodiment, R 5 is halogen; in another embodiment, R 5 For F.

[0185] In one embodiment, R 6 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 deuteration; in another embodiment, R 6 C 1-3 Alkyl or C 1-3 haloalkyl, wherein the C 1-3 Alkyl and C 1-3 Haloalkyl is optionally substituted with one or more D, up to full deuteration; in another embodiment, R 6 Methyl, CD 3 , ethyl, isopropyl, CHF 2 , CH 2 F or CF 3 In another embodiment, R 6 Methyl, CF 3 or CD 3 In another embodiment, R 6 Methyl or CD 3 .

[0186] R s and m

[0187] In one embodiment, R s H, D, halogen, 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 full deuteration; in another embodiment, R s H, D, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, wherein the C 1-3 Alkyl and C 1-3 Haloalkyl is optionally substituted with one or more D, up to full deuteration; in another embodiment, R s is H, D or halogen; in another embodiment, R s is H, D or F; in another embodiment, R s For-OR a or -NR b R c In another embodiment, R s For-OR a .

[0188] In one embodiment, m is 0, 1, 2 or 3; in another embodiment, m is 0, 1 or 2; in another embodiment, m is 0 or 1; in another embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3.

[0189] In one embodiment, m is 1, and R s H, D, F, methyl, CD 3 or CF 3 In another specific embodiment, m is 1, and R s is H, D, F, methyl or CD 3 In another specific embodiment, m is 1, and R s is H, D or F; in another specific embodiment, m is 1, and R s Methyl or CD 3 .

[0190] R t and n

[0191] In one embodiment, R t H, D, halogen, 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 full deuteration; in another embodiment, R t H, D, halogen, C 1-3 Alkyl or C 1-3 haloalkyl, wherein the C 1-3 Alkyl and C 1-3 Haloalkyl is optionally substituted with one or more D, up to full deuteration; in another embodiment, R t H, D, halogen or C 1-3 Alkane, wherein the C 1-3 Alkyl is optionally substituted with one or more D, up to full deuteration; in another embodiment, R t is H, D or halogen; in another embodiment, R t is H, D or F; in another embodiment, R t For-OR a or -NR b R c In another embodiment, R t For-OR a .

[0192] In one embodiment, n is 0, 1, 2, 3 or 4; in another embodiment, n is 0, 1, 2 or 3; in another embodiment, n is 0, 1 or 2; in another embodiment, n is 0 or 1; in another embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; in another embodiment, n is 4.

[0193] In one embodiment, n is 1, and R t H, D, F, methyl, CD 3 or CF 3 In another specific embodiment, n is 1, and R t is H, D, F, methyl or CD 3 In another specific embodiment, n is 1, and R t is H, D or F; in another specific embodiment, n is 1, and R t Methyl or CD 3 .

[0194] R

[0195] In one embodiment, each R is independently

[0196] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0197] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, -C 1-6 Alkylene-C 3-6Cycloalkyl, -C 1-6 Alkylene-3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0198] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted by one or more R".

[0199] In another embodiment, each R is independently

[0200] 1)H, D, halogen, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d or -P(=O)R e R f ;or

[0201] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0202] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted by one or more R".

[0203] In another embodiment, each R is independently

[0204] 1)H, D, halogen, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R dor -P(=O)R e R f ;or

[0205] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0206] 3) The two R on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted by one or more R".

[0207] In another embodiment, each R is independently

[0208] 1)H, D, halogen, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d ;or

[0209] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0210] 3) The two R on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted by one or more R".

[0211] In another embodiment, each R is independently

[0212] 1)H, D, halogen, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O)2 R d ;or

[0213] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0214] 3) Two R's on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered monocyclic heterocyclic group, a 6-12 membered fused bicyclic heterocyclic group or a 5-10 membered heteroaryl group, wherein the group is optionally substituted by one or more R's.

[0215] In another embodiment, each R is independently

[0216] 1) H, D or halogen; or

[0217] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 5-6 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0218] 3) Two R on two adjacent atoms together with the atoms to which they are attached form a 5-10 membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the group is optionally substituted by one or more R".

[0219] In another embodiment, each R is independently

[0220] 1) H, D or halogen; or

[0221] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 5-6 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0222] 3) Two R on two adjacent atoms together with the atoms to which they are attached form a 5-6 membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the group is optionally substituted by one or more R".

[0223] In another embodiment, each R is independently

[0224] 1) H, D or halogen; or

[0225] 2) C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclyl, wherein said group is optionally substituted by one or more R"; or

[0226] 3) Two R on two adjacent atoms together with the atoms to which they are attached form a 5-6 membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the group is optionally substituted by one or more R".

[0227] In another embodiment, each R is independently

[0228] 1) H, D or halogen; or

[0229] 2) C 1-6 Alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more R"; or

[0230] 3) Two R on two adjacent atoms together with the atoms to which they are attached form a 5-6 membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the group is optionally substituted by one or more R".

[0231] In another embodiment, each R is independently

[0232] 1) H or D; or

[0233] 2) Me, CHF 2 , CH 2 CF 3 or piperidinyl, wherein said group is optionally substituted with one or more R"; or

[0234] 3) Two R on two adjacent atoms together with the atoms to which they are attached form a 5-6 membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the group is optionally substituted by one or more R".

[0235] R'

[0236] In one embodiment, each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R".

[0237] In another embodiment, each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl or 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R".

[0238] In another embodiment, each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d or -C(O)NR e R f .

[0239] In another embodiment, each R' is independently H, D or halogen.

[0240] In another embodiment, each R' is independently H or D.

[0241] R a , R b and R c

[0242] In one embodiment, each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R.

[0243] In another embodiment, each R a , R b and R c Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more R groups.

[0244] In another embodiment, each R a , R b and R c are independently H or C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more R groups.

[0245] R d , R e and R f

[0246] In one embodiment, each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R".

[0247] In another embodiment, each R d , R e and R f Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl or C 6-10 Aryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl and C 6-10 The aryl group is optionally substituted with one or more R".

[0248] In another embodiment, each R d , R e and R f Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R".

[0249] R”

[0250] In one embodiment, each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0251] In another embodiment, each R" is independently H, D, -C(O)OR g、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl or 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0252] In another embodiment, R" is substituted with one or more R'".

[0253] R''

[0254] In one embodiment, each R'' is independently H; in one embodiment, each R'' is independently D; in one embodiment, each R'' is independently halogen; in one embodiment, each R'' is independently C 1-6 In one embodiment, each R"' is independently C 1-6 haloalkyl; in one embodiment, each R"' is independently C 3-6 Cycloalkyl; in one embodiment, each R"' is independently a 3-7 membered heterocyclyl; in one embodiment, each R"' is independently C 6-10 aryl; in one embodiment, each R "' is independently substituted by 5-10 membered heteroaryl; in one embodiment, each R "' is substituted by one or more D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0255] R g , R h and R j

[0256] In one embodiment, H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R jTogether with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0257] In another embodiment, each R g , R h and R j Independently H, D, C 1-6 Alkyl or C 1-6 A haloalkyl group, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0258] In another embodiment, each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0259] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. 1 , X 2 and R 2 , R 1 , R 3 and R 4 , R 5 and R 6 , R s and m, R t and n, R, R', R", R d , R e and R f , R g , R h and R jThe present invention is intended to include all of these technical solutions, which are not listed one by one due to space limitations.

[0260] In a more specific embodiment, the present invention relates to the compound of formula (A) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate:

[0261]

[0262] in,

[0263] Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

[0264] X 1 N, CD or CH;

[0265] X 2 N or CR 2 ;

[0266] R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0267] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0268] R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0269] R 3 and R 4 are independently H, D, halogen, C 1-6 Alkyl or C 1-6haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0270] R 5 is a halogen;

[0271] R 6 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 until fully deuterated;

[0272] R s and R t are independently H, D, halogen, -OR a 、-NR b R c , 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 until fully deuterated;

[0273] m is 0, 1, 2 or 3;

[0274] n is 0, 1, 2, 3 or 4;

[0275] Each R is independently:

[0276] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0277] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0278] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0279] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)Re R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0280] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0281] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"';

[0282] Each R'' is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more D, halogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0283] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0284] In a more specific embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0285]

[0286] in,

[0287] X 1 N, CD or CH;

[0288] X 2 N or CR 2 ;

[0289] R 1 H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b Rc 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O) 2 R b 、-S(O) 2 NR b R c 、-S(O)R a 、-S(O) 2 R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0290] Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0291] R2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0292] R 3 and R 4 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 is optionally substituted with one or more D until fully deuterated;

[0293] R 5 is a halogen;

[0294] R 6 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 until fully deuterated;

[0295] 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 is optionally substituted with one or more D until fully deuterated;

[0296] m is 0, 1, 2 or 3;

[0297] n is 0, 1, 2, 3 or 4;

[0298] Each R is independently:

[0299] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e Rf 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0300] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0301] 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0302] Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR dC(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0303] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0304] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0305] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0306] In a more specific embodiment, the present invention relates to the compound of the above formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein R 1 H, D, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R;

[0307] Preferably, R 1 For H, D,

[0308] wherein the above groups are optionally substituted by one or more R;

[0309] Preferably, R 1 for

[0310] wherein the above groups are optionally substituted by one or more R;

[0311] Preferably, R 1 for

[0312] wherein the above groups are optionally substituted by one or more R;

[0313] Preferably, R 1 For H.

[0314] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein R 2 H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R';

[0315] Preferably, R 2 H, D, halogen, methyl, -CHF 2 , ethyl, isopropyl,

[0316]

[0317] wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0318] Preferably, R 2 H, D, halogen, methyl, -CHF 2 , ethyl, isopropyl,

[0319] wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0320] Preferably, R 2 H, D, methyl, -CHF 2 , wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0321] Preferably, R 2 H, D, -CHF 2 or wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0322] Preferably, R 2 is H or D;

[0323] Preferably, R 2 -CHF 2 or wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0324] Preferably, R 2 for The above groups are optionally substituted by one or more Ds until fully deuterated.

[0325] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein R 5 For F.

[0326] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein R 6 Methyl or -CD 3 .

[0327] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (II):

[0328]

[0329] in,

[0330] X 2 N or CR 2 ;

[0331] R 2 H, D, halogen, 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 until fully deuterated;

[0332] R 5 is a halogen;

[0333] R 6 C 1-6 Alkyl or C1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0334] R t H, D, halogen, 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 until fully deuterated;

[0335] Y 1 N or CR 12 ;

[0336] R 10 , R 11 and R 12 Independently for:

[0337] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0338] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0339] 3) R 11 and R 12 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more R"; or

[0340] 4) R 10 and R 11 or R 11 and R 12 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, wherein said group is optionally substituted with one or more R"; or

[0341] 5) R 11 and R 12 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted with one or more R";

[0342] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0343] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NRg C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0344] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R jTogether with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0345] In a more specific embodiment, the present invention relates to the compound of formula (II) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0346] X 2 N or CR 2 ;

[0347] R 2 H, D, halogen, 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 until fully deuterated;

[0348] R 5 is a halogen;

[0349] R 6 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 until fully deuterated;

[0350] R t H, D, halogen, 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 until fully deuterated;

[0351] Y 1 N or CR 12 ;

[0352] R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0353] R 11 and R 12 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 is optionally substituted with one or more D until fully deuterated;

[0354] Or, R 11 and R 12 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more R"; or

[0355] R 10 With R 11 or R 11 With R 12 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclyl, a 6-12 membered fused bicyclic heterocycle, or a 5-10 membered heteroaryl, wherein said groups are optionally substituted with one or more R"; or

[0356] R 11 and R 12 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted with one or more R";

[0357] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0358] Each R g , R h and R j Independently H, D, 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 deuteration.

[0359] In a more specific embodiment, the present invention relates to the compound of formula (II) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0360] X 2 N or CR 2 ;

[0361] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0362] R 5 is halogen; preferably, R 5 is F;

[0363] R 6 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 full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0364] R t is H, D or halogen; preferably, R t is H, D or F;

[0365] Y 1 N or CR 12 ;

[0366] R 10 H, 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 R"; preferably, R 10 H, C 1-3 Alkyl or C 1-3 haloalkyl, wherein the C 1-3 Alkyl and C 1-3 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0367] R 11 and R 12 are independently H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 11 and R 12 independently H or D;

[0368] Or, R 11 and R 12 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted by one or more R"; preferably, R 11 With R 12 together with the atoms to which they are attached form a cyclohexyl group, which is optionally substituted with one or more R"; or

[0369] R 10 With R 11 or R 11 With R 12 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 10 With R 11 or R 11 With R 12 Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0370] R 10 With R 11 or R 11 With R 12 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 10 With R 11 or R 11 With R 12 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0371] R 11 and R 12 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted by one or more R"; preferably, R 11 With R 12 together with the atoms to which they are attached form a phenyl group, which is optionally substituted with one or more R"; or

[0372] R 10 With R 11 or R 11 With R 12Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 10 With R 11 or R 11 With R 12 together with the atoms to which they are attached form a 5- or 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, wherein said group is optionally substituted with one or more R″;

[0373] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, 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 until fully deuterated;

[0374] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0375] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is a compound of formula (II-1):

[0376]

[0377] in,

[0378] R 5 is halogen; preferably, R 5 is F;

[0379] R 6 C1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0380] R t is H, D or halogen; preferably, R t is H, D or F;

[0381] Y 1 N, CH or CD;

[0382] R 10 With R 11 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 10 With R 11 Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0383] R 10 With R 11 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 10 With R 11 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0384] R 10 With R 11 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 10 With R 11 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R″;

[0385] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, 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 until fully deuterated;

[0386] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0387] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (II-1), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0388] R 5 is F;

[0389] R 6 Methyl or -CD 3 ;

[0390] R t is H, D or F;

[0391] Y 1 N, CH or CD;

[0392] R 10 With R 11 Together with the atoms to which they are attached they form the following groups:

[0393]

[0394] wherein the group is optionally substituted with one or more D, up to full deuteration;

[0395] Preferably, R 10 With R 11 Together with the atoms to which they are attached they form the following groups:

[0396] The groups described are optionally substituted by one or more D, up to full deuteration.

[0397] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (III):

[0398]

[0399] in,

[0400] X 2 N or CR 2 ;

[0401] R 2 H, D, halogen, 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 until fully deuterated;

[0402] R 5 is a halogen;

[0403] R 6 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 until fully deuterated;

[0404] R t H, D, halogen, 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 until fully deuterated;

[0405] R 13 , R 14 and R 15 Independently for:

[0406] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e Rf 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0407] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0408] 3) R 13 and R 14 or R 13 and R 15 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, wherein said group is optionally substituted with one or more R";

[0409] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0410] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0411] Each R g , Rh and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0412] In a more specific embodiment, the present invention relates to the compound of formula (III) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0413] X 2 N or CR 2 ;

[0414] R 2 H, D, halogen, 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 until fully deuterated;

[0415] R 5 is a halogen;

[0416] R 6 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 until fully deuterated;

[0417] R t H, D, halogen, 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 until fully deuterated;

[0418] R 13 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0419] R 14 and R 15 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 is optionally substituted with one or more D until fully deuterated;

[0420] Or, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclyl, a 6-12 membered fused bicyclic heterocycle, or a 5-10 membered heteroaryl, wherein said groups are optionally substituted with one or more R″;

[0421] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0422] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0423] In a more specific embodiment, the present invention relates to the compound of formula (III) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0424] X 2 N or CR 2 ;

[0425] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0426] R 5 is halogen; preferably, R 5 is F;

[0427] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0428] R t is H, D or halogen; preferably, R t is H, D or F;

[0429] R 13 H, C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 13 H, C 1-3 Alkyl, C 1-3 haloalkyl or a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, wherein said C 1-3 Alkyl, C 1-3 Haloalkyl and 6-membered heterocyclyl are optionally substituted with one or more R";

[0430] R 14 and R 15 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 is optionally substituted with one or more D, up to full deuteration; preferably, R 14 and R15 independently H or D;

[0431] Or, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0432] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0433] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R″;

[0434] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D until fully deuterated;

[0435] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0436] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is a compound of formula (III-1):

[0437]

[0438] in,

[0439] R 5 is halogen; preferably, R 5 is F;

[0440] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0441] R t is H, D or halogen; preferably, R t is H, D or F;

[0442] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R15 Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0443] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0444] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R″;

[0445] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, 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 until fully deuterated;

[0446] Each R g , R h and R jIndependently H, D, 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 full deuteration.

[0447] In a more specific embodiment, the present invention relates to the compound of formula (III-1) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0448] R 5 is F;

[0449] R 6 Methyl or -CD 3 ;

[0450] R t is H, D or F;

[0451] R 13 With R 14 or R 13 With R 15 Together with the atoms to which they are attached, they form The groups described are optionally substituted by one or more D, up to full deuteration.

[0452] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (IV):

[0453]

[0454] in,

[0455] X 2 N or CR 2 ;

[0456] R 2 H, D, halogen, 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 until fully deuterated;

[0457] R 5 is a halogen;

[0458] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0459] R t H, D, halogen, 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 until fully deuterated;

[0460] Y 2 O or S;

[0461] R 16 and R 17 Independently

[0462] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0463] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0464] 3) R 16 and R 17 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0465] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0466] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NRh R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0467] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0468] In a more specific embodiment, the present invention relates to the compound of the above formula (IV), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0469] X 2 N or CR 2 ;

[0470] R 2 H, D, halogen, 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 until fully deuterated;

[0471] R 5 is a halogen;

[0472] R 6 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 until fully deuterated;

[0473] R t H, D, halogen, 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 until fully deuterated;

[0474] Y 2 O or S;

[0475] R 16 and R 17 Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0476] Or, R 16 and R 17 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more R"; or

[0477] R 16 and R 17Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclyl group, which is optionally substituted with one or more R"; or

[0478] R 16 and R 17 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; or

[0479] R 16 and R 17 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted with one or more R"; or

[0480] R 16 and R 17 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R";

[0481] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0482] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0483] In a more specific embodiment, the present invention relates to the compound of the above formula (IV), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0484] X 2 N or CR 2 ;

[0485] R 2 is H, D or halogen; preferably, R 2is H, D or F; preferably, R 2 is H;

[0486] R 5 is halogen; preferably, R 5 is F;

[0487] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0488] R t is H, D or halogen; preferably, R t is H, D or F;

[0489] Y 2 O or S;

[0490] R 16 and R 17 Independently H, D, 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 R"; preferably, R 10 H, D, C 1-3 Alkyl or C 1-3 haloalkyl, wherein the C 1-3 Alkyl and C 1-3 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0491] Or, R 16 and R 17 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted by one or more R"; preferably, R 16 and R 17 together with the atoms to which they are attached form a cyclohexyl group, which is optionally substituted with one or more R"; or

[0492] R 16 and R 17 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 16 and R 17Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0493] R 16 and R 17 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 16 and R 17 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0494] R 16 and R 17 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted by one or more R"; preferably, R 16 and R 17 together with the atoms to which they are attached form a phenyl group, which is optionally substituted with one or more R"; or

[0495] R 16 and R 17 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 16 and R 17 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R″;

[0496] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, 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 until fully deuterated;

[0497] Each Rg , R h and R j Independently H, D, 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 full deuteration.

[0498] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is a compound of formula (IV-1):

[0499]

[0500] in,

[0501] R 5 is halogen; preferably, R 5 is F;

[0502] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0503] R t is H, D or halogen; preferably, R t is H, D or F;

[0504] Y 2 O or S;

[0505] R 16 and R 17 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted by one or more R"; preferably, R 16 and R 17 together with the atoms to which they are attached form a cyclohexyl group, which is optionally substituted with one or more R"; or

[0506] R 16 and R 17 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 16 and R 17Together with the atoms to which they are attached, they form a 6-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, which is optionally substituted by one or more R"; or

[0507] R 16 and R 17 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 16 and R 17 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0508] R 16 and R 17 Together with the atoms to which they are attached, they form C 6-10 Aryl, which is optionally substituted by one or more R"; preferably, R 16 and R 17 together with the atoms to which they are attached form a phenyl group, which is optionally substituted with one or more R"; or

[0509] R 16 and R 17 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 16 and R 17 Together with the atoms to which they are attached, they form a 6-membered heteroaryl group having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R″;

[0510] Each R" is independently D, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more D, up to full deuteration; preferably, each R" is independently D, 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 until fully deuterated;

[0511] Each Rg , R h and R j Independently H, D, 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 full deuteration.

[0512] In a more specific embodiment, the present invention relates to the compound of formula (IV-1) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0513] R 5 is F;

[0514] R 6 Methyl or -CD 3 ;

[0515] R t is H, D or F;

[0516] Y 2 O or S;

[0517] R 16 With R 17 Together with the atoms to which they are attached they form the following groups:

[0518] The groups described are optionally substituted by one or more D, up to full deuteration.

[0519] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (V):

[0520]

[0521] in,

[0522] X 2 N or CR 2 ;

[0523] R 2 H, D, halogen, 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 until fully deuterated;

[0524] R 5 is a halogen;

[0525] R 6 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 until fully deuterated;

[0526] R t H, D, halogen, 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 until fully deuterated;

[0527] n is 0, 1, 2, 3 or 4;

[0528] Y 1 N or CR 12 Preferably, Y 1 is N;

[0529] Y 2 N or CR 13 ;

[0530] R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl and 5-6 membered heterocyclyl are optionally substituted with one or more R";

[0531] R 11 , R 12 and R 13 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 is optionally substituted with one or more D until fully deuterated;

[0532] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-10 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R";

[0533] Where R" is H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-OR g 、-OC(O)R g 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more D until fully deuterated;

[0534] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0535] In a more specific embodiment, the present invention relates to the compound of the above formula (V), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0536] X 2 CR 2 ;

[0537] R 2 is H, D or -CH(CH 3 )(CF 3 );

[0538] R 5 is F;

[0539] R 6 for me;

[0540] R t is H or D;

[0541] n is 0, 1, 2, 3 or 4;

[0542] Y 1 N or CR 12 Preferably, Y 1 is N;

[0543] Y 2 N or CR 13 ;

[0544] R 10 H, Me, CHF 2 , CH 2 CF 3 or piperidinyl, which is optionally substituted with one or more R";

[0545] R 11 is H, D or Me;

[0546] R 12 and R 13 independently H or D;

[0547] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-10 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-10 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0548] Where R" is Me, Et, -C(O)OR g 、-C(O)NR h R j 、-NR g C(O)R h or oxetane;

[0549] Each R g , R h and R j Independently H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0550] In a more specific embodiment, the present invention relates to the compound of the above formula (V), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0551] X 2 N or CR 2 ;

[0552] R 2 H, D, halogen, 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 until fully deuterated;

[0553] R 5 is a halogen;

[0554] R 6 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 until fully deuterated;

[0555] R t H, D, halogen, 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 until fully deuterated;

[0556] n is 0, 1, 2, 3 or 4;

[0557] Y 1 N or CR 12 Preferably, Y 1 is N;

[0558] Y2 N or CR 13 ;

[0559] R 10 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl and 5-6 membered heterocyclyl are optionally substituted with one or more R";

[0560] R 11 , R 12 and R 13 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 is optionally substituted with one or more D until fully deuterated;

[0561] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0562] Where R" is H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-OR g 、-OC(O)R g 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 Rg , C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more D until fully deuterated;

[0563] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0564] In a more specific embodiment, the present invention relates to the compound of formula (V) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0565] X 2 CR 2 ;

[0566] R 2 H, D, halogen, 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 until fully deuterated;

[0567] R 5 is a halogen;

[0568] R 6 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 until fully deuterated;

[0569] R t H, D, halogen, 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 until fully deuterated;

[0570] n is 0, 1, 2, 3 or 4;

[0571] Y 1 N or CR 12 Preferably, Y 1 is N;

[0572] Y 2 N or CR 13 ;

[0573] R 10 H, C 1-6 Alkyl, C 1-6 haloalkyl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heterocyclyl are optionally substituted with one or more R";

[0574] R 11 H, D, halogen, 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 until fully deuterated;

[0575] R 12 and R 13 are independently H, D or halogen;

[0576] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0577] Where R" is H, D, halogen, -C(O)OR g 、-C(O)NR h Rj , C 1-6 Alkyl, C 1-6 haloalkyl or 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more D until fully deuterated;

[0578] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0579] In a more specific embodiment, the present invention relates to the compound of the above formula (V), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0580] X 2 CR 2 ;

[0581] R 2 is H, D or -CH(CH 3 )(CF 3 );

[0582] R 5 is F;

[0583] R 6 for me;

[0584] R t is H or D;

[0585] n is 0, 1, 2, 3 or 4;

[0586] Y 1 N or CR 12 Preferably, Y 1 is N;

[0587] Y 2 N or CR 13 ;

[0588] R 10 H, Me, CHF 2 , CH 2 CF 3 or piperidinyl, which is optionally substituted with one or more R";

[0589] R 11is H, D or Me;

[0590] R 12 and R 13 independently H or D;

[0591] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0592] Where R" is Me, Et, -C(O)OR g 、-C(O)NR h R j or oxetane;

[0593] Each R g , R h and R j Independently H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0594] In a more specific embodiment, the present invention relates to the compound of the above formula (V), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0595] X 2 N or CR 2 ;

[0596] R 2 H, D, halogen, 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 until fully deuterated;

[0597] R 5 is a halogen;

[0598] R 6 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 until fully deuterated;

[0599] R t H, D, halogen, 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 until fully deuterated;

[0600] n is 0, 1, 2, 3 or 4;

[0601] Y 1 N or CR 12 Preferably, Y 1 is N;

[0602] Y 2 N or CR 13 ;

[0603] R 10 , R 11 , R 12 and R 13 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 is optionally substituted with one or more D until fully deuterated;

[0604] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0605] Where R" is H, D, halogen, 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 full deuteration.

[0606] In a more specific embodiment, the present invention relates to the compound of formula (V) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0607] X 2 CR 2 ;

[0608] R 2 H, D, halogen, 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 until fully deuterated;

[0609] R 5 is a halogen;

[0610] R 6 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 until fully deuterated;

[0611] R t H, D, halogen, 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 until fully deuterated;

[0612] n is 0, 1, 2, 3 or 4;

[0613] Y 1 N or CR 12 Preferably, Y 1 is N;

[0614] Y 2 N or CR 13 ;

[0615] R 10 H, 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 until fully deuterated;

[0616] R 11 H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0617] R 12 and R 13 are independently H, D or halogen;

[0618] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0619] Where R" is H, D, halogen, 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 full deuteration.

[0620] In a more specific embodiment, the present invention relates to the compound of the above formula (V), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0621] X 2 CR 2 ;

[0622] R 2 is H, D or -CH(CH 3 )(CF 3 );

[0623] R 5 is F;

[0624] R 6 for me;

[0625] R t is H or D;

[0626] n is 0, 1, 2, 3 or 4;

[0627] Y 1 N or CR 12 Preferably, Y 1 is N;

[0628] Y 2 N or CR 13 ;

[0629] R 10 H, Me, CHF 2 or CH 2 CF 3 ;

[0630] R 11 is H, D or Me;

[0631] R 12 and R 13 independently H or D;

[0632] Or, R 10 and R 11 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted with one or more R"; or, when Y 1 CR 12 When R 10 and R 12 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0633] wherein R" is Me or Et.

[0634] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (VI):

[0635]

[0636] in,

[0637] X 2 N or CR 2 Preferably, X 2 CR 2 ;

[0638] R 2 H, D, halogen, 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 until fully deuterated;

[0639] R 5 is a halogen;

[0640] R 6 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 until fully deuterated;

[0641] R t H, D, halogen, 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 until fully deuterated;

[0642] n is 0, 1, 2, 3 or 4;

[0643] R 10 H, D, 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 until fully deuterated;

[0644] R 12 and R 13 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 is optionally substituted with one or more D, up to full deuteration.

[0645] In a more specific embodiment, the present invention relates to the compound of formula (VI) above, or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0646] X 2 CR 2 ;

[0647] R 2 is H, D or -CH(CH 3 )(CF 3 );

[0648] R 5 is F;

[0649] R 6 for me;

[0650] R t is H or D;

[0651] n is 0, 1, 2, 3 or 4;

[0652] R 10 H, Me, CHF 2 or CH 2 CF 3 ;

[0653] R 12 and R 13 are independently H or D.

[0654] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (VII):

[0655]

[0656] in,

[0657] X 2 N or CR 2 Preferably, X 2 CR 2 ;

[0658] R 2 H, D, halogen, 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 until fully deuterated;

[0659] R 5 is a halogen;

[0660] R 6 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 until fully deuterated;

[0661] R t H, D, halogen, 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 until fully deuterated;

[0662] n is 0, 1, 2, 3 or 4;

[0663] Y 3 O or S;

[0664] R 10 and R 11 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 is optionally substituted with one or more D until fully deuterated;

[0665] Or, R 10 and R 11 Together with the atoms to which they are attached, they form C 5-8 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, wherein the C 5-8 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0666] Where R" is H, D, halogen, 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 full deuteration.

[0667] In a more specific embodiment, the present invention relates to the compound of the above formula (VII), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0668] X 2 CR 2 ;

[0669] R 2 is H, D, halogen or -CH(CH 3 )(CF 3 );

[0670] R 5 is F;

[0671] R 6 for me;

[0672] R t is H or D;

[0673] n is 0, 1, 2, 3 or 4;

[0674] Y 3 O or S;

[0675] R 10 H, Me, CHF 2 or CH 2CF 3 ;

[0676] R 11 is H or D;

[0677] Or, R 10 and R 11 Together with the atoms to which they are attached, they form C 5-8 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, wherein the C 5-8 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally substituted with one or more R";

[0678] wherein R" is Me or Et.

[0679] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (VIII), (VIII-1) or (VIII-2):

[0680]

[0681] in,

[0682] X 2 CR 2 ;

[0683] R 2 H, D, halogen, 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 full deuteration; preferably, R 2 is H or D;

[0684] R 5 is a halogen;

[0685] R 6 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 until fully deuterated;

[0686] R t H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0687] n is 0, 1, 2, 3 or 4;

[0688] Z 1 N or CR 20 ;

[0689] Z 2 N or CR 21 ;

[0690] Z 3 N or CR 22 ;

[0691] Z 4 N or CR 23 ;

[0692] R 20 , R 22 and R 23 are independently H, D, halogen, -OC(O)R d 、-NR d C(O)R e 、-C(O)NR e R f 、-C(O)OR d , C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more Ds, up to full deuteration, and R 20 , R 22 and R 23 are independently optionally substituted with one or more R";

[0693] R 21 H, D, halogen, -OR d 、-NR e R f 、-C(O)R d 、-OC(O)R d 、-NR d C(O)R e 、-C(O)NR e R f 、-C(O)OR d 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)Re R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration, and R 21 optionally substituted with one or more R";

[0694] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration, which are optionally substituted with one or more R";

[0695] Where R" is H, D, halogen, -OR g 、-NR h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclyl, wherein R" is optionally substituted by one or more D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0696] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0697] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (VIII), (VIII-1) or (VIII-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0698] X 2 CR 2 ;

[0699] R 2 H, D, F, Me, CHF 2 CF 3 or -CH(CH 3 )(CF 3 ); preferably, R 2 is H or D;

[0700] R 5 is F;

[0701] R 6 for me;

[0702] R t is H or D;

[0703] n is 0, 1, 2, 3 or 4;

[0704] Z 1 N or CR 20 ;

[0705] Z 2 N or CR 21 ;

[0706] Z 3 N or CR 22 ;

[0707] Z 4 N or CR 23 ;

[0708] R 20 is H or D;

[0709] R 21 H, D, F, Cl, Me, CHF 2 CF3 , CH 2 CF 3 、-C(OH)(CH 3 ) 2 、-OR d 、-NR d C(O)R e 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f or a 4-7 membered heterocyclyl, which is optionally substituted with one or more R";

[0710] R 22 H, D, -NR d C(O)R e or -C(O)NR e R f , which is optionally substituted with one or more R";

[0711] R 23 is H or D;

[0712] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more R";

[0713] Where R" is Me, Et, -OR g 、-NR h R j or a 4-7 membered heterocyclic group, wherein R" is optionally substituted by one or more D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0714] Each R g , R h and R j Independently H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0715] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (VIII), (VIII-1) or (VIII-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0716] X 2 N or CR 2 ;

[0717] R 2 H, D, halogen, 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 full deuteration; preferably, R 2 is H or D;

[0718] R 5 is a halogen;

[0719] R 6 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 until fully deuterated;

[0720] R t H, D, halogen, 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 until fully deuterated;

[0721] n is 0, 1, 2, 3 or 4;

[0722] Z 1 N or CR 20 ;

[0723] Z 2 N or CR 21 ;

[0724] Z 3 N or CR 22 ;

[0725] Z 4 N or CR 23 ;

[0726] R 20 , R 22 and R 23 are independently H, D, halogen, -OC(O)Rd 、-NR d C(O)R e 、-C(O)NR e R f 、-C(O)OR d , C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more Ds, up to full deuteration, and R 20 , R 22 and R 23 are independently optionally substituted with one or more R";

[0727] R 21 H, D, halogen, -OR d 、-NR e R f 、-OC(O)R d 、-NR d C(O)R e 、-C(O)NR e R f 、-C(O)OR d 、-S(O)R d 、-S(O) 2 R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration, and R 21 optionally substituted with one or more R";

[0728] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration, which are optionally substituted with one or more R";

[0729] Where R" is H, D, halogen, -OR g 、-NR h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclyl, wherein R" is optionally substituted by one or more D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0730] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0731] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (VIII), (VIII-1) or (VIII-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0732] X 2 CR 2 ;

[0733] R 2 H, D, halogen, 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 full deuteration; preferably, R 2 is H or D;

[0734] R 5is a halogen;

[0735] R 6 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 until fully deuterated;

[0736] R t H, D, halogen, 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 until fully deuterated;

[0737] n is 0, 1, 2, 3 or 4;

[0738] Z 1 N or CR 20 ;

[0739] Z 2 N or CR 21 ;

[0740] Z 3 N or CR 22 ;

[0741] Z 4 N or CR 23 ;

[0742] R 20 and R 23 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 is optionally substituted with one or more D until fully deuterated;

[0743] R 21 H, D, halogen, -OR d 、-NR d C(O)R e 、-S(O)R d 、-S(O) 2 R d , C 1-6 Alkyl, C 1-6 haloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more D until fully deuterated, and R 21optionally substituted with one or more R";

[0744] R 22 H, D, -NR d C(O)R e or -C(O)NR e R f , which is optionally substituted with one or more R";

[0745] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more R";

[0746] Where R" is H, D, halogen, -OR g 、-NR h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclyl, wherein R" is optionally substituted by one or more D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0747] Each R g , R h and R j Independently H, D, 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 full deuteration.

[0748] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (VIII), (VIII-1) or (VIII-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0749] X 2 CR 2 ;

[0750] R 2 H, D, Me, CHF 2 or -CH(CH 3)(CF 3 ); preferably, R 2 is H or D;

[0751] R 5 is F;

[0752] R 6 for me;

[0753] R t is H or D;

[0754] n is 0, 1, 2, 3 or 4;

[0755] Z 1 N or CR 20 ;

[0756] Z 2 N or CR 21 ;

[0757] Z 3 N or CR 22 ;

[0758] Z 4 N or CR 23 ;

[0759] R 20 is H or D;

[0760] R 21 H, D, F, Cl, Me, CHF 2 CF 3 , CH 2 CF 3 、-C(OH)(CH 3 ) 2 、-OR d 、-NR d C(O)R e 、-S(O)R d 、-S(O) 2 R d or a 4-7 membered heterocyclyl, which is optionally substituted with one or more R";

[0761] R 22 H, D, -NR d C(O)R e or -C(O)NR e R f , which is optionally substituted with one or more R";

[0762] R 23 is H or D;

[0763] Each R d , Re and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more R";

[0764] Where R" is Me, Et, -OR g 、-NR h R j or a 4-7 membered heterocyclic group, wherein R" is optionally substituted by one or more D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0765] Each R g , R h and R j Independently H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0766] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (IX):

[0767]

[0768] in,

[0769] X 2 N or CR 2 ;

[0770] R 2 H, D, halogen, 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 until fully deuterated;

[0771] R 5 is a halogen;

[0772] R 6 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 until fully deuterated;

[0773] R t H, D, halogen, 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 until fully deuterated;

[0774] Y 3 N or CR 111 ;

[0775] R 18 , R 19 , R 110 and R 111 Independently for:

[0776] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0777] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0778] 3) R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0779] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0780] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NRg S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0781] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group or a 5-10 membered heteroaryl group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0782] In a more specific embodiment, the present invention relates to the compound of the above formula (IX), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0783] X 2 N or CR 2 ;

[0784] R 2 H, D, halogen, 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 until fully deuterated;

[0785] R 5 is a halogen;

[0786] R 6 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 until fully deuterated;

[0787] R t H, D, halogen, 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 until fully deuterated;

[0788] Y 3 N or CR 111 ;

[0789] R 18 H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6

[0790] Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0791] R 110 H, D, halogen, -NR d C(O)R e , 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 until fully deuterated;

[0792] R 19 and R 111 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 is optionally substituted with one or more D until fully deuterated;

[0793] Or, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0794] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0795] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0796] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0797] In a more specific embodiment, the present invention relates to the compound of the above formula (IX), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0798] X 2 N or CR 2 ;

[0799] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0800] R 5 is halogen; preferably, R 5 is F;

[0801] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0802] R t is H, D or halogen; preferably, R t is H, D or F;

[0803] Y 3 N or CR 111 ;

[0804] R 18 H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6

[0805] Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 18 Halogen, -C(O)NR e R f 、-OR d 、-S(O) 2 R d , C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0806] R 110 H, D, halogen, -NR d C(O)R e , 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 full deuteration; preferably, R 19 is H or D;

[0807] R 19 and R 111 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 is optionally substituted with one or more D, up to full deuteration; preferably, R 110 is H or D;

[0808] Or, R 18 and R 19 or R 18 and R 110 or R110 and R 111 Together with the atoms to which they are attached, they form a 3-7 membered monocyclic heterocyclic group, which is optionally substituted with one or more R"; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic group having 1 or 2 ring heteroatoms selected from N, O and S, wherein said group is optionally substituted with one or more R"; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 together with the atoms to which they are attached form a 5-membered heterocyclyl having 1 or 2 ring heteroatoms selected from N, wherein said group is optionally substituted with one or more R"; or

[0809] R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 6-12 membered fused bicyclic heterocyclic ring, which is optionally substituted with one or more R"; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms selected from N, O and S, which is optionally substituted with one or more R"; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form an 8-10 membered fused bicyclic heterocycle having 1 or 2 ring heteroatoms selected from N, which is optionally substituted with one or more R"; or

[0810] R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5-10 membered heteroaryl group, which is optionally substituted with one or more R"; preferably, R 18 and R19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5- or 6-membered heteroaryl group having 1-3 ring heteroatoms selected from N, O and S, which is optionally substituted by one or more R″; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5-membered heteroaryl group having 1-3 ring heteroatoms selected from N, O and S, wherein said group is optionally substituted with one or more R"; preferably, R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5-membered heteroaryl group having 1 or 2 heteroatoms selected from the N ring, wherein said group is optionally substituted with one or more R″;

[0811] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0812] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0813] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0814] In a more specific embodiment, the present invention relates to the compound of the above formula (IX), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0815] X 2 for CH;

[0816] R 5 is F;

[0817] R 6 Methyl or -CD 3 ;

[0818] R t is H, D or F;

[0819] Y 3 N or CR 111 ;

[0820] R 18 and R 19 or R 18 and R 110 or R 110 and R 111 Together with the atoms to which they are attached, they form a 5-membered heteroaryl group having 1 or 2 heteroatoms selected from the N ring, wherein said group is optionally substituted with one or more R″;

[0821] Each R" is independently D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0822] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (IX-1):

[0823]

[0824] in,

[0825] R 5 is halogen; preferably, R 5 is F;

[0826] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0827] R t is H, D or halogen; preferably, R t is H, D or F;

[0828] Y 3 is N, CH or CD; preferably, Y 3 N or CH;

[0829] R 18 H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6

[0830] Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 18 Halogen, -C(O)NR e R f 、-OR d 、-S(O) 2 R d , C 1-6 Alkyl, C1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0831] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0832] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0833] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0834] In a more specific embodiment, the present invention relates to the compound of the above formula (IX-1), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0835] R 5 is F;

[0836] R 6 Methyl or -CD 3 ;

[0837] R t is H, D or F;

[0838] Y 3 N or CH;

[0839] R 18 H, F, Cl, -CH 3 , -CHF 2 , -CF 3 、-OCF 3 ,

[0840] wherein the group is optionally substituted by one or more D until fully deuterated; preferably, R 18 For F, Cl, -CH 3 , -CHF 2 , -CF 3 、-OCF 3 ,

[0841] wherein the group is optionally substituted with one or more D, up to full deuteration;

[0842] Preferably, R 18 -CH 3 ,, The groups described are optionally substituted by one or more D, up to full deuteration.

[0843] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (X):

[0844]

[0845] in,

[0846] X 2 N or CR 2 ;

[0847] R 2 H, D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C1-6 Alkyl and C 1-6 Haloalkyl is optionally substituted with one or more D until fully deuterated;

[0848] R 5 is a halogen;

[0849] R 6 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 until fully deuterated;

[0850] R t H, D, halogen, 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 until fully deuterated;

[0851] Y 3 N, CH or CD;

[0852] Y 4 N, CH or CD;

[0853] Y 5 and Y 6 are independently N or C and Y 5 and Y 6 At least one of them is N;

[0854] W 1 N or CR 112 ;

[0855] W 2 N or CR 113 ;

[0856] W 3 N or CR 114 ;

[0857] represents a single bond or a double bond;

[0858] The premise is that Y 3 , Y 4 , Y 5 , Y 6 , W 1 , W 2 and W 3 The bicyclic ring is an aromatic ring;

[0859] R 112 , R 113 and R114 Independently for:

[0860] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0861] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0862] 3) R 112 and R 113 or R 113 and R 114 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0863] Each R d , R e and R fIndependently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0864] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0865] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0866] In a more specific embodiment, the present invention relates to the compound of the above formula (X), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0867] X 2 N or CR 2 ;

[0868] R 2 H, D, halogen, 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 until fully deuterated;

[0869] R 5is a halogen;

[0870] R 6 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 until fully deuterated;

[0871] R t H, D, halogen, 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 until fully deuterated;

[0872] Y 3 N, CH or CD;

[0873] Y 4 N, CH or CD;

[0874] Y 5 and Y 6 are independently N or C and Y 5 and Y 6 At least one of them is N;

[0875] W 1 N or CR 112 ;

[0876] W 2 N or CR 113 ;

[0877] W 3 N or CR 114 ;

[0878] represents a single or double bond;

[0879] The premise is that Y 3 , Y 4 , Y 5 , Y 6 , W 1 , W 2 and W 3 The bicyclic ring is an aromatic ring;

[0880] R 112 , R 113 and R 114 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0881] Or, R 112 and R 113 or R 113 and R 114 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0882] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0883] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0884] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0885] In a more specific embodiment, the present invention relates to the compound of the above formula (X), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0886] X 2 N or CR 2 ;

[0887] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0888] R 5 is halogen; preferably, R 5 is F;

[0889] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0890] R t is H, D or halogen; preferably, R t is H, D or F;

[0891] Y 3 is N, CH or CD; preferably, Y 3 N or CH;

[0892] Y 4 is N, CH or CD; preferably, Y 4 N or CH;

[0893] Y 5 and Y 6 are independently N or C and Y 5 and Y 6 At least one of them is N;

[0894] W 1 N or CR 112 ;

[0895] W 2 N or CR 113 ;

[0896] W 3 N or CR 114 ;

[0897] represents a single or double bond;

[0898] The premise is that Y 3 , Y 4 , Y 5 , Y 6 , W 1 , W 2 and W 3 The bicyclic ring is an aromatic ring;

[0899] R 112 , R 113 and R 114 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 112 , R 113 and R 114 Independently H, D, 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 R";

[0900] Or, R 112 and R 113 or R 113 and R 114 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group, which is optionally substituted with one or more R"; preferably, R 112 and R 113 or R113 and R 114 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O and S, which is optionally substituted with one or more R";

[0901] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0902] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0903] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0904] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (A) or formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, which is a compound of formula (X-1) or (X-2):

[0905]

[0906] in,

[0907] R 5 is halogen; preferably, R 5 is F;

[0908] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0909] R t is H, D or halogen; preferably, R t is H, D or F;

[0910] Y 3 is N, CH or CD; preferably, Y 3 N or CH;

[0911] Y 4 is N, CH or CD; preferably, Y 4 N or CH;

[0912] W 1 N or CR 112 ;

[0913] W 2 N or CR 113 ;

[0914] W 3 N or CR 114 ;

[0915] R 112 , R 113 and R 114 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 112 , R 113 and R 114 Independently H, D, 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 R";

[0916] Or, R 112 and R 113 or R 113 and R 114 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group, which is optionally substituted with one or more R"; preferably, R 112 and R 113 or R 113 and R 114 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O and S, wherein said group is optionally substituted with one or more R";

[0917] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0918] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0919] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0920] In a more specific embodiment, the present invention relates to the compound of the above formula (X-1) or (X-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0921] R 5 is F;

[0922] R 6 Methyl or -CD 3 ;

[0923] R t is H, D or F;

[0924] Y 3 N or CH;

[0925] Y 4 N or CH;

[0926] W 1 N or CR 112 ;

[0927] W 2 N or CR 113 ;

[0928] W 3 N or CR 114 ;

[0929] R 112 , R 113 and R 114 is H;

[0930] Or, R 112 and R 113 or R 113 and R 114 Together with the atoms to which they are attached they form the following groups:

[0931] The groups described are optionally substituted by one or more D, up to full deuteration.

[0932] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (XI):

[0933]

[0934] in,

[0935] X 2 N or CR 2 ;

[0936] R 2 H, D, halogen, 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 until fully deuterated;

[0937] R 5 is a halogen;

[0938] R 6 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 until fully deuterated;

[0939] R t H, D, halogen, 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 until fully deuterated;

[0940] Y 3 N, CH or CD;

[0941] Y 7 and Y 8 are independently N or C and Y 7 and Y 8 At least one of them is N;

[0942] Y 9 N, CH or CD;

[0943] W 4 N or CR 115 ;

[0944] W 5 N or CR 116 ;

[0945] W 6 N or CR 117 ;

[0946] represents a single or double bond;

[0947] The premise is that Y 3 , Y 7 , Y 8 , Y 9 , W 4 , W 5 and W 6 The bicyclic ring is an aromatic ring;

[0948] R 115 , R 116 and R 117 Independently for:

[0949] 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O) 2 R e 、-S(O) 2 NR e R f 、-S(O)R d 、-S(O) 2 R d 、-P(=O)R e R f 、-OP(=O)R e R f ;or

[0950] 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0951] 3) R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or

[0952] Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R";

[0953] Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g、-OC(O)NR h R j 、-NR g S(O) 2 R h 、-S(O) 2 NR h R j 、-S(O)R g 、-S(O) 2 R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated;

[0954] Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

[0955] In a more specific embodiment, the present invention relates to the compound of the above formula (XI), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0956] X 2 N or CR 2 ;

[0957] R 2 H, D, halogen, 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 until fully deuterated;

[0958] R 5 is a halogen;

[0959] R 6 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 until fully deuterated;

[0960] R t H, D, halogen, 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 until fully deuterated;

[0961] Y 3 N, CH or CD;

[0962] Y 7 and Y 8 are independently N or C and Y 7 and Y 8 At least one of them is N;

[0963] Y 9 N, CH or CD;

[0964] W 4 N or CR 115 ;

[0965] W 5 N or CR 116 ;

[0966] W6 N or CR 117 ;

[0967] represents a single or double bond;

[0968] The premise is that Y 3 , Y 7 , Y 8 , Y 9 , W 4 , W 5 and W 6 The bicyclic ring is an aromatic ring;

[0969] R 115 , R 116 and R 117 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6 Alkyl, C 1-6 A haloalkyl group or a 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0970] Or, R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R";

[0971] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0972] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0973] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0974] In a more specific embodiment, the present invention relates to the compound of the above formula (XI), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[0975] X 2 N or CR 2 ;

[0976] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0977] R 5 is halogen; preferably, R 5 is F;

[0978] R 6 C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6Haloalkyl is optionally substituted with one or more D, up to full deuteration; preferably, R 6 Methyl or -CD 3 ;

[0979] R t is H, D or halogen; preferably, R t is H, D or F;

[0980] Y 3 is N, CH or CD; preferably, Y 3 N or CH;

[0981] Y 7 and Y 8 are independently N or C and Y 7 and Y 8 At least one of them is N;

[0982] Y 9 is N, CH or CD; preferably, Y 4 N or CH;

[0983] W 4 N or CR 115 ;

[0984] W 5 N or CR 116 ;

[0985] W 6 N or CR 117 ;

[0986] represents a single bond or a double bond;

[0987] The premise is that Y 3 , Y 7 , Y 8 , Y 9 , W 4 , W 5 and W 6 The bicyclic ring is an aromatic ring;

[0988] R 115 , R 116 and R 117 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 115 , R 116 and R 117 Independently H, D, 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 R";

[0989] Or, R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group, which is optionally substituted with one or more R"; preferably, R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, wherein said group is optionally substituted with one or more R";

[0990] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[0991] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[0992] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[0993] In a more specific embodiment, the present invention relates to a compound of formula (A) or formula (I) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (XI-1) or (XI-2):

[0994]

[0995] in,

[0996] X 2 N or CR 2 ;

[0997] R 2 is H, D or halogen; preferably, R 2 is H, D or F; preferably, R 2 is H;

[0998] R 5 is halogen; preferably, R 5 is F;

[0999] R 6 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 full deuteration; preferably, R 6 Methyl or -CD 3 ;

[1000] R t is H, D or halogen; preferably, R t is H, D or F;

[1001] Y 3 is N, CH or CD; preferably, Y 3 N or CH;

[1002] Y 9 is N, CH or CD; preferably, Y 9 N or CH;

[1003] W 4 N or CR 115 ;

[1004] W 5 N or CR 116 ;

[1005] W 6 N or CR 117 ;

[1006] R 115 , R 116 and R 117 are independently H, D, halogen, -C(O)NR e R f 、-NR d C(O)R e 、-OR d 、-S(O) 2 R d 、-P(=O)R e R f , C 1-6 Alkyl, C 1-6 haloalkyl or 3-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 The haloalkyl and 3-7 membered heterocyclyl groups are optionally substituted with one or more R"; preferably, R 115 , R 116 and R 117 Independently H, D, 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 R";

[1007] Or, R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group, which is optionally substituted with one or more R"; preferably, R 115 and R 116 or R 116 and R 117 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O and S, wherein said group is optionally substituted with one or more R";

[1008] Each R d , R e and R f Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more R";

[1009] Each R" is independently D, halogen, -C(O)OR g 、-NR h R j 、-NR g C(O)R h 、-OR g , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic group, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration;

[1010] Each R g , R h and R j are independently H or C 1-6 Alkyl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic group; wherein the C 1-6 Alkyl and 3-7 membered heterocyclyl are optionally substituted with one or more D, up to full deuteration.

[1011] In a more specific embodiment, the present invention relates to the above-mentioned compound of formula (XI-1) or (XI-2), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein:

[1012] X 2 N or CR 2 ;

[1013] R 2 is H, D or halogen; preferably, R 2is H, D or F; preferably, R 2 is H;

[1014] R 5 is F;

[1015] R 6 Methyl or -CD 3 ;

[1016] R t is H, D or F;

[1017] Y 3 N or CH;

[1018] Y 9 N or CH;

[1019] W 4 N or CR 115 ;

[1020] W 5 N or CR 116 ;

[1021] W 6 N or CR 117 ;

[1022] R 115 , R 116 and R 117 is H;

[1023] Or, R 115 and R 116 or R 116 and R 117 Together with the atoms to which they are attached they form the following groups:

[1024] The groups described are optionally substituted by one or more D, up to full deuteration.

[1025] In a more specific embodiment, the present invention relates to the compound of the above formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein the compound is selected from:

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereoisomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[1047] "Tautomer" refers to a functional group in certain compounds that changes its structure to become another functional group isomer, and can rapidly convert into each other, resulting in two isomers in dynamic equilibrium, and these two isomers are called tautomers.

[1048] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

[1049] The term "solvate" refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. 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 able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[1050] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrate of a compound can be represented by, for example, the general formula RxxH 2 O represents, where R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R×0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R×2H 2 O) and hexahydrate (R×6H 2 O)).

[1051] The compounds of the present invention can be in amorphous or crystalline form (crystal form or polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to a crystalline form dominating. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[1052] The present invention also includes isotopically labeled compounds which are identical to those described in formula (I) but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, 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. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which a radioactive isotope (e.g. 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged half-life in vivo or reduced dosage requirements, and thus may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents when carrying out the processes disclosed in the following schemes and / or Examples and Preparation Examples.

[1053] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form having a medical effect in vivo by, for example, hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and 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 of which is incorporated herein by reference.

[1054] Prodrugs are any covalently bonded compounds of the present invention that release the parent compound in vivo when such prodrugs are administered to a patient. Prodrugs are usually prepared by modifying functional groups, and the modification is carried out in a manner that allows the modification to be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which hydroxyl, amino or sulfhydryl groups are bonded to any group, which can be cleaved to form hydroxyl, amino or sulfhydryl groups when administered to a patient. Therefore, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide and benzoate / amide derivatives of hydroxyl, sulfhydryl and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl esters, ethyl esters, etc. can be used. Esters themselves can be active and / or can be hydrolyzed under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or its salt.

[1055] Pharmaceutical compositions, preparations and kits

[1056] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "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 preventively effective amount of the active ingredient.

[1057] The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or medium that does not destroy the pharmacological activity of the compound formulated together. The pharmaceutically acceptable carrier, adjuvant or medium that can be used in the composition of the present invention include, but are not limited to, ion exchangers, aluminum oxide, 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, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[1058] The present invention also includes a kit (e.g., a pharmaceutical package). The kit provided may include a compound of the invention, other therapeutic agents, and a first and second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispersible package or other suitable container) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.

[1059] Pharmaceutical composition provided by the invention can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration and intracranial injection or infusion technology.

[1060] Generally, an effective amount of the compounds provided herein is administered. The amount of the compound actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[1061] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice of a physician and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a specific condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[1062] The pharmaceutical compositions provided herein can also be administered over a long period of time ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may continue indefinitely, e.g., for the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, e.g., within a therapeutic window.

[1063] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by push injection, for example, in order to quickly increase the concentration of the compound in the blood to an effective level. The push dose depends on the target systemic level of the active component, for example, the intramuscular or subcutaneous push dose slowly releases the active component, and the push delivered directly to the vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the push dose can be first given, and then continuous infusion.

[1064] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired administration form.

[1065] For oral dosage, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosage modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.

[1066] In order to provide blood levels similar to those using an injectable dose, or lower blood levels than using an injectable dose, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[1067] From about 1 to about 120 hours, especially 24 to 96 hours, the injected dosage level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. In order to obtain sufficient steady state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be given. For a 40 to 80 kg human patient, the maximum total dose cannot exceed about 2 g / day.

[1068] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[1069] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, and the remainder is an injectable excipient, etc.

[1070] Typically, transdermal compositions are formulated as topical ointments or creams containing active ingredients. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as an ointment together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the invention.

[1071] The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.

[1072] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

[1073] The compounds of the invention may also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[1074] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. 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 consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, 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, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[1075] Indications

[1076] In another aspect, provided is the use of the compound of formula (I) disclosed in the present invention (including all individual embodiments and generic subsets disclosed herein) or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate as a medicine.

[1077] The compounds of the invention exhibit potent and selective BTK inhibition. For example, the compounds of the invention exhibit nanomolar potency against wild-type BTK and BTK kinases encoded by the BTK gene that include BTK kinase inhibitor resistance mutations (including, for example, BTK C481S, BTK T474I or BTK L528W).

[1078] In some embodiments, the compounds of the present invention selectively target BTK kinase. For example, relative to another kinase or non-kinase target, the compounds of the present invention can selectively target BTK kinase. In some embodiments, relative to one or more kinases in BRK, CSK, ERBB4, FYN, MEK1, MEK2, TEC, TXK, YES1, BMX, BLK, EGFR, ITK, SRC, JAK1, JAK2 and JAK3, the compounds of the present invention can selectively target BTK kinase. In other embodiments, relative to one or more kinases in TEC, EGFR and ITK, the compounds of the present invention can selectively target BTK kinase. In other embodiments, relative to one or more kinases in TEC and EGFR, the compounds of the present invention can selectively target BTK kinase.

[1079] In some embodiments, relative to another kinase, the compounds of the present invention exhibit at least 30 times selectivity for BTK kinase. For example, relative to another kinase, the compounds of the present invention exhibit at least 40 times selectivity for BTK kinase; at least 50 times selectivity; at least 60 times selectivity; at least 70 times selectivity; at least 80 times selectivity; at least 90 times selectivity; at least 100 times selectivity; at least 200 times selectivity; at least 300 times selectivity; at least 400 times selectivity; at least 500 times selectivity; at least 600 times selectivity; at least 700 times selectivity; at least 800 times selectivity; at least 900 times selectivity; or at least 1000 times selectivity. In some embodiments, relative to another kinase, the compounds of the present invention exhibit at least 100 times selectivity for BTK kinase. In some embodiments, the selectivity for BTK kinase relative to another kinase is measured in a cell assay (e.g., a cell assay provided herein).

[1080] In some embodiments, the compounds of the invention can be used to treat BTK kinase-mediated diseases with covalent BTK kinase inhibitor resistance mutations. In more specific embodiments, the covalent BTK kinase inhibitor resistance mutations are C481S, C481F, C481Y, C481R, C481T, C481G and C481W.

[1081] In some embodiments, the compounds of the invention can be used to treat BTK kinase-mediated diseases with non-covalent BTK kinase inhibitor resistance mutations. In more specific embodiments, the non-covalent BTK kinase inhibitor resistance mutations are V416L, A428D, M437R, T474I and L528W.

[1082] In some embodiments, the BTK kinase inhibitor resistance mutation is one or more point mutations in the BTK gene. In some embodiments, the one or more point mutations in the BTK gene result in the translation of a BTK protein having one or more amino acid substitutions at one or more of the following amino acid positions: 117, 316, 416, 428, 437, 474, 481, 528, 560, 562, and 601. In some embodiments, the one or more point mutations in the BTK gene result in the translation of a BTK protein having one or more of the following amino acid substitutions: T117P, T316A, V416L, A428D, M437R, T474I, T474M, T474S, C481S, C481F, C481T, C481G, C481R, L528W, P560L, R562W, R562G, and F601L.

[1083] The compounds of the invention are useful for treating diseases and conditions that are treated with BTK kinase inhibitors, such as diseases and conditions associated with BTK, such as proliferative diseases, such as cancer, including hematological cancers and solid tumors, and inflammatory conditions, immune diseases or fibrosis.

[1084] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a cancer associated with BTK) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a cancer associated with BTK) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a cancer associated with BTK) is a B cell malignancy. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a BTK-related cancer) is Hodgkin 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 lymphocytic 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 glioma.

[1085] In some embodiments, the hematological cancer is selected from leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma or myeloma, for example, acute lymphocytic 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 (AML), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), trilineage myeloproliferation Acute myeloid leukemia (AML / TMDs), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPDs), 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, precursor B-cell lymphoblastic leukemia, hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma. Other examples of hematological cancers include myelodysplastic disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer is mantle cell lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, or marginal zone lymphoma.

[1086] 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, head and neck cancer.

[1087] 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, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus syndrome, obsessive compulsive disorder, 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 and vulvar pain, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, colitis, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, inflammatory enteritis, suppurative inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis inflammation, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, graft-versus-host disease, transplantation, transfusion, anaphylactic reaction, allergic reaction, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[1088] 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, osteomyelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, lung disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

[1089] In some embodiments, the autoimmune disease is selected from lupus and Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren'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, hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.

[1090] In some embodiments, the heteroimmune disease is selected from the group consisting of graft versus host disease, transplantation, transfusion, anaphylaxis, allergic reaction, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[1091] In some embodiments, fibrosis is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., non-alcoholic steatohepatitis (NASH), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct damage, biliary fibrosis, cholestasis, or bile duct disease.

[1092] In the therapeutic method of the present invention, "effective amount" is intended to refer to an amount or dosage sufficient to produce the desired therapeutic benefit in an individual in need of the treatment. The effective amount or dosage of the compounds of this invention can be determined by conventional methods (e.g., modeling, dose escalation or clinical trials) and conventional factors (e.g., the mode or approach of drug delivery, the pharmacokinetics of the agent, the severity and process of infection, the health status and body weight of the individual, and the judgment of the treating physician). An exemplary dosage is in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dose can be single or separate dosage units (e.g., BID, TID, QID).

[1093] After the patient's disease improves, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or the frequency of administration or both can be reduced to the amount that maintains the desired treatment or preventive effect according to the symptoms. Of course, if the symptoms have been alleviated to an appropriate degree, the treatment can be stopped. However, when any symptom recurs, the patient may need long-term intermittent treatment. The patient may also need long-term slow treatment.

[1094] Drug combinations

[1095] The compounds of the present invention described herein may be used in combination with one or more other active ingredients in a pharmaceutical composition or method to treat the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of therapeutic agents on the intended disease target. The combination can be used to increase efficacy, improve other disease symptoms, reduce one or more negative effects, or reduce the required dose of the compounds of the present invention. Additional active ingredients may be formulated into a pharmaceutical composition separate from the compounds of the present invention or may be included in a single pharmaceutical composition with the compounds of the present invention. Additional active ingredients may be administered simultaneously with, before, or after the administration of the compounds of the present invention.

[1096] Combination agents include those additional active ingredients that are known or observed to be effective in treating the diseases and conditions described herein, including those that are effective against another target associated with the disease. For example, the compositions and formulations of the present invention, and the methods of treatment may further comprise other drugs or medicines, such as other active agents that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, other such agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the present invention may additionally comprise one or more of the active agents, and the methods of treatment may additionally comprise administering an effective amount of one or more of the active agents.

[1097] Example

[1098] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise indicated, parts and percentages are by weight and weight percentage.

[1099] Usually, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.

[1100] The abbreviations used herein have the following meanings:

[1101]

[1102]

[1103] Synthesis of related intermediate compounds

[1104] Preparation of Intermediate A-1 ((5-fluoro-2-methoxybenzoyl)amino)methyl potassium trifluoroborate

[1105]

[1106] The following synthetic route was used

[1107]

[1108] Step 1 Synthesis of compound 5-fluoro-2-methoxybenzoyl chloride

[1109] Add 5-fluoro-2-methoxybenzoic acid (26 g, 150 mmol) and anhydrous dichloromethane (300 mL) to a 100 mL three-necked flask equipped with a magnetic stirrer, stir until dissolved, cool in an ice-water bath, dropwise add oxalyl chloride (38 g, 300 mmol) and anhydrous N,N-dimethylformamide (1.1 g, 15 mmol) under a nitrogen atmosphere, remove the ice bath, stir and react at room temperature overnight. Evaporate the solvent and unreacted oxalyl chloride under reduced pressure for standby use.

[1110] Step 2 Synthesis of Intermediate A-1

[1111] Bromomethylboronic acid pinacol ester (36.3 g, 165 mmol) and anhydrous tetrahydrofuran (300 mL) were added to a 1000 mL three-necked flask equipped with a magnetic stirrer, cooled to -78 ° C under a nitrogen atmosphere, and a tetrahydrofuran solution (165 mL, 1 M) of potassium bis(trimethylsilyl)amide was added dropwise. The mixture was stirred for 30 minutes at room temperature and stirred for 30 minutes. Anhydrous methanol (21.1 g, 660 mmol) was added and stirred at room temperature for 1 hour. The insoluble solid was filtered out, and the filtrate solvent was evaporated at no more than 30 ° C. Anhydrous tetrahydrofuran (200 mL) was added to evaporate the solvent, and the reaction was repeated twice. The residue was dissolved in anhydrous tetrahydrofuran (200 mL), and a tetrahydrofuran solution (200 mL) of 5-fluoro-2-methoxybenzoyl chloride was slowly added dropwise. After the dropwise addition, the reaction was stirred at room temperature under a nitrogen atmosphere overnight. The solvent was evaporated, and the residue was dissolved in methanol (300 mL), and potassium bifluoride aqueous solution (64 g, 825 mmol, 200 mL) was added, and the reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and toluene (100 mL) was azeotropically refluxed to remove water twice, and the residue was washed with methyl tert-butyl ether, filtered, and the filter cake was washed with hot methanol / acetone (1 / 3, 1000 mL) solution. The filtrate was concentrated to dryness, methyl tert-butyl ether was added for pulping, solids were precipitated, filtered, and the filter cake was dried to obtain 31 g of white solids, with a yield of 70.7%. 1 H NMR (400 MHz, DMSO-D 6 )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).

[1112] Preparation of Intermediate A-2(Z)-3-amino-3-(4-bromophenyl)acrylonitrile

[1113]

[1114] The following synthetic route was used

[1115]

[1116] Add 4-bromobenzonitrile (50 g, 274.7 mmol) and anhydrous tetrahydrofuran (500 mL) to a 1000 mL three-necked flask equipped with a magnetic stirrer, stir to dissolve, evacuate and replace with nitrogen 3 times, lower the temperature to -78 ° C, add lithium diisopropylamide (206 mL, 412.0 mmol) dropwise, react at -78 ° C for 4 hours, add anhydrous acetonitrile (17.3 g, 412.0 mmL), and stir at room temperature under nitrogen atmosphere for 12 hours. Add water (500 mL) to quench the reaction, extract with ethyl acetate (500 mL × 2), combine the organic phases, wash with saturated brine (500 mL), dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 42.6 g of a white solid with a yield of 70.0%. LC-MS (APCI): m / z = 223.0 (M+1) + .

[1117] Intermediate A-3 2-(4-bromophenyl)-4-oxo-6-(1,1,1-trifluoropropan-2-yl)-1,4-dihydropyridine-3-carbonitrile Preparation

[1118]

[1119] The following synthetic route was used

[1120]

[1121] Step 1 Synthesis of compound 5,5,5-trifluoro-4-methyl-3-oxopentanoic acid ethyl ester

[1122] Add N, N'-carbonyldiimidazole (68.5g, 422.3mmol), anhydrous tetrahydrofuran (600mL) and 3,3,3-trifluoro-2-methylpropionic acid (50g, 351.9mmol) to a 1000mL three-necked flask equipped with a magnetic stirrer, stir to dissolve, stir and react at room temperature for 4 hours under a nitrogen atmosphere, add anhydrous magnesium chloride (33.5g, 351.9mmol) and potassium 3-ethoxy-3-oxopropanoate (89.8g, 527.8mmol), stir and react at room temperature for 12 hours under a nitrogen atmosphere. Add hydrochloric acid (1M) dropwise to the reaction solution to adjust the pH to about 3, extract with ethyl acetate (500mL×2), combine the organic phases, wash with saturated brine (500mL), dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 44.8g of a white solid with a yield of 60.0%. LC-MS (APCI): m / z = 213.0 (M+1) + .

[1123] Step 2 Synthesis of Intermediate A-3

[1124] Add intermediate A-2 (42.6 g, 200.9 mmol), ethyl 5,5,5-trifluoro-4-methyl-3-oxopentanoate (22.3 g, 100.4 mmol) and N-methylpyrrolidone (60 mL) to a 500 mL three-necked flask equipped with a magnetic stirrer, stir and react at 250 ° C for 1 hour under a nitrogen atmosphere, cool to room temperature, add water (200 mL) and ethyl acetate (200 mL×2) for extraction, combine the organic phases, wash with saturated brine (500 mL), dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 14.9 g of a white solid, with a yield of 40.0%. LC-MS (APCI): m / z=371.0 (M+1) + .

[1125] Preparation of intermediate A-4 (4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)boronic acid

[1126]

[1127] The following synthetic route was used

[1128]

[1129] To a 500mL single-necked flask equipped with a magnetic stirrer and a condenser, add tetrahydrofuran (120mL), 4-aminomethylphenylborate hydrochloride (12g, 64.1mmol) and 5-fluoro-2-methoxybenzoic acid (10.9g, 64.1mmol), stir to dissolve, add 1-propylphosphoric anhydride in ethyl acetate (75.5mL, 128.3mmol, 1.7M) and N,N-diisopropylethylamine (33g, 256mmol) while stirring, evacuate and replace with nitrogen three times, heat to 70°C, and stir and react overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and water (120 mL) and dichloromethane (200 mL) were added to separate the organic phase. The aqueous phase was extracted with dichloromethane (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and dichloromethane (100 mL) was added. The mixture was stirred for 60 minutes and filtered. The filter cake was washed with a small amount of dichloromethane and then dried with a vacuum pump to obtain 17.6 g of a white solid with a yield of 90.7%.

[1130] Preparation of Intermediate A-5 4-(Benzyloxy)-2-chloronicotinonitrile

[1131]

[1132] The following synthetic route was used

[1133]

[1134] In an ice-water bath, add 2,4-dichloronicotinonitrile (21.7g, 125.4mmol), benzyl alcohol (13.55g, 125.4mmol) and anhydrous tetrahydrofuran (200mL) to a 1L three-necked flask equipped with a magnetic stirrer, protect with nitrogen, stir and dissolve evenly, slowly add sodium hydride (6g, 150mmol, 60%, 0.5g each time) in batches, and add it all in 30 minutes. After the addition, react in an ice-water bath for 30 minutes, remove the ice-water bath and continue to react for 1 hour. Add water (100mL) to quench the reaction, remove tetrahydrofuran by rotary evaporation, and a large amount of solid precipitates in the system. Filter and wash the filter cake with water. Dissolve the washed solid with dichloromethane (200mL), wash with water (100mL), wash with saturated brine (100mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 28.1g of light yellow oil. Ethyl acetate (50 mL) was added under stirring, and the mixture was heated in an oil bath to dissolve, and petroleum ether (120 mL) was slowly added. The temperature was slowly cooled to room temperature, and a large amount of white solid precipitated from the system. The filter cake was filtered and washed with petroleum ether and dried in vacuo to obtain 22.1 g of white solid, with a yield of 72%. LC-MS (APCI): m / z = 245.0 (M+1) + .

[1135] Preparation of Intermediate A-6 2-bromo-6-fluoro-4-(1-trifluoromethyl-vinyl)benzonitrile

[1136]

[1137] The following synthetic route was used

[1138]

[1139] Step 1 Synthesis of compound 2-fluoro-4-(1-trifluoromethyl-vinyl)benzonitrile

[1140] 4-Bromo-2-fluorobenzonitrile (5g, 25mmol), ethylene glycol dimethyl ether (100mL), 1-(trifluoromethyl)ethylene boric acid hexyl ester (8.325g, 37.5mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (910mg, 1.25mmol), cesium carbonate (24.4g, 75mmol) and water (25mL) were added to the container, replaced with nitrogen three times, and heated to 110°C for overnight reaction. The reaction solution was cooled to room temperature, water (100mL) was added, and extracted with ethyl acetate (150mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column to obtain 4.5g of light yellow oil, with a yield of 83%. 1 H NMR (400 MHz, DMSO-D 6)δ(ppm):8.05-8.01(t,J=8.0Hz,1H),7.70(d,J=10.8Hz,1H),7.52(d,J=8.0Hz,1H),6.42(t,J=2.8Hz,1H),6.33(s,1H).

[1141] Step 2 Synthesis of Intermediate A-6

[1142] Add 2-fluoro-4-(1-trifluoromethyl-vinyl)benzonitrile (4.5g, 20.93mmol), p-toluenesulfonic acid monohydrate (4.38g, 23.02mmol), N-bromosuccinimide (4.1g, 23.02mmol), palladium acetate (235mg, 1.05mmol) and 1,2-dichloroethane (80mL) to the container, and heat to 70°C to react overnight. The reaction solution was cooled to room temperature, water (100mL) was added, and extracted with ethyl acetate (200mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column to obtain 2.0g of light yellow solid, with a yield of 32%. LC-MS (APCI): m / z=294.0 (M+1) + .

[1143] Preparation of Intermediate A-7 2-(4-bromophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile

[1144]

[1145] The following synthetic route was used

[1146]

[1147] Add diethyl malonate (2.16 g, 13.5 mmol), intermediate A-2 (2.0 g, 9 mmol) and N-methylpyrrolidone (10 mL) to a 20 mL microwave tube equipped with magnetic stirring, seal, microwave heat to 250 ° C for 10 minutes, and repeat the reaction twice. The reaction solution was cooled to room temperature, saturated brine (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 2) was used for extraction. The organic phases were combined, concentrated and passed through a silica gel column to obtain 2.0 g of a white solid with a yield of 25.9%. LC-MS (APCI): m / z = 291.0 (M+1) + .

[1148] Intermediate A-8 3-(3-amino-4-(4-bromophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic Preparation of benzyl ester

[1149]

[1150] The following synthetic route was used

[1151]

[1152] Step 1 Synthesis of compound 3-(3-ethoxy-3-oxopropionyl)piperidine-1-carboxylic acid benzyl ester

[1153] 1-((Benzyloxy)carbonyl)piperidine-3-carboxylic acid (5 g, 19.0 mmol) and tetrahydrofuran (75 mL) were added to a 250 mL three-necked flask equipped with a magnetic stirrer, stirred to dissolve, N,N'-carbonyldiimidazole (3.70 g, 22.8 mmol) was added, stirred at room temperature for 4 hours under a nitrogen atmosphere, magnesium chloride (1.81 g, 19.0 mmol) and potassium 3-ethoxy-3-oxopropanoate (4.85 g, 28.5 mmol) were added, and stirred at room temperature for 12 hours under a nitrogen atmosphere. 1M hydrochloric acid was added to adjust the pH to about 3, and ethyl acetate (50 mL × 2) was used for extraction. 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 obtain 4.56 g of a white solid with a yield of 72.0%. LC-MS (APCI): m / z = 334.0 (M+1) + .

[1154] Step 2 Synthesis of compound 3-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)piperidine-1-carboxylic acid benzyl ester

[1155] 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylic acid benzyl ester (4.5 g, 13.51 mmol), intermediate A-2 (1 g, 4.504 mmol) and N-methylpyrrolidone (5 mL) were added to a 20 mL microwave tube, stirred at 250 ° C for 1 hour under a nitrogen atmosphere, and water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 2) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 1.03 g of a white solid, with a yield of 46.6%. LC-MS (APCI): m / z = 492.0 (M+1) + .

[1156] Step 3 Synthesis of compound 3-(6-(4-bromophenyl)-4-chloro-5-cyanopyridin-2-yl)piperidine-1-carboxylic acid benzyl ester

[1157] 3-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)piperidine-1-carboxylic acid benzyl ester (1.03 g, 2.098 mmol) and phosphorus oxychloride (5 mL) were added to a 25 mL single-mouth bottle equipped with a magnetic stirrer and a condenser, and the mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. A saturated aqueous sodium bicarbonate solution was added under ice-water cooling to adjust the pH to about 9, and the mixture was extracted with ethyl acetate (50 mL×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 obtain 573 mg of a white solid with a yield of 53.6%. LC-MS (APCI): m / z=510.0 (M+1) + .

[1158] Step 4 Synthesis of Intermediate A-8

[1159] 3-(6-(4-bromophenyl)-4-chloro-5-cyanopyridin-2-yl)piperidine-1-carboxylic acid benzyl ester (573 mg, 1.126 mmol), hydrazine hydrate (281.8 mg, 5.63 mmol) and N,N-dimethylformamide (3 mL) were added to a 25 mL sealed tube, and the mixture was stirred at 110°C for 1.5 hours under a nitrogen atmosphere. Under ice-water cooling, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to alkaline, and ethyl acetate (30 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 500 mg of a white solid, with a yield of 87.9%. LC-MS (APCI): m / z=506.0 (M+1) + .

[1160] Intermediate A-9 4-(3-amino-4-(4-bromophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-1-carboxylic acid Preparation of benzyl ester

[1161]

[1162] The following synthetic route was used

[1163]

[1164] Step 1 Synthesis of compound 4-(3-ethoxy-3-oxopropionyl)piperidine-1-carboxylic acid benzyl ester

[1165] 1-((Benzyloxy)carbonyl)piperidine-4-carboxylic acid (10 g, 38 mmol), anhydrous tetrahydrofuran (200 mL) and N,N'-carbonyldiimidazole (7.4 g, 45.6 mmol) were added to the container, the temperature was raised to 70°C for reaction for 1 hour, and after cooling to room temperature, potassium 3-ethoxy-3-oxopropanoate (5.93 g, 38 mmol) and anhydrous magnesium chloride (3.62 g, 38 mmol) were added, and the temperature was raised to 70°C for stirring and reaction overnight. After the reaction solution was cooled, 1N hydrochloric acid was added to quench, water (100 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (200 mL×3), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column to obtain 10.5 g of transparent oily liquid, with a yield of 82.1%. LC-MS (APCI): m / z=334.0 (M+1) + .

[1166] Step 2 Synthesis of compound 4-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)piperidine-1-carboxylic acid benzyl ester

[1167] 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylic acid benzyl ester (1.5 g, 4.5 mmol), intermediate A-2 (500 mg, 2.25 mmol) and N-methylpyrrolidone (15 mL) were added to the container and microwaved for 10 minutes at 250°C. The reaction solution was cooled to room temperature, water (100 mL) was added, and it was extracted with ethyl acetate (100 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column to obtain 700 mg of light brown solid, with a yield of 63%. LC-MS (APCI): m / z=494.1 (M+1) + .

[1168] Step 3 Synthesis of compound 4-(6-(4-bromophenyl)-4-chloro-5-cyanopyridin-2-yl)piperidine-1-carboxylic acid benzyl ester

[1169] 4-(6-(4-bromophenyl)-5-cyano-4-hydroxypyridin-2-yl)piperidine-1-carboxylic acid benzyl ester (3.9 g, 7.91 mmol) and phosphorus oxychloride (30 mL) were added to the container, heated to 80°C for 2 hours, the reaction solution was concentrated, quenched with warm water, the pH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate (200 mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel column to obtain 2.5 g of brown solid, with a yield of 61%. LC-MS (APCI): m / z=510.1 (M+1) + .

[1170] Step 4 Synthesis of intermediate A-9

[1171] Add 4-(6-(4-bromophenyl)-4-chloro-5-cyanopyridin-2-yl)piperidine-1-carboxylic acid benzyl ester (2.5 g, 4.9 mmol), N,N-dimethylformamide (25 mL) and hydrazine hydrate (1.25 g, 24.51 mmol) to the container, and heat to 110°C for 1.5 hours. Add water (100 mL) to the reaction solution for dilution, extract with ethyl acetate (150 mL×3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The residue is separated by silica gel column to obtain 1.5 g of light yellow solid, with a yield of 60%. LC-MS (APCI): m / z=506.0 (M+1) + .

[1172] Preparation of intermediate A-10 compound 6-bromo-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester Preparation

[1173]

[1174] The following synthetic route was used

[1175]

[1176] To a 500mL single-necked flask equipped with a magnetic stirrer and a condenser, 2-bromo-5-iodopyridine (15.0g, 53.2mmol), N-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester (18g, 18.5mmol), 1,4-dioxane (100mL) and water (25mL) were added in sequence, and the mixture was stirred to dissolve. Potassium phosphate tripotassium (22g, 133mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (3.8g, 5.32mmol) were added, and the mixture was evacuated and replaced with nitrogen three times. The temperature was slowly raised to 100°C under a nitrogen atmosphere, and the mixture was stirred and reacted for 12 hours. Cool to room temperature, filter out insoluble solids, wash with ethyl acetate (20 mL), evaporate the organic solvent under reduced pressure, add ethyl acetate (150 mL), separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness and pass through a silica gel column to obtain 15.1 g of white solid, with a yield of 83.8%. LC-MS (APCI): m / z=339.0 (M+1) + .

[1177] Preparation of Intermediate A-11 Compound 4-(6-bromopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

[1178]

[1179] The following synthetic route was used

[1180]

[1181] Into a 500mL three-necked flask equipped with a magnetic stirrer and a condenser, 1-(tert-butyloxycarbonyl)piperazine (20.00g, 106.38mmol), 2-bromo-5-iodopyridine (36.24g, 127.66mmol), tris(dibenzylideneacetone)dipalladium (2.43g, 2.66mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (3.08g, 5.32mmol), sodium tert-butoxide (30.64g, 319.14mmol) and toluene (200mL) were added in sequence, the mixture was evacuated and replaced with nitrogen three times, the mixture was dispersed with stirring, and the reaction was stirred at 60°C overnight. After cooling 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×2), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 30.50 g of a white solid, with a yield of 84.1%. LC-MS (APCI): m / z=342.1 (M+1) + .

[1182] Preparation of Intermediate A-12 Compound 4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[1183]

[1184] The following synthetic route was used

[1185]

[1186] Step 1 Synthesis of compound (6-bromopyridin-3-yl) methanesulfonic acid methyl ester

[1187] 6-bromo-3-hydroxymethylpyridine (5.0 g, 26.88 mmol), triethylamine (8.15 g, 80.64 mmol) and dichloromethane (60 mL) were added to the container in sequence, stirred until dissolved, and methylsulfonyl chloride (6.16 g, 53.76 mmol) was added dropwise under an ice-water bath. After the addition was completed, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (50 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was directly used in the next step.

[1188] Step 2 Synthesis of Intermediate A-12

[1189] Add the (6-bromopyridin-3-yl) methanesulfonic acid methyl ester (about 26.88mmol), acetonitrile (60mL), 1-(tert-butyloxycarbonyl)piperazine (3.22g, 32.26mmol) and N,N-diisopropylethylamine (10.4g, 80.64mmol) obtained in the previous step to the container in sequence, stir to dissolve, heat to 70°C, and stir to react for 2 hours. Cool to room temperature, evaporate the solvent under reduced pressure, add water (50mL) and ethyl acetate (50mL), stir for 2 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, concentrate, mix and pass through a column, and obtain 4.3g of white solid, with a yield of 45.1%. LC-MS (APCI): m / z=356.1 (M+1) + .

[1190] Preparation of Intermediate A-13 Compound 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[1191]

[1192] The following synthetic route was used

[1193]

[1194] N-tert-Butyloxycarbonyl-4-hydroxypiperidine (4.0 g, 20 mmol), triethylamine (4.0 g, 39.5 mmol) and dichloromethane (40 mL) were added to the container in sequence, cooled to 0°C in an ice bath, and methylsulfonyl chloride (3.0 g, 26.2 mmol) was added dropwise. After the addition was completed, the temperature was naturally raised to room temperature. The reaction was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane (100 mL×3), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and used directly in subsequent reactions.

[1195] Intermediate B-1 4-(4-bromophenyl)-6-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridine-3- Preparation of amines

[1196]

[1197] The following synthetic route was used

[1198]

[1199] Step 1 Synthesis of compound 2-(4-bromophenyl)-4-chloro-6-(1,1,1-trifluoropropan-2-yl)nicotinonitrile

[1200] Add intermediate A-3 (500 mg, 1.351 mmol) and phosphorus oxychloride (2 mL) to a 25 mL single-mouth bottle equipped with a magnetic stirrer and a condenser, stir and react at 90 ° C for 1 hour under a nitrogen atmosphere, cool to room temperature, add saturated sodium bicarbonate aqueous solution to adjust the pH to about 9, extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 311 mg of a white solid, with a yield of 60%. LC-MS (APCI): m / z = 389.0 (M+1) + .

[1201] Step 4 Synthesis of Intermediate B-1

[1202] 2-(4-bromophenyl)-4-chloro-6-(1,1,1-trifluoropropan-2-yl)nicotinonitrile (311 mg, 0.801 mmol), hydrazine hydrate (200.6 mg, 4.008 mmol) and N,N-dimethylformamide (3 mL) were added to a 25 mL sealed tube, stirred at 110°C for 1.5 hours under a nitrogen atmosphere, cooled to room temperature, added with saturated brine (10 mL), extracted with ethyl acetate (30 mL×2), combined organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 240 mg of a white solid, with a yield of 78%. LC-MS (APCI): m / z=385.0 (M+1) + .

[1203] Preparation of intermediate B-2N-(4-(3-cyano-4-hydroxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide Preparation

[1204]

[1205] The following synthetic route is adopted①

[1206]

[1207] Step 1 Synthesis of compound N-(4-(3-cyano-4-methoxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1208] 2-Chloro-4-methoxynicotinonitrile (5.0 g, 27.8 mmol), intermediate A-4 (11.0 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol), potassium carbonate (10.3 g, 74.6 mmol) and 1,4-dioxane (50 mL) were added to a 100 mL single-necked flask equipped with a magnetic stirrer and a condenser. The mixture was evacuated and replaced with nitrogen three times. The temperature was raised to 80 ° C under a nitrogen atmosphere and stirred for 12 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, filtered, concentrated and passed through a silica gel column to obtain 6.0 g of a white solid with a yield of 50.1%. LC-MS (APCI): m / z=392.14 (M+1) + .

[1209] Step 2 Synthesis of intermediate B-2

[1210] Add N-(4-(3-cyano-4-methoxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (6.0 g, 8.0 mmol) and N,N-dimethylformamide (60 mL) to a 250 mL single-necked flask equipped with a magnetic stirrer and a condenser, stir to dissolve, add p-toluenesulfonic acid (27.0 g, 69 mmol) and lithium chloride (6.5 g, 154 mmol), evacuate and replace with nitrogen 3 times, heat to 180 ° C, and react for 30 minutes. Cool to room temperature, pour the reaction solution into stirred ice water (400 mL), precipitate a large amount of white solid, filter, wash with ice water, dissolve the filter cake in dichloromethane (100 mL), dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 4.0 g of white solid, with a yield of 72%. LC-MS (APCI): m / z=378.12 (M+1) + . 1 H NMR (400 MHz, DMSO-D 6 )δ(ppm):12.39(s,1H),8.95(t,J=6.0Hz,1H),7.80(s,1H),7.68(d,J=8.0 Hz,2H),7.54-7.51(m,3H),7.38-7.33(m,1H),7.22-7.18(m,1H),6.35(br s, 1H), 4.86 (br s, 2H), 4.60 (d, J = 6.0Hz, 2H), 3.90 (s, 3H).

[1211] Or use the following synthetic route ②

[1212]

[1213] Step 1 Synthesis of compound N-(4-(4-(benzyloxy)-3-cyanopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1214] To a 500mL three-necked flask equipped with a magnetic stirrer and a condenser, add intermediate A-5 (9.76g, 40mmol), intermediate A-4 (14.5g, 48mmol), potassium carbonate (15.56g, 120mmol), tetrakis(triphenylphosphine)palladium (2.3g, 4mmol), 1,4-dioxane (200mL) and water (40mL) in sequence, and heat to 105°C for 4 hours under nitrogen protection. Cool to room temperature, add ethyl acetate (200mL) to the reaction solution to dilute, filter, wash the filter cake with ethyl acetate (30mL), wash the filtrate with saturated brine (60mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 21g of a light yellow oil. Ethyl acetate (50 mL) was added to the reaction solution under stirring, and the mixture was heated in an oil bath to dissolve. The mixture was slowly cooled to room temperature. A large amount of white solid was precipitated from the system. The filter cake was washed with ethyl acetate and dried in vacuo to obtain 12.4 g of a white solid with a yield of 66.4%. LC-MS (APCI): m / z=468.2 (M+1) + .

[1215] Step 2 Synthesis of intermediate B-2

[1216] N-(4-(4-(benzyloxy)-3-cyanopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (40 g, 85.65 mmol), methanol (300 mL), dichloromethane (200 mL) and palladium carbon (10%, 4 g) were added to a 1L three-necked flask equipped with a magnetic stirrer, and the hydrogen was replaced. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was collected. The filter cake was added to a reaction bottle, and N,N-dimethylformamide (100 mL) was added. The mixture was heated to 60°C and stirred for 4 hours. The mixture was filtered, and the filter cake was washed with N,N-dimethylformamide and then added to the reaction bottle again. N,N-dimethylformamide (100 mL) was added, and the mixture was heated to 60°C and stirred for 4 hours. The mixture was filtered, and the filter cake was washed with N,N-dimethylformamide. The filtrates were combined, and methanol, dichloromethane and a small amount of toluene were removed by rotary evaporation. Water (300 mL) was slowly added dropwise under stirring at 60° C. in an oil bath. The heating was stopped and the mixture was naturally cooled to room temperature. A large amount of off-white solid precipitated from the system. The mixture was filtered, and the filter cake was washed with water and dried in vacuo to obtain 27 g of off-white solid with a yield of 83.6%. LC-MS (APCI): m / z=378.2 (M+1) + . 1 HNMR (400 MHz, DMSO-D 6)δ(ppm):12.36(s,1H),8.93(t,J=6.0Hz,1H),7.77-7.76(m,1H),7.65(d,J=8.0Hz,2H),7.53-7.49(m ,3H),7.36-7.31(m,1H),7.20-7.16(m,1H),6.31(d,J=8.0Hz,1H),4.58(d,J=6.4Hz,2H),3.89(s,3H).

[1217] Intermediate B-3N-(4-(3-amino-7-bromo-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methyl Oxybenzoyl Preparation of amides

[1218]

[1219] The following synthetic route was used

[1220]

[1221] Step 1 Synthesis of compound N-(4-(5-bromo-3-cyano-4-hydroxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1222] Add intermediate B-2 (4.0 g, 10.6 mmol, synthesized by route ①) and N,N-dimethylformamide (20 mL) to a 250 mL single-necked flask equipped with a magnetic stirrer, stir to dissolve, add N-bromosuccinimide (2.5 g, 14 mmol), stir at room temperature under nitrogen atmosphere and react overnight. Pour the reaction solution into stirred ice water (200 mL), a large amount of white solid precipitates, filter, wash with ice water, dissolve the filter cake in dichloromethane (100 mL), dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 3.0 g of white solid, with a yield of 70%. LC-MS (APCI): m / z=457.03 (M+2) + . 1 H NMR (400 MHz, DMSO-D 6 )δ(ppm):12.90(s,1H),8.94(t,J=6.0Hz,1H),8.37(s,1H),7.66(d,J=8.4Hz,2H),7.54 -7.49(m,3H),7.37-7.32(m,1H),7.21-7.18(m,1H),4.59(d,J=6.0Hz,2H),3.91(s,3H).

[1223] Step 2 Synthesis of compound N-(4-(5-bromo-4-chloro-3-cyanopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1224] N-(4-(5-bromo-3-cyano-4-hydroxypyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (3.0 g, 6.6 mmol) and phosphorus oxychloride (20 mL) were added to a 100 mL single-necked flask equipped with a magnetic stirrer, and the mixture was evacuated and replaced with nitrogen three times. The mixture was heated to 90°C and stirred overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and a saturated aqueous sodium bicarbonate solution (80 mL) was carefully added under stirring. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×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 obtain 2.0 g of a white solid with a yield of 65%. LC-MS (APCI): m / z=474.99 (M+1) + .

[1225] Step 3 Synthesis of intermediate B-3

[1226] Add N-(4-(5-bromo-4-chloro-3-cyanopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (2.0 g, 4.2 mmol) and N,N-dimethylformamide (20 mL) to a 100 mL single-necked flask equipped with a magnetic stirrer, stir to dissolve, add hydrazine hydrate (2.1 g, 42 mmol, 80%), heat to 110°C, and stir to react for 2 hours. Cool to room temperature, add saturated brine (80 mL), separate the organic phase, extract the aqueous phase with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 1.5 g of a white solid, with a yield of 55%. LC-MS (APCI): m / z=471.05 (M+2) + . 1 H NMR (400 MHz, DMSO-D 6 )δ(ppm):12.68(s,1H),8.87(t,J=6.0Hz,1H),8.37(s,1H),7.65(d,J=8.0 Hz,1H),7.53-7.48(m,3H),7.36-7.31(m,1H),7.20-7.17(m,1H),4.84(br s, 2H), 4.59 (d, J = 6.0Hz, 2H), 3.90 (s, 3H).

[1227] Intermediate B-4N-(4-(3-amino-7-iodo-1H-pyrazolo[4,3-c]pyridin-4-yl)benzyl)-5-fluoro-2-methyl Preparation of oxybenzamide

[1228]

[1229] The following synthetic route was used

[1230]

[1231] Step 1 Synthesis of compound N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1232] In a 500mL three-necked flask equipped with a magnetic stirrer, intermediate B-2 (20g, 53mmol, synthesized by route ②) and acetonitrile (300mL) were added, and N-iodosuccinimide (14.4g, 48mmol) was added under stirring. Under nitrogen protection, the temperature was raised to 70°C for reaction for 4 hours while stirring, cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate and dried in vacuo at 80°C to obtain 20.5g of off-white solid with a yield of 76.9%. LC-MS (APCI): m / z=504.0 (M+1) + . 1 H NMR (400 MHz, DMSO-D 6 )δ(ppm):12.74(s,1H),8.93(t,J=6.0Hz,1H),8.38(s,1H),7.66(d,J=8.4Hz,2H),7.54 -7.49(m,3H),7.37-7.32(m,1H),7.21-7.18(m,1H),4.59(d,J=6.0Hz,2H),3.90(s,3H).

[1233] Step 2 Synthesis of compound N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide

[1234] N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (7g, 13.9mmol) and phosphorus oxychloride (21mL) were added to a 100mL single-necked flask equipped with a magnetic stirrer and a condenser. The temperature was raised to 80°C during stirring, and the reaction was carried out for 4 hours. The system gradually became clear. Most of the phosphorus oxychloride was removed by rotary evaporation, ethyl acetate (70mL) was added, and the mixture was stirred until it was completely dissolved. The mixture was cooled to 5°C in an ice-water bath, and ice water (50mL) was slowly added. The mixture was stirred for 10 minutes, and the mixture was separated. The aqueous phase was adjusted to a pH of about 11 with a 4% sodium hydroxide solution, and extracted with ethyl acetate (50mL). The organic phases were combined, and the pH was adjusted to about 9 with a saturated sodium bicarbonate solution. The organic phases were separated, and the organic phases were washed with a saturated sodium bicarbonate solution (50mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 6.0g of a white solid with a yield of 82.7%. LC-MS (APCI): m / z = 522.0 (M+1) + .

[1235] Step 3 Synthesis of intermediate B-4

[1236] Add N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)benzyl)-5-fluoro-2-methoxybenzamide (6g, 11.5mmol) and N,N-dimethylformamide (30mL) to a 100mL single-necked flask equipped with a magnetic stirrer and a condenser, stir to dissolve, add hydrazine hydrate (5g, 50mmol, 50%), heat to 80°C while stirring, and react for 2 hours. Pour the reaction mixture into water (60mL), extract with dichloromethane (30mL×3), combine the organic phases, wash with water (30mL×3), wash with saturated brine (30mL) in turn, dry with anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to obtain 2.88g of a yellow solid, with a yield of 48.4%. LC-MS (APCI): m / z=518.1(M+1) + . 1 H NMR (400 MHz, DMSO-D 6 )δ(ppm):12.64(s,1H),8.88(t,J=6.0Hz,1H),8.37(s,1H),7.65(d,J=8.0 Hz,1H),7.53-7.48(m,3H),7.36-7.31(m,1H),7.20-7.17(m,1H),4.84(br s, 2H), 4.59 (d, J = 6.0Hz, 2H), 3.91 (s, 3H).

[1237] Intermediate B-5N-(4-(3-amino-7-iodo-1H-pyrazolo[4,3-c]pyridin-4-yl)-3-fluorobenzyl)-5-fluoro- Preparation of 2-methoxybenzamide

[1238]

[1239] The following synthetic route was used

[1240]

[1241] Step 1 Synthesis of compound N-(4-bromo-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide

[1242] 3-Fluoro-4-bromobenzylamine hydrochloride (5.0 g, 20.8 mmol), 3-fluoro-6-methoxybenzoic acid (4.2 g, 24.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.2 g, 20.97 mmol), 1-hydroxybenzotriazole (3.65 g, 20.97 mmol) and dichloromethane (50 mL) were added to a 50 mL single-necked flask equipped with a magnetic stirrer, and the mixture was evacuated and nitrogen was added. The gas was replaced 3 times, stirred evenly in an ice bath, N,N-diisopropylethylamine (9.0 mL, 62.25 mmol) was added dropwise, stirred and reacted at room temperature overnight, cooled to room temperature, saturated brine (50 mL) was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL × 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 obtain 6.6 g of a white solid, with a yield of 89.9%. LC-MS (APCI): m / z = 356.0 (M+1) + .

[1243] Step 2 Synthesis of compound 5-fluoro-N-(3-fluoro-4-boric acid pinacol ester benzyl)-2-methoxybenzamide

[1244] To a 250 mL three-necked flask equipped with a magnetic stirrer and a condenser, N-(4-bromo-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide (5.0 g, 14.08 mmol), bipyraclostrobin (5.0 g, 19.69 mmol), dichloromethane [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.14 g, 1.4 mmol), potassium acetate (4.1 g, 42.2 mmol), 1,4-dioxane (40 mL) and N,N-dimethylformamide (10 mL) were added. The mixture was evacuated and replaced with nitrogen three times. The reaction was stirred at 100°C overnight. After cooling to room temperature, saturated brine (30 mL) was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (40 mL × 2), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 5.6 g of a white solid, with a yield of 98.7%. LC-MS (APCI): m / z = 404.0 (M+1) + .

[1245] Step 3 Synthesis of compound N-(4-(4-(benzyloxy)-3-cyanopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide

[1246] 5-Fluoro-N-(3-fluoro-4-boronic acid pinacol benzyl ester)-2-methoxybenzamide (3.0 g, 7.44 mmol), intermediate A-5 (2.18 g, 8.93 mmol), tetrakis(triphenylphosphine)palladium (859.9 mg, 0.744 mmol), sodium carbonate (2.37 g, 22.32 mmol), 1,4-dioxane (30 mL) and water (7 mL) were added to a 100 mL three-necked flask equipped with a magnetic stirrer and a condenser, and the mixture was evacuated and replaced with nitrogen three times, and stirred at 90°C for overnight reaction. After cooling to room temperature, saturated brine (30 mL) was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 2.17 g of a white solid with a yield of 60.1%. LC-MS (APCI): m / z = 486.0 (M+1) + .

[1247] Step 4 Synthesis of compound N-(4-(3-cyano-4-hydroxypyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide

[1248] N-(4-(4-(benzyloxy)-3-cyanopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide (2.1 g, 4.33 mmol), palladium carbon (5%, 210 mg) and methanol (30 mL) were added to a 100 mL single-necked flask equipped with a magnetic stirrer. The mixture was evacuated and replaced with hydrogen three times. The reaction was stirred at room temperature overnight. The filter cake was filtered and washed with methanol. The organic phases were combined and concentrated to obtain 1.7 g of a white solid with a yield of 99.4%. LC-MS (APCI): m / z=396.0 (M+1) + .

[1249] Step 5: Synthesis of compound N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide

[1250] In a 100 mL single-necked flask equipped with a magnetic stirrer, N-(4-(4-(benzyloxy)-3-cyanopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide (1.7 g, 4.3 mmol), N-iodosuccinimide (1.1 g, 4.84 mmol) and acetonitrile (40 mL) were added in sequence, and the mixture was evacuated and replaced with hydrogen for 3 times. The mixture was stirred at 60°C for overnight reaction. The mixture was filtered, washed with ethyl acetate, and the residue was collected and dried to obtain 1.55 g of a white solid with a yield of 69.2%. LC-MS (APCI): m / z=522.0 (M+1) + .

[1251] Step 6 Synthesis of compound N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide

[1252] N-(4-(3-cyano-4-hydroxy-5-iodopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide (1.7 g, 4.3 mmol) and phosphorus oxychloride (15 mL) were added to a 50 mL single-necked flask equipped with a magnetic stirrer, and the mixture was evacuated and replaced with hydrogen three times. The mixture was stirred at 90°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.07 g of a white solid with a yield of 66.73%. LC-MS (APCI): m / z=540.0 (M+1) + .

[1253] Step 7 Synthesis of Intermediate B-5

[1254] N-(4-(4-chloro-3-cyano-5-iodopyridin-2-yl)-3-fluorobenzyl)-5-fluoro-2-methoxybenzamide (500 mg, 0.93 mmol), hydrazine hydrate (0.15 mL, 0.79 mmol) and N,N-dimethylformamide (5 mL) were added to a 20 mL sealed tube equipped with magnetic stirring, sealed, and stirred at 110°C for 2 hours. After cooling to room temperature, saturated br...

Claims

1. A compound of formula (A), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof: in, Ring A is a benzene ring or a 5-6 membered heteroaromatic ring; X1 is N, CD or CH; X2 is N or CR2; R1 is H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O)2R b 、-S(O)2NR b R c 、-S(O)R a 、-S(O)2R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; R2 is H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'; R3 and R4 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 is optionally substituted with one or more D until fully deuterated; R5 is halogen; R6 is 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 until fully deuterated; R s and R t are independently H, D, halogen, -OR a 、-NR b R c , 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 until fully deuterated; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; Each R is independently: 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O)2R e 、-S(O)2NR e R f 、-S(O)R d 、-S(O)2R d 、-P(=O)R e R f 、-OP(=O)R e R f ; or 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O)2R e 、-S(O)2NR e R f 、-S(O)R d 、-S(O)2R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"; Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"; Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O)2R h 、-S(O)2NR h R j 、-S(O)R g 、-S(O)2R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"'; Each R'' is independently H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

2. A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof: in, X1 is N, CD or CH; X2 is N or CR2; R1 is H, D, halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-NR b R c 、-NR a C(O)R b 、-NR a C(O)OR b 、-NR a C(O)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)NR b R c 、-NR a S(O)2R b 、-S(O)2NR b R c 、-S(O)R a 、-S(O)2R a 、-P(=O)R b R c 、-OP(=O)R b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; Each R a , R b and R c Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R b and R c Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; R2 is H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'; R3 and R4 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 is optionally substituted with one or more D until fully deuterated; R5 is halogen; R6 is 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 until fully deuterated; 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 is optionally substituted with one or more D until fully deuterated; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; Each R is independently: 1) H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O)2R e 、-S(O)2NR e R f 、-S(O)R d 、-S(O)2R d 、-P(=O)R e R f 、-OP(=O)R e R f ; or 2) C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; or 3) Two R on the same atom or on two adjacent atoms together with the atoms they are connected to form C 3-6 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R"; Each R' is independently H, D, halogen, oxo, -C(O)R d 、-C(O)OR d 、-C(O)NR e R f 、-NR e R f 、-NR d C(O)R e 、-NR d C(O)OR e 、-NR d C(O)NR e R f 、-OR d 、-OC(O)R d 、-OC(O)NR e R f 、-NR d S(O)2R e 、-S(O)2NR e R f 、-S(O)R d 、-S(O)2R d 、-P(=O)R e R f 、-OP(=O)R e R f , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R's on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"; Each R d , R e and R f Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R e and R f Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R"; Each R" is independently H, D, halogen, oxo, -C(O)R g 、-C(O)OR g 、-C(O)NR h R j 、-NR h R j 、-NR g C(O)R h 、-NR g C(O)OR h 、-NR g C(O)NR h R j 、-OR g 、-OC(O)R g 、-OC(O)NR h R j 、-NR g S(O)2R h 、-S(O)2NR h R j 、-S(O)R g 、-S(O)2R g 、-P(=O)R h R j 、-OP(=O)R h R j , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or two R" on the same atom or on two adjacent atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D until fully deuterated; Each R g , R h and R j Independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R h and R j Together with the atoms to which they are attached, they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more D, up to full deuteration.

3. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is H, D, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R; Preferably, R1 is H, D, wherein the above groups are optionally substituted by one or more R; Preferably, R1 is wherein the above groups are optionally substituted by one or more R; Preferably, R1 is wherein the above groups are optionally substituted by one or more R; Preferably, R1 is H.

4. The compound of any one of claims 1 to 3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-7 membered monocyclic heterocyclic group, 6-12 membered fused bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with one or more R'; Preferably, R2 is H, D, halogen, methyl, -CHF2, ethyl, isopropyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Preferably, R2 is H, D, halogen, methyl, -CHF2, ethyl, isopropyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Preferably, R2 is H, D, methyl, -CHF2, wherein the above groups are optionally substituted by one or more D until fully deuterated; Preferably, R2 is H, D, -CHF2 or wherein the above groups are optionally substituted by one or more D until fully deuterated; Preferably, R2 is H or D; Preferably, R2 is -CHF2 or wherein the above groups are optionally substituted by one or more D until fully deuterated; Preferably, R2 is The above groups are optionally substituted by one or more Ds, up to complete deuteration.

5. The compound of any one of claims 1 to 4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R5 is F.

6. The compound of any one of claims 1 to 5, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R6 is methyl or -CD3.

7. A compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents.

9. Use of a compound according to any one of claims 1 to 7, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease mediated by wild-type and / or mutant BTK kinase; preferably, the mutant BTK kinase is selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G or BTK C481W; preferably, the mutant BTK kinase is BTK C481S; preferably, the mutant BTK kinase is BTK V416L, BTK A428D, BTK M437R, BTK T474I or BTK L528W; preferably, the mutant BTK kinase is BTK T474I or BTK L528W.

10. The use of claim 9, wherein the BTK-mediated disease is selected from the group consisting of an allergic disease, an autoimmune disease, an inflammatory disease or cancer.

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