Heteroaryl compound, preparation method thereof and application of heteroaryl compound in medicine

Abstract

The invention relates to a heteroaryl compound, a preparation method thereof and application of the heteroaryl compound in medicine. Specifically, the invention relates to a heteroaryl compound as shown in a general formula (I), a preparation method of the heteroaryl compound, a pharmaceutical composition containing the heteroaryl compound and application of the heteroaryl compound as a therapeutic agent, especially application of the heteroaryl compound as a Bruton's tyrosine kinase (BTK) inhibitor and application of the heteroaryl compound in treatment and / or prevention of various diseases related to excessive BTK activity. Including cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection and metabolic / endocrine dysfunction and neurological disorders. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to inhibitors of Bruton's tyrosine kinase (BTK) (including wild-type and mutant BTK), which are used for treating and / or preventing BTK-related diseases or disorders, such as cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection reactions, and metabolic / endocrine dysfunctions and neurological disorders. Background Art

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase of the TEC family. Its protein structure contains an N-terminal pleckstrin homology (PH) domain, a TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, and a kinase domain with enzymatic activity (Hendriks RW et al., Nat Rev Cancer. 2014, 14:219-232). Its PH domain recruits BTK to the cell membrane by interacting with phosphatidylinositol-3,4,5-trisphosphate (PIP3) generated by phosphatidylinositol-3 kinase (PI3K). Transmembrane proteins (such as the B cell receptor (BCR) complex) promote phosphorylation of BTK at Y551 through SYK or SRC family kinases, resulting in BTK kinase activation and subsequent autophosphorylation of Y223 in its SH3 domain (Rawlings DJ et al., Science. 1996, 271:822-825). BTK is expressed in B lymphocytes and is essential at all stages of B lymphocyte development (Burger JA et al., Nat Rev Cancer. 2018, 18:148-167). BTK was initially shown to be mutated in human primary immunodeficiency X-linked agammaglobulinemia (XLA). XLA patients are characterized by a low number of B cells and little antibody in their circulation (Vetrie D, et al., Nature. 1993, 361:226–233; Tsukada S et al., Cell, 1993, 72:279–290). At an early stage of B cell bone marrow development, BTK promotes the differentiation of early B cells into mature B cells by regulating IL-7-induced proliferation of circulating early B cells and the transformation of resting early B cells, as well as the expression of immunoglobulin light chains (Rip, J. et al. Crit. Rev. Immunol. 2018, 38:17–62). BTK also regulates the negative selection of autoreactive immature B cells in the bone marrow. In the peripheral lymphatic system, BTK regulates the migration of B cells to follicles and the maturation, activation, and differentiation of B cells, memory B cells, and plasma cells (Torke, S. et al. Exp. Opin. Investig. Drugs 2020, 29, 1143–1150).

[0003] Although the function of BTK has been mainly studied in detail in BCR signal transduction, BTK has also been reported to play important functions in signal transduction mediated by toll-like receptors (TLRs), Fc receptors (FCRs), and chemokine receptors (Croford et al., Expert Rev Clin Immunol, 2016, 12:763-773). The IgE receptor FcεR on the surface of mast cells and basophils binds IgE. When the corresponding antigen cross-links IgE, it activates the intracellular ITAM-binding domain of FcεR to recruit downstream LYN and SYK kinases, thereby activating other kinases such as BTK, mediating the production of intracellular second messengers IP3 and DAG, promoting cell activation and degranulation, and simultaneously activating the expression of downstream transcription factors such as NFAT and AP-1 to express cytokines (Saitoh, S. et al., Immunity. 2000, 12, 525–535). In addition, BTK plays an important role in the signal transduction of IgG-specific Fc receptors (FcγRs) in macrophages and microglia, promoting the expression of inflammatory factors IL-1β, IL-6, and TNF (Di Paolo, J.A. et al., Nat. Chem. Biol. 2011, 7, 41–50).

[0004] BTK inhibitors have been developed for the purpose of treating cancers such as chronic lymphocytic leukemia (CLL). Several covalent BTK inhibitors have been clinically used for B-cell malignancies. In addition to B-cell lymphoma, the function of BTK in the immune system has also promoted the development of BTK inhibitors for autoimmune diseases and allergic diseases such as rheumatoid arthritis (RA), Sjogren’s Syndrome, Systemic lupus erythematosus, and Multiple sclerosis. So far, multiple compounds such as Evobrutinib, Tolebrutinib, and Fenebrutinib have been tested for their efficacy in clinical trials for multiple sclerosis and have obtained positive results. However, the problem of hepatotoxicity has led to the suspension of multiple drug clinical trials (Montalban X et al., 2019, N Engl J Med, 380(25):2406-17). Therefore, an object of the present disclosure is to provide a covalent binding inhibitor of BTK to explore its improvement in the problem of hepatotoxicity and improve safety for the treatment of autoimmune diseases.

[0005] The currently disclosed patent applications for BTK inhibitor compounds include WO2015079417A1, WO2021133894A1, WO2022094172A2, WO2022032019A1, CN115785098A, CN115785123A, CN114085207A, and CN115785097A, etc. Summary of the Invention

[0006] The object of the present disclosure is to provide a compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein:

[0009] Ring A is a heterocyclic group;

[0010] Ring B is a heteroaryl or a heterocyclic group;

[0011] Each R 1 and each R 2 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxy, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-OC(O)NR 18 R 19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-S(O) u R 17 、-S(O) u NR 18 R 19 、-NR 20 S(O) u R 17 、-(CR a R b )v cycloalkyl, -(CR a R b ) v heterocycloalkyl, -(CR a R b ) v aryl, -(CR a R b ) v heteroaryl, oxo, =S, =NR 21 and =CR 22 R 23 ; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted by one or more R 0 substituents;

[0012] Alternatively, two R 1 and the ring atoms to which they are attached together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted by one or more R 0 substituents;

[0013] Alternatively, two R 2 and the ring atoms to which they are attached together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted by one or more R 0 substituents;

[0014] R 3 is selected from a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl;

[0015] X 1 is CR 4a or N;

[0016] X 2 is CR 4b or N;

[0017] X 3 is CR 4c or N;

[0018] X 4 is CR 4d or N;

[0019] B 1 is CR 5a or N;

[0020] B 2 is CR 5b or N;

[0021] B 3 is CR5c or N;

[0022] R 4a , R 4b , R 4c , R 4d , R 5a , R 5b and R 5c are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxy group, a nitro group, -(CR a R b ) v OR 17 , -(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 , -C(O)NR 18 R 19 , -OC(O)NR 18 R 19 , -OC(O)R 17 , -OC(O)OR 17 , -NR 20 C(O)R 17 , -NR 20 C(O)OR 17 , -S(O) u R 17 , -S(O) u NR 18 R 19 , -NR 20 S(O) u R 17 , -(CR a R b ) v cycloalkyl, -(CR a R b ) v heterocyclic group, -(CR a R b ) v aryl and -(CR a R b ) v heteroaryl; wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 0 substituents;

[0023] Or R4b and R 4c together with the carbon atoms to which they are respectively attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted with one or more R 0 substituents;

[0024] Or R 4c and R 4d together with the carbon atoms to which they are respectively attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted with one or more R 0 substituents;

[0025] Or R 5a and R 5b together with the carbon atoms to which they are respectively attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted with one or more R 0 substituents;

[0026] Or R 5b and R 5c together with the carbon atoms to which they are respectively attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted with one or more R 0 substituents;

[0027] R 6 is selected from a hydrogen atom, -NHR 7 and -NHC(O)R 7 ;

[0028] R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxy group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a cycloalkylalkyl group and a heterocyclicalkyl group;

[0029] L is selected from CR 8 R 9 、C(O), O, NR 10 and S(O) u ;

[0030] R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group, a cyano group, an amino group, a cycloalkyl group and a cycloalkylalkyl group;

[0031] Or R 8 and R 9and, together with the attached carbon atom, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 substituents;

[0032] R 10 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxy group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, a cycloalkylalkyl group, and a heterocyclicalkyl group;

[0033] R 11 , R 12 , R 13 , R 14 , R x and R y are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group, a cyano group, an amino group, a nitro group, -(CR a R b ) v OR 17 , -(CR a R b ) v NR 18 R 19 , -(CR a R b ) v cycloalkyl, -(CR a R b ) v heterocyclic group, -(CR a R b ) v aryl, and -(CR a R b ) v heteroaryl; wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted by one or more R 0 substituents;

[0034] or any two of R 11 , R 12 , R 13 , R 14 , R x and R y together with the attached carbon atoms form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 substituents;

[0035] or R 11 and R 12 together form =O;

[0036] or R 13 and R 14 together form ═O;

[0037] or R on the same carbon atom x and R y together form ═O;

[0038] R 15 is selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclicalkyl group, an arylalkyl group, and a heteroarylalkyl group; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclicalkyl group, arylalkyl group, and heteroarylalkyl group are each independently optionally substituted by one or more R 0 substituents;

[0039] Alternatively, R 11 , R 12 , R 13 , R 14 , R x and R y any one of which together with R 15 and the atoms directly connected thereto forms a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 substituents;

[0040] W is selected from -C(O)R 16 , -S(O)2R 16 and -CN;

[0041] R 16 is selected from an alkenyl group, an alkynyl group, and an alkenyl oxide; wherein the alkenyl group, alkynyl group, and alkenyl oxide are each independently optionally substituted by a group selected from a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group, a cyano group, an amino group, a nitro group, -(CR a R b ) v OR 17 , -(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 , -C(O)NR 18 R 19 , -OC(O)R 17 , -OC(O)OR 17 , -NR 20 C(O)R 17 , -NR20 C(O)OR 17 、 -S(O) u R 17 、 -S(O) u NR 18 R 19 、 -NR 20 S(O) u R 17 、 -(CR a R b ) v cycloalkyl, -(CR a R b ) v heterocyclic group, -(CR a R b ) v aryl, -(CR a R b ) v heteroaryl, oxo group, =S, =NR 21 and =CR 22 R 23 and is substituted with one or more substituents selected from among;

[0042] R 0 is the same or different at each occurrence and is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxy, nitro, -(CR a R b ) v OR 17 、 -(CR a R b ) v NR 18 R 19 、 -C(O)R 17 、 -C(O)OR 17 、 -C(O)NR 18 R 19 、 -OC(O)NR 18 R 19 、 -OC(O)R 17 、 -OC(O)OR 17 、 -NR 20 C(O)R 17 、 -NR 20 C(O)OR 17 、 -S(O) u R 17 、 -S(O) u NR 18 R 19 、 -NR 20 S(O)u R 17 ,-(CR a R b ) v cycloalkyl,-(CR a R b ) v heterocyclic group,-(CR a R b ) v aryl,-(CR a R b ) v heteroaryl,oxo group,=S,=NR 21 and =CR 22 R 23 ;

[0043] R 17 、R 18 and R 19 are the same or different each time they appear and are each independently selected from a hydrogen atom,alkyl,alkenyl,alkynyl,-(CR a R b ) v cycloalkyl,-(CR a R b ) v heterocyclic group,-(CR a R b ) v aryl and -(CR a R b ) v heteroaryl;wherein the alkyl,alkenyl,alkynyl,cycloalkyl,heterocyclic group,aryl and heteroaryl are each independently optionally substituted by one or more R 01 substituents;

[0044] Or R 18 and R 19 together with the attached nitrogen atom form a nitrogen-containing heterocyclic group,which is optionally substituted by one or more R 01 substituents;

[0045] R 20 is the same or different each time it appears and is each independently selected from a hydrogen atom,alkyl,alkenyl,alkynyl,cycloalkyl,heterocyclic group,aryl,heteroaryl,haloalkyl,hydroxyalkyl,alkoxyalkyl,cycloalkylalkyl and heterocyclic alkyl;

[0046] R 21 is the same or different each time it appears and is each independently selected from a hydrogen atom,alkyl,alkenyl,alkynyl,cycloalkyl,heterocyclic group,aryl,heteroaryl,haloalkyl,hydroxyalkyl,alkoxyalkyl,cycloalkylalkyl,heterocyclic alkyl,hydroxy,alkoxy and haloalkoxy;

[0047] R 22 and R 23 are the same or different each time they appear, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkylalkyl group, a heterocyclicalkyl group, a hydroxy group, an alkoxy group, a haloalkoxy group, a cyano group, a C(O)alkyl group, and a C(O)Oalkyl group;

[0048] Alternatively, R 22 and R 23 together with the atoms to which they are attached form a cycloalkyl group or a heterocyclic group, and the cycloalkyl group or the heterocyclic group is optionally substituted with one or more R 01 substituents;

[0049] R 01 are the same or different each time they appear, and are each independently selected from an oxo group, =S, =NH, =N(OH), =C(halogen)2, =CH2, =CH(halogen), -S(alkyl), a halogen, a hydroxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, an amino group, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)halogen, -C(O)alkyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclic group, a heterocyclicalkyl group, a heterocyclicoxy group, an aryl group, an arylalkyl group, an aryloxy group, a heteroaryl group, a heteroarylalkyl group, and a heteroaryloxy group;

[0050] R a and R b are the same or different each time they appear, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group;

[0051] m1 is 0, 1, 2, 3, 4, 5, or 6;

[0052] m2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0053] n is 0, 1, 2, or 3;

[0054] u is 0, 1, or 2;

[0055] v is 0, 1, 2, or 3.

[0056] In some embodiments of the present disclosure, the compound of the general formula (I) or a pharmaceutically acceptable salt thereof is the compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] Wherein:

[0059] Ring D is a nitrogen-containing heterocyclic group;

[0060] p is 0, 1, 2 or 3;

[0061] Ring A, Ring B, R 1 -R 3 、m1, m2, X 1 、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、L, R 6 、R 11 、R 12 、R x 、R y 、n, W and R 0 are as defined in general formula (I).

[0062] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Wherein:

[0065] Ring A, Ring B, R 1 -R 3 、m1, m2, R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R x 、R y and n are as defined in general formula (I).

[0066] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein is selected from k is 0, 1, 2 or 3; m1 is 0, 1 or 2; m2 is 0, 1 or 2; m3 is 0, 1 or 2; Z is selected from N, CH and CR 2; a is 0, 1, 2 or 3; b is 1, 2, 3 or 4; R 1 and R 2 as defined in general formula (I); preferably, selected from

[0067] m1 is 0, 1 or 2; m2 is 0, 1 or 2; R 1 and R 2 as defined in general formula (I).

[0068] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein is k is 0, 1, 2 or 3; ring B, R 1 , R 2 , m1 and m2 are as defined in general formula (I); in some embodiments, is k is 0, 1, 2 or 3 (preferably, k is 0 or 1); Z is N or CR 2c ; R 2a , R 2b and R 2c are the same or different and each independently is a hydrogen atom or R 2 ; or, R 2a and R 2b together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 ; or, R 2a and R 2c together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 ; R 1 , R 2 and m1 are as defined in general formula (I).

[0069] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0070]

[0071] Wherein:

[0072] k is 0, 1, 2 or 3 (preferably, k is 0 or 1);

[0073] Z is N or CR 2c ;

[0074] R 2a , R 2b and R 2c are the same or different and are each independently a hydrogen atom or R 2 ;

[0075] Or, R 2a and R 2b Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 replace;

[0076] Or, R 2a and R 2c Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 replace;

[0077] R 1 、m1、R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , B 3 , R 6 , R 11 -R 16 , R x , R y and n are as defined in the general formula (I).

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1; in some embodiments, k is 0; in some embodiments, k is 1.

[0079] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein a is 1 or 2; in some embodiments, a is 1; in some embodiments, a is 2.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein b is 1 or 2; in some embodiments, b is 1.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein W is -C(O)R 16 ; R 16 is as defined in general formula (I); in some embodiments, W is -C(O)-CH=CH2.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein L is O.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein B 1 is N.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein B 2 is CR 5b ; R 5b is as defined in general formula (I); in some embodiments, B 2 is CH.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 5a is selected from a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 5a is a hydrogen atom.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 5b is selected from a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 5b is a hydrogen atom.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein B 1 is N; B 2 is CR 5b ; B 3 is CR 5c or N; R 5b and R 5c are as defined in general formula (I); in some embodiments, B 1 is N; B 2 is CH; B 3 is CH or N; in some embodiments, B 1 is N; B 2is CH; B 3 is N.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 4a ; X 2 is CR 4b ; X 3 is CR 4c ; X 4 is CR 4d ; R 4a , R 4b , R 4c and R 4d are as defined in general formula (I); in some embodiments, X 1 is CR 4a ; X 2 is CH; X 3 is CR 4c ; X 4 is CH; R 4a and R 4c are as defined in general formula (I); in some embodiments, X 1 is CR 4a ; R 4a is C 1-6 alkyl; X 2 is CH; X 3 is CR 4c ; R 4c is halogen; X 4 is CH; in some embodiments, X 1 is CR 4a ; R 4a is methyl; X 2 is CH; X 3 is CR 4c ; R 4c is F; X 4 is CH.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; X 2 is CR 4b ; X 3 is CR 4c ; X 4 is CR 4d ; R 4b , R 4c and R 4d are as defined in general formula (I); in some embodiments, X 1 is CR4a ; X 2 is N; X 3 is CR 4c ; X 4 is CR 4d ; R 4a , R 4c and R 4d as defined in general formula (I); in some embodiments, X 1 is CR 4a ; X 2 is N; X 3 is CR 4c ; X 4 is CR 4d ; R 4a , R 4c and R 4d are the same or different and each independently selected from a hydrogen atom, C 1-6 alkyl, halogen, and C 1-6 hydroxyalkyl; in some embodiments, X 1 is CR 4a ; X 2 is CR 4b ; X 3 is N; X 4 is CR 4d ; R 4a , R 4b and R 4d as defined in general formula (I); in some embodiments, X 1 is CR 4a ; X 2 is CR 4b ; X 3 is CR 4c ; X 4 is N; R 4a , R 4b and R 4c as defined in general formula (I); in some embodiments, X 1 is CR 4a ; X 2 is N; X 3 is CH; X 4 is CH; R 4a as defined in general formula (I) (preferably C 1-6 hydroxyalkyl, more preferably hydroxymethyl).

[0090] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heterocyclic group; in some embodiments, ring A is a 5-membered heterocyclic group; in some embodiments, ring A is a 6-membered heterocyclic group.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 14-membered heteroaryl group; in some embodiments, ring B is a 7- to 10-membered bicyclic heteroaryl group; in some embodiments, ring B is a 9- to 14-membered tricyclic heteroaryl group; in some embodiments, ring B is a 5- or 6-membered heteroaryl group; in some embodiments, ring B is a 5-membered heteroaryl group; in some embodiments, ring B is a pyrazolyl group or a pyrrolyl group; in some embodiments, ring B is an 8-membered bicyclic heteroaryl group; in some embodiments, ring B is a 10-membered tricyclic heteroaryl group.

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from ; a is 0, 1, 2 or 3; b is 1, 2, 3 or 4; Z is N or CH; in some embodiments, ring B is selected from

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered cycloalkyloxy group and cyano; in some embodiments, each R 1 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 1 is C 1-6 alkyl; in some embodiments, R 1 is methyl.

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein m1 is 0 or 1; in some embodiments, m1 is 0; in some embodiments, m1 is 1.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein each R 2 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyloxy and cyano; in some embodiments, each R 2 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 2 is C 1-6 alkyl or 3- to 6-membered cycloalkyl; in some embodiments, R 2 is methyl or cyclopropyl.

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (II), or a pharmaceutically acceptable salt thereof, wherein m2 is 0, 1 or 2; in some embodiments, m2 is 0; in some embodiments, m2 is 1; in some embodiments, m2 is 2.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (II), or a pharmaceutically acceptable salt thereof, wherein m3 is 0, 1 or 2; in some embodiments, m3 is 0.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are the same or different and are independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3- to 6-membered cycloalkyl; or R 2a and R 2b together with the atoms to which they are attached form a 4- to 8-membered cycloalkyl, the 4- to 8-membered cycloalkyl being optionally substituted with a group selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6Alkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl and C3-6 cycloalkyl; in some embodiments, R 2a and R 2b are the same or different and each independently selected from a hydrogen atom, C 1-6 alkyl and C3-6 cycloalkyl; in some embodiments, R 2a and R 2b are the same or different and each independently a hydrogen atom or C3-6 cycloalkyl; in some embodiments, R 2a and R 2b are the same or different and each independently a hydrogen atom or cyclopropyl; in some embodiments, R 2a and R 2b together with the atoms to which they are attached form a C4-8 cycloalkyl optionally substituted by one or more C 1-6 alkyl; in some embodiments, R 2a and R 2b together with the atoms to which they are attached form a cyclopentyl optionally substituted by one or more C 1-6 alkyl; in some embodiments, R 2a and R 2b together with the atoms to which they are attached form a 5 / 3 spirocycloalkyl optionally substituted by one or more C 1-6 alkyl.

[0099] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together with the atoms to which they are attached form m2 is 0, 1 or 2; m3 is 0, 1 or 2; a is 0, 1, 2 or 3; b is 1, 2, 3 or 4; R 2 is as defined in formula (I); in some embodiments, R 2a and R 2b together with the atoms to which they are attached form m2 is 0, 1 or 2; R 2 is as defined in formula (I); in some embodiments, R 2a and R 2b together with the atoms to which they are attached form m2 is 0, 1 or 2; R 2 is as defined in formula (I). In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein Z is N or CH.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2c is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 2c is a hydrogen atom.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 4a is C 1-6 alkyl or C 1-6 hydroxyalkyl; in some embodiments, R 4a is C 1-6 alkyl; in some embodiments, R 4a is methyl; in some embodiments, R 4a is C 1-6 hydroxyalkyl; in some embodiments, R 4a is hydroxymethyl.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4b is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 4b is a hydrogen atom.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4c is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 4cis a halogen; in some embodiments, R 4c is a hydrogen atom; in some embodiments, R 4c is F.

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4d is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 4d is a hydrogen atom.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 4c and R 4d are the same or different and are each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 4a is C 1-6 alkyl; R 4b is a hydrogen atom; R 4c is a halogen; R 4d is a hydrogen atom; in some embodiments, R 4a is methyl; R 4b is a hydrogen atom; R 4c is F; R 4d is a hydrogen atom.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a hydrogen atom, C 1-6 alkyl and cyclopropyl; in some embodiments, R 3 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 3 is a hydrogen atom.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5c is selected from a hydrogen atom, a halogen and C 1-6Alkyl; in some embodiments, R 5c is a hydrogen atom.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein B 3 is CH or N; in some embodiments, B 3 is N.

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 6 is -NHR 7 ; R 7 is as defined in the general formula (I); in some embodiments, R 6 is an amino group.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 7 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 7 is a hydrogen atom.

[0111] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; in some embodiments, n is 0.

[0112] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 11 , R 12 , R 13 and R 14 are the same or different and are each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 11 , R 12 , R 13 and R 14 are hydrogen atoms.

[0113] In some embodiments of the present disclosure, the compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are the same or different and each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, and a C 1-6 haloalkyl; in some embodiments, R 11 and R 12 are the same or different and each independently is a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 11 and R 12 are hydrogen atoms.

[0114] In some embodiments of the present disclosure, the compound of the general formula (I), general formula (II), or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 , and R 14 are hydrogen atoms; and / or n is 0.

[0115] In some embodiments of the present disclosure, the compound of the general formula (I), general formula (I-1), general formula (II), or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R x and R y are the same or different and each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl, and a C 1-6 haloalkyl; in some embodiments, R x and R y are the same or different and each independently is a hydrogen atom or a C 1-6 alkyl; in some embodiments, R x and R y are hydrogen atoms.

[0116] In some embodiments of the present disclosure, the compound of the general formula (I), general formula (II), or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 15 is selected from a hydrogen atom, a C 1-6 alkyl, and a 3- to 6-membered cycloalkyl; in some embodiments, R 15 is a C 1-6 alkyl or a 3- to 6-membered cycloalkyl; in some embodiments, R 15 is a C 1-6 alkyl; in some embodiments, R 15 is methyl or cyclopropyl; in some embodiments, R 15 is methyl; in some embodiments, R 15 is cyclopropyl.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein R 13 is a hydrogen atom; R 14 together with R 15 and the atoms respectively connected thereto form a 4- to 7-membered nitrogen-containing heterocyclic group; wherein the 4- to 7-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 ; R 0 is as defined in the general formula (I); in some embodiments, R 13 is a hydrogen atom; R 14 together with R 15 and the atoms respectively connected thereto form a 5-membered nitrogen-containing heterocyclic group; wherein the 5-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 ; R 0 is as defined in the general formula (I); in some embodiments, R 13 is a hydrogen atom; R 14 together with R 15 and the atoms respectively connected thereto form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted by one or more R 0 ; R 0 is as defined in the general formula (I); in some embodiments, R 13 is a hydrogen atom; R 14 together with R 15 and the atoms respectively connected thereto form a pyrrolidinyl group.

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 , R 14 , R x and R y are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl and a C 1-6 haloalkyl; R 15 is selected from a hydrogen atom, a C 1-6 alkyl and a 3- to 6-membered cycloalkyl; or, R 11 , R 12 , R x and R y are the same or different and are each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl and a C 1-6 haloalkyl; R 13 is a hydrogen atom; R 14 together with R 15and together with their respective attached atoms form a 4- to 7-membered nitrogen-containing heterocyclic group; wherein the 4- to 7-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 as defined in general formula (I); 0 In some embodiments, R

[0119] , R 11 , R 12 , R 13 , R 14 , R x and R y are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; R 15 is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group; or R 11 , R 12 , R x and R y are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; R 13 is a hydrogen atom; R 14 together with R 15 and their respective attached atoms form a 5-membered nitrogen-containing heterocyclic group; wherein the 5-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 as defined in general formula (I); 0 In some embodiments, R

[0120] , R 11 , R 12 , R 13 , R 14 , R x and R y are hydrogen atoms; R 15 is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group; or R 11 , R 12 , R x and R y are hydrogen atoms; R 13 is a hydrogen atom; R 14 together with R 15 and their respective attached atoms form a 5-membered nitrogen-containing heterocyclic group;

[0121] In some embodiments, R 11 , R 12 , R 13 , R 14 , R x and R y are hydrogen atoms; R 15 is a C 1-6 alkyl group; or R 11 , R12 , R x and R y is a hydrogen atom; R 13 is a hydrogen atom; R 14 and R 15 together with the atoms to which they are respectively attached form a pyrrolidinyl group.

[0122] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 16 is C 2-6 alkenyl; wherein the C 2-6 alkenyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and -NR 18 R 19 ; R 18 and R 19 are each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 16 is C 2-6 alkenyl; in some embodiments, R 16 is -CH=CH2.

[0123] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 0 is the same or different each time it appears, and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 0 is the same or different each time it appears, and is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.

[0124] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 01 is the same or different each time it appears, and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; in some embodiments, R 01The same or different at each occurrence, and each independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.

[0125] In some embodiments of the present disclosure, the compound of formula (I-1) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; in some embodiments, p is 0.

[0126] In some embodiments of the present disclosure, the compound of formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring D is a 4- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, ring D is a 5-membered nitrogen-containing heterocyclic group; in some embodiments, ring D is pyrrolidinyl.

[0127] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R 17 , R 18 , R 19 and R 20 The same or different at each occurrence, and each independently is a hydrogen atom or C 1-6 alkyl.

[0128] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R 21 is a hydrogen atom or C 1-6 alkyl.

[0129] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R 22 and R 23 The same or different at each occurrence, and each independently is a hydrogen atom or halogen.

[0130] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1; in some embodiments, v is 0.

[0131] In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein u is 0; in some embodiments, u is 1; in some embodiments, u is 2.

[0132] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or general formula (III), or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and each independently selected from a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R a and R b are hydrogen atoms.

[0133] In some embodiments of the present disclosure, the compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof, wherein, is selected from

[0134] m1 is 0 or 1; m2 is 0, 1 or 2; each R 1 is the same or different and each independently selected from a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 hydroxyalkyl; each R 2 is the same or different and each independently selected from a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and 3- to 6-membered cycloalkyl; R 3 is a hydrogen atom; R 4a is C 1-6 alkyl; R 4b is a hydrogen atom; R 4c is a halogen; R 4d is a hydrogen atom; B 3 is N; R 6 is an amino group; R 11 , R 12 , R 13 and R 14 are hydrogen atoms; n is 0; R 15 is C 1-6 alkyl; R 16 is -CH=CH2.

[0135] In some embodiments of the present disclosure, the compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, wherein, R 2a and R 2b are the same or different and each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6hydroxyalkyl and 3- to 6-membered cycloalkyl; or R 2a and R 2b together with the atoms to which they are attached form a 4- to 8-membered cycloalkyl, which 4- to 8-membered cycloalkyl is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3- to 6-membered cycloalkyl; k is 0 or 1; m1 is 0 or 1; each R 1 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl; Z is N or CH; R 3 is a hydrogen atom; R 4a is C 1-6 alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 is N; R 6 is amino; R 11 , R 12 , R 13 and R 14 are hydrogen atoms; n is 0; R 15 is C 1-6 alkyl; R 16 is -CH=CH2.

[0136] Exemplary compounds of the present disclosure include, but are not limited to:

[0137]

[0138] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (I-1), formula (II), formula (III) and those shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0139] The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II), formula (III) and those shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by BTK.

[0140] The present disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II), formula (III) and those shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a BTK inhibitor.

[0141] The present disclosure further relates to the use of the compounds of general formula (I), general formula (I-1), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for the treatment and / or prevention of a disease or disorder; the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection and metabolic / endocrine dysfunctions and neurological disorders; preferably, the disease or disorder is an autoimmune disease or an inflammatory disease;More preferably, the disease or disorder is selected from B cell malignancies, multiple myeloma, leukemia (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, and hairy cell leukemia), malignant lymphoma (such as small lymphocytic lymphoma, diffuse large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B cell non-Hodgkin lymphoma, B cell lymphoma, and follicular lymphoma), Waldenström macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenström macroglobulinemia, bone cancer, bone metastasis, arthritis (such as rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SOJIA)), multiple sclerosis (such as relapsing multiple sclerosis), amyotrophic lateral sclerosis, osteoporosis, diabetes (such as type I diabetes, type II diabetes), arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria (such as chronic spontaneous urticaria, chronic inducible urticaria, chronic autoimmune urticaria), liver insufficiency, allergy (such as atopic dermatitis, specific dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic diseases, myocardial infarction, angina, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, complications resulting from organ transplantation, foreign body transplantation, antibody-mediated rejection (AMR), graft-versus-host disease, B cell-mediated hyperacute, acute, and chronic transplant rejection; wherein the arthritis is preferably rheumatoid arthritis; wherein the diabetes is preferably type I diabetes; wherein the urticaria is preferably chronic autoimmune urticaria.;

[0142] The present disclosure further relates to a method of inhibiting BTK, which comprises administering to a patient in need a compound of general formula (I), general formula (I-1), general formula (II), general formula (III), and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0143] The present disclosure further relates to a method for treating and / or preventing a BTK-mediated disease or disorder, which comprises administering to a patient in need a compound of general formula (I), general formula (I-1), general formula (II), general formula (III), and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0144] The present disclosure further relates to a method for treating and / or preventing a disease or disorder, which comprises administering to a patient in need thereof a compound of general formula (I), general formula (I-1), general formula (II), general formula (III) and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection and metabolic / endocrine dysfunctions and neurological disorders; preferably, the disease or disorder is an autoimmune disease or an inflammatory disease;More preferably, the disease or disorder is selected from B cell malignancies, multiple myeloma, leukemia (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, and hairy cell leukemia), malignant lymphoma (such as small lymphocytic lymphoma, diffuse large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B cell non-Hodgkin lymphoma, B cell lymphoma, and follicular lymphoma), Waldenström macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstroem macroglobulinemia, bone cancer, bone metastasis, arthritis (such as rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SOJIA)), multiple sclerosis (such as relapsing multiple sclerosis), amyotrophic lateral sclerosis, osteoporosis, diabetes (such as type I diabetes, type II diabetes), arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria (such as chronic spontaneous urticaria, chronic inducible urticaria, chronic autoimmune urticaria), liver insufficiency, allergy (such as atopic dermatitis, specific dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic diseases, myocardial infarction, angina, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, complications due to organ transplantation, foreign body transplantation, antibody-mediated rejection (AMR), graft-versus-host disease, B cell-mediated hyperacute, acute, and chronic transplant rejection; wherein the arthritis is preferably rheumatoid arthritis; wherein the diabetes is preferably type I diabetes; wherein the urticaria is preferably chronic autoimmune urticaria.;

[0145] The present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (III), and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0146] The present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (III), and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a BTK inhibitor.

[0147] The present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (III), and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing a disease or disorder mediated by BTK.

[0148] The present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (III) and those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing a disease or disorder; the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection and metabolic / endocrine dysfunctions and neurological disorders; preferably, the disease or disorder is an autoimmune disease or an inflammatory disease;More preferably, the disease or disorder is selected from B cell malignancies, multiple myeloma, leukemia (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, and hairy cell leukemia), malignant lymphoma (such as small lymphocytic lymphoma, diffuse large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B cell non-Hodgkin lymphoma, B cell lymphoma, and follicular lymphoma), Waldenström macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstroem macroglobulinemia, bone cancer, bone metastasis, arthritis (such as rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA)), multiple sclerosis (such as relapsing multiple sclerosis), amyotrophic lateral sclerosis, osteoporosis, diabetes (such as type I diabetes, type II diabetes), arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria (such as chronic spontaneous urticaria, chronic inducible urticaria, chronic autoimmune urticaria), liver insufficiency, allergy (such as atopic dermatitis, specific dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic diseases, myocardial infarction, angina, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, complications due to organ transplantation, foreign body transplantation, antibody-mediated rejection (AMR), graft-versus-host disease, B cell-mediated hyperacute, acute, and chronic transplant rejection; wherein the arthritis is preferably rheumatoid arthritis; wherein the diabetes is preferably type I diabetes; wherein the urticaria is preferably chronic autoimmune urticaria.;

[0149] In some embodiments, the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, and metabolic / endocrine dysfunctions and neurological disorders; in some embodiments, the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is selected from cancer, autoimmune diseases, and inflammatory diseases; the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is an autoimmune disease or an inflammatory disease; in some embodiments, the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is selected from B cell malignancies, B cell lymphomas, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma (such as ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré 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, temporal arteritis, warm-type autoimmune hemolytic anemia, Wegener'sgranulomatosis), psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, focal pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (such as non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (such as primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis or cholangiopathy, liver or liver fibrosis (including but not limited to liver fibrosis associated with alcoholism), viral infection (such as hepatitis, hepatitis C, B or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (such as alcohol, drugs and environmental toxins), renal fibrosis (such as chronic kidney fibrosis), kidney disease associated with injury / fibrosis (such as chronic kidney disease associated with diabetes (such as diabetic nephropathy)), lupus, scleroderma renal, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, renal fibrosis associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy injury, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents; fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; with pre-inflammatory bowel diseases (such as Barrett'sfibrosis associated with esophagus) and chronic gastritis), and / or fibrosis associated with post-enteric inflammatory diseases such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma;

[0150] In some embodiments, the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is selected from B cell malignancies, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, and hairy cell leukemia), malignant lymphoma (e.g., small lymphocytic lymphoma, diffuse large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B cell non-Hodgkin lymphoma, B cell lymphoma, and follicular lymphoma), Waldenström macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstroem macroglobulinemia, bone cancer, bone metastasis, arthritis (e.g., rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SOJIA)), multiple sclerosis (e.g., relapsing multiple sclerosis), amyotrophic lateral sclerosis, osteoporosis, diabetes (e.g., type I diabetes, type II diabetes), arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria (e.g., chronic spontaneous urticaria, chronic inducible urticaria, chronic autoimmune urticaria), liver insufficiency, allergy (e.g., atopic dermatitis, eczema, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic diseases, myocardial infarction, angina, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, complications due to organ transplantation, foreign body transplantation, antibody-mediated rejection (AMR), graft-versus-host disease, B cell-mediated hyperacute, acute, and chronic transplant rejection; wherein the arthritis is preferably rheumatoid arthritis; wherein the diabetes is preferably type I diabetes; wherein the urticaria is preferably chronic autoimmune urticaria;

[0151] In some embodiments, the disease or disorder described in the present disclosure or the BTK-mediated disease or disorder is selected from rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, osteoporosis, diabetes, arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, autoimmune thyroid disease, lupus, systemic lupus erythematosus, psoriasis, chronic autoimmune urticaria, liver insufficiency, allergy, ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, parotitis, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic diseases, myocardial infarction, angina pectoris, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, and myasthenia gravis.

[0152] In some embodiments, the cancer described in the present disclosure is a malignant hematological tumor; in some embodiments, the cancer is selected from leukemia, multiple myeloma, and malignant lymphoma; in some embodiments, the cancer is selected from acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, hairy cell leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma, follicular lymphoma, Waldenström macroglobulinemia, and multiple myeloma.

[0153] In some embodiments, the cancer described in the present disclosure is selected from the group consisting of:

[0154] Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0155] Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

[0156] Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0157] Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0158] Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0159] Biliary tract: gallbladder cancer, ampullary cancer, cholangiocarcinoma;

[0160] Bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronfroma) (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor;

[0161] Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma);

[0162] Gynecological: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa-thecal cell tumor, sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer);

[0163] Hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma);

[0164] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0165] And adrenal gland: neuroblastoma.

[0166] The active compound can be made into a form suitable for administration by any appropriate route, and the compositions of the present disclosure are formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0167] As a general guidance, the active compound is preferably in the form of a unit dose, or in a form that the patient can self-administer in a single dose. The unit dose expression of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials of medicine, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 - 1000 mg.

[0168] In addition to the active compound, the pharmaceutical compositions of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the different administration methods, the composition may contain 0.1 to 99% by weight of the active compound.

[0169] Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets. These excipients can be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets can be uncoated or can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect for a longer period of time.

[0170] Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0171] The aqueous suspension contains an active substance and excipients suitable for preparing an aqueous suspension for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweetening agents.

[0172] The oily suspension can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickening agent. The above-mentioned sweetening agents and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant.

[0173] The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such preparations may also contain demulcents, preservatives, colorants and antioxidants.

[0174] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion can be injected into the bloodstream of the patient by topical bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous injection pump.

[0175] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension can be formulated with the above-mentioned suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any compatible fixed oil can be used. In addition, fatty acids can also be used to prepare injectables.

[0176] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid in the rectum and thus will melt in the rectum to release the drug.

[0177] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent or one or more preservatives.

[0178] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt, can be verified according to traditional treatment regimens.

[0179] Term Explanation

[0180] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0181] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkyl). The alkyl preferably has an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6(alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0182] The term "alkylene" refers to a divalent alkyl group, where the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene). The alkylene group preferably has an alkylene group with 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group with 1 to 6 carbon atoms (i.e., C 1-6(Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. The alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0183] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the definition of alkyl is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkenyl). The alkenyl preferably has an alkenyl group with 2 to 6 carbon atoms (i.e., C 2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0184] The term "alkenyl oxide" refers to a branched or unbranched hydrocarbon group containing an epoxy group in the molecule and having 2 - 12 carbon atoms, preferably C 2-6 alkenyl oxide. Representative examples of "alkenyl oxide" include vinyl oxide, propenyl 1,2-oxide, butenyl 1,2-oxide, etc.

[0185] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the definition of alkyl is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkynyl). The alkynyl preferably has an alkynyl group with 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0186] The term "alkoxy" means -O-(alkyl), where alkyl is defined as above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, etc. The alkoxy group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0187] The term "cycloalkyl" means a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl preferably has a cycloalkyl with 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl), more preferably a cycloalkyl with 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), most preferably a cycloalkyl with 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl) or a cycloalkyl with 5 or 6 ring atoms (i.e., 5- or 6-membered cycloalkyl) or a cycloalkyl with 5 ring atoms (i.e., 5-membered cycloalkyl).

[0188] Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0189] The polycyclic cycloalkyl includes: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0190] The term "spiroalkyl" refers to a polycyclic system in which the rings share a single carbon atom (the spiro atom), and which may contain one or more double bonds within the rings, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the rings (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on this all-carbon ring, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered spiroalkyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered spiroalkyl). The spiroalkyl includes monospiroalkyl and polyspiroalkyl (such as bisspiroalkyl, etc.), preferably monospiroalkyl or bisspiroalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospiroalkyl. Non-limiting examples include:

[0191] The point of attachment can be at any position;

[0192] etc.

[0193] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused with one or more of a heterocyclic group, an aryl group, or a heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl, and one or more double bonds may be contained within the ring, and having 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has a fused cycloalkyl having 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyls and polycyclic fused cycloalkyls (such as tricyclic fused cycloalkyls, tetracyclic fused cycloalkyls, etc.), preferably bicyclic fused cycloalkyls or tricyclic fused cycloalkyls, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic fused cycloalkyls. Non-limiting examples include: The point of attachment can be at any position;

[0194]

[0195] etc.

[0196] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and one or more double bonds may be contained within the ring, and having 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5- to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyls and polycyclic bridged cycloalkyls (such as tricyclic bridged cycloalkyls, tetracyclic bridged cycloalkyls, etc.), preferably bicyclic bridged cycloalkyls or tricyclic bridged cycloalkyls. Non-limiting examples include:

[0197] The point of attachment can be at any position.

[0198] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available linking point, and the substituents are preferably selected from one or more of D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0199] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclic group), which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., form a nitrogen oxide; the sulfur may be optionally oxo, i.e., form a sulfoxide or a sulfone, but does not include -O-O-, -O-S-, or -S-S-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered heterocyclic group). The heterocyclic group preferably has a heterocyclic group with 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclic group); more preferably has a heterocyclic group with 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclic group); still more preferably has a heterocyclic group with 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclic group) or a heterocyclic group with 4 to 7 ring atoms (i.e., 4- to 7-membered heterocyclic group); most preferably has a heterocyclic group with 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclic group) or a heterocyclic group with 5 ring atoms (i.e., 5-membered heterocyclic group).

[0200] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, dihydropyrrolyl, dihydrofuryl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0201] The polycyclic heterocyclic group described above includes a spiro heterocyclic group, a fused heterocyclic group, and a bridged heterocyclic group. The term "spiro heterocyclic group" refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom). It may contain one or more double bonds within the ring, and at least one (such as 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., form a nitrogen oxide; the sulfur may be optionally oxo, i.e., form a sulfoxide or a sulfone, but does not include -O-O-, -O-S-, or -S-S-), provided that at least one monocyclic heterocyclic group is included and the connection point is on the monocyclic heterocyclic group, and it has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered spiro heterocyclic group). The spiro heterocyclic group preferably has a spiro heterocyclic group with 6 to 14 ring atoms (i.e., a 6- to 14-membered spiro heterocyclic group), more preferably a spiro heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered spiro heterocyclic group); further preferably a spiro heterocyclic group with 7 to 9 ring atoms (i.e., a 7- to 9-membered spiro heterocyclic group); still more preferably a spiro heterocyclic group with 7 or 8 ring atoms (i.e., a 7- or 8-membered spiro heterocyclic group). The spiro heterocyclic group includes a monospiro heterocyclic group and a polyspiro heterocyclic group (such as a bispiro heterocyclic group, etc.), preferably a monospiro heterocyclic group or a bispiro heterocyclic group, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6-membered monospiro heterocyclic group. Non-limiting examples include:

[0202] etc.

[0203] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., form a nitrogen oxide; the sulfur may be optionally oxo, i.e., form a sulfoxide or sulfone, but does not include -O-O-, -O-S-, or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclic group, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclic group). The fused heterocyclic group preferably has a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused heterocyclic group); further preferably a fused heterocyclic group having 7 to 9 ring atoms (i.e., a 7- to 9-membered fused heterocyclic group); further preferably a fused heterocyclic group having 8 or 9 ring atoms (i.e., an 8- or 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic fused heterocyclic groups. Non-limiting examples include:

[0204]

[0205] etc.

[0206] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., form an N-oxide; the sulfur may be optionally oxo, i.e., form a sulfoxide or a sulfone, but does not include -O-O-, -O-S-, or -S-S-), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group preferably has a bridged heterocyclic group with 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). It can be classified into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.) according to the number of constituent rings, and bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups are preferred. Non-limiting examples include:

[0207] etc.

[0208] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0209] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, which has 6 to 22 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22) ring atoms (i.e., 6 to 22-membered aryl). The aryl preferably has an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl) or an aryl having 10 to 15 ring atoms (i.e., 10 to 15-membered aryl); in some embodiments, the aryl preferably has an aryl having 11 to 14 ring atoms (i.e., 11 to 14-membered aryl); in some embodiments, the aryl preferably has an aryl having 8 to 14 ring atoms (i.e., 8 to 14-membered aryl); in some embodiments, the aryl preferably has an aryl having 11 or 12 ring atoms (i.e., 11 or 12-membered aryl); in some embodiments, the aryl preferably has an aryl having 11 ring atoms (i.e., 11-membered aryl). The monocyclic aryl, for example, is phenyl. Non-limiting examples of the polycyclic aryl include: naphthyl, anthryl, phenanthryl, etc. The polycyclic aryl also includes one or more fusions of phenyl with a heterocyclic group or a cycloalkyl group, or one or more fusions of naphthyl with a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system (preferably bicyclic aryl or tricyclic aryl), non-limiting examples include:

[0210]

[0211] etc.

[0212] The aryl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0213] The number of rings in the "tricyclic aryl" ring system is 3, and the point of attachment is on the phenyl. The "tricyclic aryl" preferably has a tricyclic aryl having 11 to 14 ring atoms (i.e., 11 to 14-membered tricyclic aryl); more preferably a tricyclic aryl having 11 or 12 ring atoms (i.e., 11 or 12-membered tricyclic aryl); more preferably a tricyclic aryl having 11 ring atoms (i.e., 11-membered tricyclic aryl). Taking ring A in the general formula (I) of the present disclosure as an example, non-limiting examples of the "tricyclic aryl" include etc

[0214] The "tetracyclic aryl" ring system has 4 rings, and the connection points are on the phenyl group. The "tetracyclic aryl" preferably has a tetracyclic aryl with 12 to 19 ring atoms (i.e., 12- to 19-membered tetracyclic aryl); more preferably a tetracyclic aryl with 12 to 14 ring atoms (i.e., 12- to 14-membered tetracyclic aryl); even more preferably a tetracyclic aryl with 13 ring atoms (i.e., 13-membered tetracyclic aryl). Taking ring A in the general formula (I) of the present disclosure as an example, non-limiting examples of the "tetracyclic aryl" include etc.

[0215] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur is contained in the ring (the nitrogen can be optionally oxidized, i.e., form a nitrogen oxide; the sulfur can be optionally oxygenated, i.e., form a sulfoxide or a sulfone, but does not include -O-O-, -O-S-, or -S-S-), and it has 5 to 22 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22) ring atoms (i.e., 5- to 22-membered heteroaryl). In some embodiments, the heteroaryl has a heteroaryl with 5 to 14 ring atoms (i.e., 5- to 14-membered heteroaryl); in some embodiments, a heteroaryl with 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl); in some embodiments, a heteroaryl with 9 to 14 ring atoms (i.e., 9- to 14-membered heteroaryl); in some embodiments, a heteroaryl with 8 to 14 ring atoms (i.e., 8- to 14-membered heteroaryl); in some embodiments, the heteroaryl preferably has a heteroaryl with 11 or 12 ring atoms (i.e., 11- or 12-membered heteroaryl); in some embodiments, the heteroaryl preferably has a heteroaryl with 11 ring atoms (i.e., 11-membered heteroaryl); in some embodiments, preferably a heteroaryl with 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl), and most preferably a 5-membered heteroaryl.

[0216] Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridone, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.

[0217] The polycyclic heteroaryl group (preferably a 9- to 14-membered heteroaryl group, more preferably an 8- to 14-membered heteroaryl group), non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more aryl groups, where the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more cycloalkyl groups or heterocyclic groups, where the connection point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system (preferably a bicyclic heteroaryl group or a tricyclic heteroaryl group). Non-limiting examples include:

[0218]

[0219] etc.

[0220] The number of rings in the "tricyclic heteroaryl" ring system is 3, and the connection point is on the monocyclic heteroaryl ring. The "tricyclic heteroaryl" preferably has a tricyclic heteroaryl group with 11 to 14 ring atoms (i.e., an 11- to 14-membered tricyclic heteroaryl group); more preferably a tricyclic heteroaryl group with 12 or 13 ring atoms (i.e., a 12- or 13-membered tricyclic heteroaryl group); more preferably a tricyclic heteroaryl group with 12 ring atoms (i.e., a 12-membered tricyclic heteroaryl group).

[0221] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any available connection point, and the substituents are preferably selected from one or more of D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0222] The term "cycloalkyloxy" refers to cycloalkyl-O-, where the cycloalkyl is as defined above.

[0223] The term "heterocyclyloxy" refers to heterocyclic-O-, where the heterocyclic group is as defined above.

[0224] The term "aryloxy" refers to aryl-O-, where the aryl is as defined above.

[0225] The term "heteroaryloxy" refers to heteroaryl-O-, where the heteroaryl is as defined above.

[0226] The term "cycloalkylalkyl" refers to an alkyl group substituted by one or more cycloalkyl groups, where the alkyl group and the cycloalkyl group are as defined above.

[0227] The term "heterocyclic alkyl" means an alkyl group substituted by one or more heterocyclic groups, where the alkyl group and the heterocyclic group are as defined above.

[0228] The term "arylalkyl" means an alkyl group substituted by one or more aryl groups, where the alkyl group and the aryl group are as defined above; for example, -CH2Ph.

[0229] The term "heteroarylalkyl" means an alkyl group substituted by one or more heteroaryl groups, where the alkyl group and the heteroaryl group are as defined above.

[0230] The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, where the alkyl group is as defined above.

[0231] The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms, where the alkoxy group is as defined above; for example, -OCF3.

[0232] The term "hydroxyalkyl" means an alkyl group substituted by one or more hydroxyl groups, where the alkyl group is as defined above; for example, -CH2OH.

[0233] The term "alkoxyalkyl" means an alkyl group substituted by one or more alkoxy groups, where the alkyl group and the alkoxy group are as defined above; for example, -CH2OCH3.

[0234] The term "aminoalkyl" means an alkyl group substituted by one or more amino groups, where the alkyl group is as defined above; for example, -CH2NH2.

[0235] The term "methylene" means =CH2.

[0236] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0237] The term "hydroxyl" means -OH.

[0238] The term "mercapto" means -SH.

[0239] The term "amino" means -NH2.

[0240] The term "cyano" means -CN.

[0241] The term "nitro" means -NO2.

[0242] The term "oxo" or "oxo group" means "=O".

[0243] The term "carbonyl" means C=O.

[0244] The term "carboxyl" means -C(O)OH.

[0245] The term "carboxylate group" means -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where the alkyl group and the cycloalkyl group are as defined above.

[0246] In the general formula (III) of the present disclosure, when j is 0, it is equivalent to A 1 or A 2 is a bond.

[0247] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0248] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative.

[0249] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% - 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% - 98% of a pharmaceutically acceptable excipient.

[0250] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis- and trans- (or Z- and E-) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (such as racemates, mixtures of diastereoisomers). The substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming diastereomeric salts with an appropriate optically active acid or base, and then separating the diastereoisomers by conventional methods well known in the art to obtain the pure isomer. In addition, the separation of enantiomers and diastereoisomers is usually accomplished by chromatography.

[0251] In the chemical structure of the compounds described in the present disclosure, the bond " " represents an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond " " can be " " or " ", or can contain both " " and " " configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-form and the E-form are included.

[0252] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. It includes all possible tautomers, which may exist in the form of a single isomer or as a mixture of any proportion of the said tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc.

[0253] For example, the compound should be understood to include either of the following two structures or a mixture of the two tautomers:

[0254]

[0255] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomers.

[0256] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, etc., such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., and deuterium is preferred.

[0257] Compared with the non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing efficacy, prolonging the biological half-life of the drug, etc. All isotopic composition transformations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete. Partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0258] For a compound of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to have a deuterium abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

[0259] "Optionally" or "optional" means that the subsequently described event or circumstance may but does not necessarily occur, including both the occurrence and non-occurrence of the event or circumstance. For example, "optionally (optionally) alkyl substituted by halogen or cyano" includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0260] "Substituted" or "substituent" means that one or more, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are independently replaced by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without undue effort (through experiments or theories). For example, an amino group or a hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0261] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and then exert its biological activity.

[0262] "Pharmaceutically acceptable salt" refers to a salt of the compounds disclosed herein, which can be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have the due biological activity. It can be prepared separately during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0263] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are suitable for contact with patient tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0264] As used herein, the singular forms "a", "an" and "the" include plural references and vice versa, unless the context clearly indicates otherwise.

[0265] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when the parameter is not critical, numbers are usually given for illustrative purposes only and not for limitation. Detailed Description

[0266] The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[0267] Examples

[0268] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in the unit of (ppm). The NMR measurement was performed using a Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer. The solvents for measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0269] The MS measurement was carried out using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0270] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0271] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

[0272] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography instruments.

[0273] Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatography instrument.

[0274] High performance liquid chromatography preparation was carried out using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatography instruments.

[0275] Chiral preparation was carried out using a Shimadzu LC-20AP preparative chromatography instrument.

[0276] The CombiFlash rapid preparator used Combiflash Rf200 (TELEDYNE ISCO).

[0277] The thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specifications for separating and purifying products by thin layer chromatography were 0.4 mm to 0.5 mm.

[0278] Silica gel column chromatography generally uses silica gel with 200 - 300 mesh from Yantai Huanghai Silica Gel as the carrier.

[0279] The average inhibition rate of kinase and the determination of IC 50 value were measured using a NovoStar microplate reader (BMG Labtech, Germany).

[0280] The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

[0281] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0282] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0283] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0284] The catalytic hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL - 500 hydrogen generator or an HC2 - SS hydrogenator.

[0285] The hydrogenation reaction usually involves evacuating, filling with hydrogen, and repeating the operation 3 times.

[0286] The microwave reaction uses a CEM Discover - S 908860 microwave reactor.

[0287] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0288] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C - 30°C.

[0289] The progress of the reactions in the examples was monitored by thin - layer chromatography (TLC). The eluent systems for column chromatography used to purify compounds and the eluent systems for TLC include: A: dichloromethane / methanol system, B: n - hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0290] Biological evaluation

[0291] The following test examples are used to further describe and explain the present disclosure, but these test examples do not mean to limit the scope of the present disclosure.

[0292] Test Example 1 Inhibitory Activity of the Compounds of the Present Disclosure against BTK Enzyme

[0293] I. Experimental Materials and Instruments

[0294] 1. BTK Recombinant Human Protein (Thermo, PV3363)

[0295] 2. HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

[0296] 3. 1M MgCl2 (Thermo, AM9530G)

[0297] 4. 1M MnCl2 (Sigma, M1787-100ML)

[0298] 5. Adenosine 5'-Triphosphate (ATP) (New england Biolabs, P0756L)

[0299] 6. DTT 2M (Sangon Biotech, B645939)

[0300] 7. UltraPure Distillred Water (Invitrogen, 10977-015)

[0301] 8. OptiPlate-384, White Opaque 384-well Microplate (PerkinElmer, 6007290)

[0302] 9. 96-well Round Bottom Plate (Corning, 3788)

[0303] 10. Biochemical Incubator (Shanghai Boxun Medical Biological Instrument Co., Ltd., BSP-100)

[0304] 11. 15mL Centrifuge Tube (Corning)

[0305] 12. Desktop High-Speed Centrifuge (Changsha Yingtai Instrument Co., Ltd., TD4N)

[0306] 13. Multimode Plate Reader (PerkinElmer, EnVision)

[0307] 14. Bravo Liquid Workstation (Agilent Technologies, SGC120TH34702)

[0308] II. Experimental Procedures

[0309] The HTRF KinEASE-TK kit is a kit based on two technologies, fluorescence resonance energy transfer and time-resolved fluorescence, for detecting changes in BTK enzyme activity. The operation of this kit is carried out in two steps: 1) Enzyme reaction stage: Add ATP to start the enzyme reaction. The enzyme phosphorylates the substrate. Add a compound to competitively bind to BTK with ATP, thus inhibiting substrate phosphorylation; 2) Detection stage: After the enzyme reaction is completed, add a detection reagent to terminate the enzyme reaction. Different groups of the phosphorylated substrate bind to the energy donor and the energy acceptor respectively, bringing the two closer. When the instrument reads the value, the energy donor is excited by an external light source and can transfer the energy resonantly to the nearby energy acceptor, causing it to be excited and emit emission light of a specific wavelength. Thus, the change in enzyme activity can be detected by measuring the signal value and the inhibition rate of the compound on the target enzyme can be calculated, thereby evaluating the inhibitory effect of the compound on BTK enzyme activity.

[0310] Preparation of enzyme reaction buffer: Dilute 5×Kinese Buffer 5-fold with ultrapure water and add the storage solutions of MgCl2, MnCl2 and DTT. The final composition of the buffer is: 1×Kinese Buffer, 10 mM MgCl2, 1 mM MnCl2, 1 mM DTT.

[0311] Preparation of 5×BTK working solution: Take out the BTK (5.17 μM) storage solution from -20 °C. The concentration of BTK in the enzyme reaction system is 2 nM, and the concentration of the 5× working solution is 10 nM. Dilute the BTK storage solution 517-fold with the enzyme reaction buffer according to the amount required for the experiment. Add it to the 384-well plate at 2 μL / well and centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells.

[0312] Preparation of 5×SEB working solution: Take out the SEB (2500 nM) storage solution from -20 °C. The concentration of SEB in the enzyme reaction system is 50 nM, and the concentration of the 5× working solution is 250 nM. Dilute the SEB storage solution 10-fold with the enzyme reaction buffer according to the amount required for the experiment. Add it to the 384-well plate at 2 μL / well and centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells.

[0313] The 20 mM test compound dissolved in 100% DMSO was diluted to 200 μM with 100% DMSO. This is 200× the concentration at the highest concentration point of the compound in the reaction system. The compound at this concentration was serially diluted 10 concentration points by a factor of 3 with 100% DMSO. The positive control wells and negative control wells were 100% DMSO. The serially diluted compounds and 100% DMSO were further diluted 40-fold in complete medium to 5× concentration and mixed well. Take 2 μL of the 5× concentration compound or DMSO and add it to a 384-well microplate. Centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells. Place the microplate in a 25°C biochemical incubator and incubate for 0.5 hours.

[0314] Preparation of 5× TK-Substrate-biotin (substrate) working solution: Take out the substrate (500 μM) stock solution from -20°C. The substrate concentration in the enzyme reaction system is 0.5 μM, and the 5× working solution concentration is 2.5 μM. Dilute the substrate stock solution 200-fold with the enzyme reaction buffer according to the amount required for the experiment. Add 2 μL / well to a 384-well microplate and centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells.

[0315] Preparation of 5× ATP working solution: Take out the ATP (10 mM) stock solution from -20°C. The ATP concentration in the enzyme reaction system is 10 μM, and the 5× working solution concentration is 50 μM. Dilute the ATP stock solution 200-fold with the enzyme reaction buffer according to the amount required for the experiment. Add 2 μL / well to a 384-well microplate and centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells. Place the microplate in a 25°C biochemical incubator and incubate for 1 hour.

[0316] Preparation of detection reagents: Take out the Sa-XL665 (16.67 μM) stock solution and TK Antibody-EU3+-Cryptate (100X) stock solution from -20°C. Dilute the Sa-XL665 stock solution 133.4-fold and the Sa-XL665 stock solution 200-fold with the detection buffer according to the amount required for the experiment. Add 10 μL / well to a 384-well plate and centrifuge at 2000 rpm for 1 minute in a plate shaker to centrifuge the liquid to the bottom of the wells. Place the microplate in a 25°C biochemical incubator and incubate for 1 hour.

[0317] After incubation, read the TRF signal with Envision. Ratio = (Signal 665nm / Signal620nm) * 104, Inhibition rate = 100 - 100×(Ratio 测试孔 -Ratio 阴性孔 ) / (Ratio 阳性孔 -Ratio 阴性孔)。The inhibition curve was plotted using Graphpad Prism software based on the compound concentration and the corresponding inhibition rate, and the concentration of the compound corresponding to an inhibition rate of 50% was obtained by 4PL fitting, that is, the IC 50 value.

[0318] Conclusion: The compounds of the present disclosure have an inhibitory effect on BTK enzyme.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is a heterocyclic group; Ring B is a heteroaryl group or a heterocyclic group; Each R 1 and each R 2 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxy, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-OC(O)NR 18 R 19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-S(O) u R 17 、-S(O) u NR 18 R 19 、-NR 20 S(O) u R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl, -(CR a R b ) v heteroaryl, oxo, =S, =NR 21 Sum = CR 22 R 23 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; Or, two R 1 and the ring atoms to which it is attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; Or, two R 2 and the ring atoms to which it is attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; X 1 CR 4a or N; X 2 CR 4b or N; X 3 CR 4c or N; X 4 CR 4d or N; B 1 CR 5a or N; B 2 CR 5b or N; B 3 CR 5c or N; R 4a , R 4b , R 4c , R 4d , R 5a , R 5b and R 5c are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxy, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-OC(O)NR 18 R 19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-S(O) u R 17 、-S(O) u NR 18 R 19 、-NR 20 S(O) u R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; or R 4b and R 4c and the carbon atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; or R 4c and R 4d and the carbon atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; or R 5a and R 5b and the carbon atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; or R 5b and R 5c and the carbon atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 0 replace; R 6 Selected from hydrogen atoms, -NHR 7 and -NHC(O)R 7 ; R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; L is selected from CR 8 R 9 、C(O)、O、NR 10 and S(O) u ; R 8 and R 9 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, amino, cycloalkyl and cycloalkylalkyl; or R 8 and R 9 and together with the carbon atom to which it is attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace; R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; R 11 , R 12 , R 13 , R 14 , R x and R y are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, amino, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; or R 11 , R 12 , R 13 , R 14 , R x and R y Any two of them and the carbon atoms connected thereto together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally replaced by one or more R 0 replace; or R 11 and R 12 Together they form = O; or R 13 and R 14 Together they form = O; or R on the same carbon atom x and R y Together they form = O; R 15 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl is independently optionally substituted by one or more R 0 replace; Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any one of them and R 15 and the atoms to which they are attached together form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally replaced by one or more R 0 replace; W is selected from -C(O)R 16 、-S(O)2R 16 and -CN; R 16 is selected from alkenyl, alkynyl and alkenyl oxide; wherein the alkenyl, alkynyl and alkenyl oxide are each independently selected from halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, amino, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-S(O) u R 17 、-S(O) u NR 18 R 19 、-NR 20 S(O) u R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl, -(CR a R b ) v heteroaryl, oxo, =S, =NR 21 Sum = CR 22 R 23 is substituted by one or more substituents; R 0 are the same or different at each occurrence and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxy, nitro, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-OC(O)NR 18 R 19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-S(O) u R 17 、-S(O) u NR 18 R 19 、-NR 20 S(O) u R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl, -(CR a R b ) v heteroaryl, oxo, =S, =NR 21 Sum = CR 22 R 23 ; R 17 , R 18 and R 19 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, -(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace; or R 18 and R 19 and together with the nitrogen atom to which it is connected form a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 01 replace; R 20 are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl and heterocyclylalkyl; R 21 are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, hydroxyl, alkoxy and haloalkoxy; R 22 and R 23 are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, hydroxy, alkoxy, haloalkoxy, cyano, C(O)alkyl and C(O)Oalkyl; Or, R 22 and R 23 Together with the atoms to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 01 replace; R 01 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, =S, =NH, =N(OH), =C(halogen), =CH, =CH(halogen), -S(alkyl), halogen, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl), -C(O)Oalkyl, -C(O)OH, -C(O)NH, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; R a and R b is the same or different at each occurrence and is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, cycloalkyl and cycloalkylalkyl; m1 is 0, 1, 2, 3, 4, 5 or 6; m2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; n is 0, 1, 2 or 3; u is 0, 1 or 2; v is 0, 1, 2, or 3.

2. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from k is 0, 1, 2 or 3; m1 is 0, 1 or 2; m2 is 0, 1 or 2; m3 is 0, 1 or 2; Z is selected from N, CH and CR 2 ; a is 0, 1, 2 or 3; b is 1, 2, 3 or 4; R 1 and R 2 As defined in claim 1; preferably, Selected from m1 is 0, 1 or 2; m2 is 0, 1 or 2; R 1 and R 2 As defined in claim 1.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof: in: k is 0, 1, 2 or 3 (preferably, k is 0 or 1); Z is N or CR 2c ; R 2a , R 2b and R 2c are the same or different and are each independently a hydrogen atom or R 2 ; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 replace; Or, R 2a and R 2c Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 2 replace; R 1 、m1、R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , B 3 , R 6 , R 11 -R 16 , R x , R y and n is as defined in claim 1.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein m1 is 0 or 1; and / or each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; preferably, R 1 C 1-6 More preferably, R 1 is methyl; and / or each R 2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and 3 to 6-membered cycloalkyl; preferably, R 2 C 1-6 alkyl or 3 to 6-membered cycloalkyl; more preferably, R 2 is methyl or cyclopropyl; and / or R 2a and R 2b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and 3 to 6-membered cycloalkyl; or R 2a and R 2b Together with the atoms to which they are attached, they form a 4- to 8-membered cycloalkyl group, wherein the 4- to 8-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl and 3- to 6-membered cycloalkyl; and / or Z is N or CH.

5. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4a , R 4b , R 4c and R 4d are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; preferably, R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; more preferably, R 4a is methyl; R 4b is a hydrogen atom; R 4c F; R 4d is a hydrogen atom; and / or B 3 is CH or N; preferably, B 3 N; and / or R 6 R is amino group; 11 , R 12 , R 13 and R 14 is a hydrogen atom; and / or n is 0; and / or R 15 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6-membered cycloalkyl; preferably, R 15 is methyl; and / or R 16 C 2-6 alkenyl, wherein the C 2-6 Alkenyl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and -NR 18 R 19 is substituted by one or more substituents; R 18 and R 19 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 16 It is -CH=CH2.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is selected from any one of the following compounds:

7. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by BTK.

9. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing a disease or condition selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, and metabolic / endocrine dysfunction and neurological disorders; preferably, the disease or condition is an autoimmune disease or inflammatory disease; more preferably, the disease or condition is selected from B-cell malignancies, multiple myeloma, leukemia, malignant lymphoma, Waldenstrom's macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom's macroglobulinemia, bone cancer, bone metastasis, arthritis, multiple sclerosis, amyotrophic lateral sclerosis, osteoporosis, diabetes, arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, disease, Sjögren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria, liver dysfunction, allergies, ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD) , thromboembolic disease, myocardial infarction, angina pectoris, stroke, ischemic conditions, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, complications due to organ transplantation, foreign body transplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute and chronic transplant rejection.

10. The use according to claim 9, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, osteoporosis, diabetes, arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, autoimmune thyroid disease, lupus, systemic lupus erythematosus, psoriasis, chronic autoimmune urticaria, liver insufficiency, allergy, ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis nephritis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic disease, myocardial infarction, angina pectoris, stroke, ischemic conditions, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, and myasthenia gravis.

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