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

Abstract

The invention provides a heteroaryl compound, a preparation method of the heteroaryl compound and application of the heteroaryl compound in medicine. Specifically, the invention provides 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, metabolic / endocrine dysfunction, and neurological disorders.

Description

Heteroaryl compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to Bruton's tyrosine kinase (BTK) (including wild-type and mutant BTK) inhibitors for treating and / or preventing diseases or conditions associated with BTK, such as cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine dysfunction, 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 includes an N-terminal pleckstrin homology (PH) domain, a TEC homology (TH) domain, an SRC homology (SH) domain SH2 and SH3 and an enzymatically active kinase domain (Hendriks RW et al., Nat Rev Cancer.2014, 14: 219-232). Its PH domain interacts with phosphatidylinositol-3,4,5-triphosphate (PIP3) generated by phosphatidylinositol-3 kinase (PI3K) to recruit BTK to the cell membrane. Transmembrane proteins (such as B cell receptor (BCR) complexes) promote the phosphorylation of BTK at Y551 by SYK or SRC family kinases, resulting in BTK kinase activation and subsequently causing it to undergo Y223 autophosphorylation in the 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 almost no antibodies in their circulation (Vetrie D, et al., Nature. 1993, 361: 226–233; Tsukada S et al., Cell, 1993, 72: 279–290). In the early stages 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 conversion 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 self-reactive immature B cells in the bone marrow. In the peripheral lymphoid system, BTK regulates B cell migration to follicles and B cell maturation, activation and differentiation of 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 studied in detail mainly in BCR signaling, BTK has also been reported to play an important role in signaling mediated by toll-like receptors (TLRs), Fc receptors (FCRs), and chemokine receptors (Crofford et al., Expert Rev Clin Immunol, 2016, 12:763-773). The IgE receptor FcεR on the surface of mast cells and basophils binds to 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 activating 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 IgG-specific Fc receptor (FcγR) signal transduction in macrophages and microglia, promoting the expression of inflammatory factors IL-1β, IL-6 and TNF (Di Paolo, JA et al. Nat. Chem. Biol. 2011, 7, 41–50).

[0004] BTK inhibitors have been developed for the treatment of cancers such as chronic lymphocytic leukemia (CLL). Several covalent BTK inhibitors have been used clinically for B-cell malignancies. In addition to B-cell lymphoma, the function of BTK in the immune system has also prompted the development of BTK inhibitors in autoimmune and allergic diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome, systemic lupus erythematosus, and multiple sclerosis. To date, several compounds such as Evobrutinib, Tolebrutinib, and Fenebrutinib have been tested for efficacy in clinical trials for multiple sclerosis and have achieved positive results. However, liver toxicity issues have caused the suspension of several drug clinical trials (Montalban X et al., 2019, N Engl J Med, 380(25):2406-17). Therefore, one object of the present disclosure is to provide a BTK covalent binding inhibitor to explore its improvement on the liver toxicity problem, improve safety, and be used for the treatment of autoimmune diseases.

[0005] Summary of the Invention

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

[0007] in:

[0008] G is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally replaced by one or more R G replace;

[0009] Each R G are the same or different and are each independently selected from R 1 、R 2a 、R 2 and R C ;

[0010] Each R 1 and each R 2a 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0011] Or, two R 1 Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; wherein said cycloalkyl or heterocyclyl group is optionally substituted by one or more R 0 replace;

[0012] R 2 For-OR A or -alkylene-R B ; wherein the alkylene group is optionally replaced by one or more R 0 replace;

[0013] R A is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0014] R B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0015] R C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R d replace;

[0016] Each R d 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0017] 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;

[0018] X 1 CR 4a or N;

[0019] X 2 CR 4b or N;

[0020] X 3 CR 4c or N;

[0021] X 4 CR 4d or N;

[0022] B 1 CR 5a or N;

[0023] B 2 CR 5b or N;

[0024] B 3 CR 5c or N;

[0025] 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0026] or R 4b and R 4cTogether with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0027] or R 4c and R 4d Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0028] or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0029] or R 5b and R 5c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0030] R 6 Selected from hydrogen atom, -NHR 7 and -NHC(O)R 7 ;

[0031] 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;

[0032] L is selected from CR 8 R 9 、C(O),O、NR 10 , S, S(O) and S(O)2;

[0033] 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;

[0034] or R 8 and R 9 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0035] 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;

[0036] 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0037] or R 11 、R 12 、R 13 、R 14 、R x and R y Any two carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally replaced by one or more R 0 replace;

[0038] or R 11 and R 12 Together they form =O;

[0039] or R 13 and R 14 Together they form =O;

[0040] or R on the same carbon atom x and R y Together they form =O;

[0041] 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;

[0042] Or, R 11 、R 12 、R 13 、R 14 、R x and R y Any one and R 15 Together with the atoms to which they are attached, they form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 replace;

[0043] W is selected from -C(O)R 16 、-S(O)2R 16 and -CN;

[0044] R 16 selected from alkenyl, alkynyl and alkenyl oxide; wherein the alkenyl, alkynyl and alkenyl oxide are each independently optionally selected from oxo, 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 、-SR 17 、-S(O)R 17 、-S(O)2R17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 is substituted by one or more substituents in a heteroaryl group;

[0045] R 0 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) vHeterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v heteroaryl;

[0046] R 17 、R 18 、R 19 and R 20 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace;

[0047] or R 18 and R 19 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 01 replace;

[0048] R 01 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, 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;

[0049] 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;

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

[0051] v is 0, 1, 2, or 3.

[0052] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0053] in:

[0054] G is selected from

[0055] Ring A is selected from polycyclic aryl, heteroaryl, cycloalkyl and heterocyclyl;

[0056] Ring B is a monocyclic aryl group or a monocyclic heteroaryl group;

[0057] Each R 1 and each R 2a are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a deuterated alkoxy group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 and =CR p R q wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0058] Or, two R 1 Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; wherein said cycloalkyl or heterocyclyl group is optionally substituted by one or more R 0 replace;

[0059] R 2 For-OR A or -alkylene-R B ; wherein the alkylene group is optionally replaced by one or more R 0 replace;

[0060] R A is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0061] R B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0062] R C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently replaced by one or more R d replace;

[0063] Each R d are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 and =CR p R q wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0064] R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated 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;

[0065] X 1 CR 4a or N;

[0066] X 2 CR 4b or N;

[0067] X 3 CR 4c or N;

[0068] X 4 CR 4d or N;

[0069] B 1 CR 5a or N;

[0070] B 2 CR 5b or N;

[0071] B 3 CR 5c or N;

[0072] 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 a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0073] or R 4b and R 4c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0074] or R 4c and R 4d Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0075] or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0076] or R 5b and R 5c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0077] R 6 Selected from hydrogen atom, -NHR 7 and -NHC(O)R 7 ;

[0078] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, and a heterocyclylalkyl group;

[0079] L is selected from CR 8 R 9 、C(O),O、NR 10 , S, S(O) and S(O)2;

[0080] R 8 and R 9are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxyl group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group;

[0081] or R 8 and R 9 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0082] 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 deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group;

[0083] 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 deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(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, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0084] or R 11 、R 12 、R 13 、R 14 、Rx and R y Any two carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally replaced by one or more R 0 replace;

[0085] or R 11 and R 12 Together they form =O;

[0086] or R 13 and R 14 Together they form =O;

[0087] or R on the same carbon atom x and R y Together they form =O;

[0088] R 15 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, haloalkyl, deuterated alkyl, 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;

[0089] Or, R 11 、R 12 、R 13 、R 14 、R x and R y Any one and R 15 Together with the atoms to which they are attached, they form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 replace;

[0090] W is selected from -C(O)R 16 、-S(O)2R 16 and -CN;

[0091] R 16 selected from alkenyl, alkynyl and alkene oxide; wherein the alkenyl, alkynyl and alkene oxide are each independently optionally selected from oxo, =S, =CR p R q , deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, amino, nitro, -(CR a R b ) v OR 17 、-(CRa 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 is substituted by one or more substituents in a heteroaryl group;

[0092] R 0 is the same or different at each occurrence and is independently selected from oxo, =S, =CR p R q , deuterium atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, -(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 R19 、-OC(O)R 17 、-OC(O)OR 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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;

[0093] R 17 、R 18 、R 19 and R 20 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace;

[0094] or R 18 and R 19 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 01 replace;

[0095] R 01 is the same or different at each occurrence and is independently selected from oxo, =S, =CRp R q , a deuterium atom, a halogen, a hydroxyl 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 deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, an aryloxy group, a heteroaryl group, a heteroarylalkyl group, and a heteroaryloxy group;

[0096] R a and R b is the same or different at each occurrence and is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group;

[0097] R p and R q is the same or different at each occurrence and is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group;

[0098] q is an integer from 0 to 25;

[0099] m is 0, 1, 2, 3 or 4;

[0100] n is 0, 1, 2, or 3;

[0101] v is 0, 1, 2, or 3.

[0102] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0103] in:

[0104] G is selected from

[0105] Ring A is selected from polycyclic aryl, polycyclic heteroaryl, polycyclic cycloalkyl and polycyclic heterocyclyl;

[0106] Ring B is a monocyclic aryl group or a monocyclic heteroaryl group;

[0107] Each R 1 and each R 2aare 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0108] Or, two R 1 Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; wherein said cycloalkyl or heterocyclyl group is optionally substituted by one or more R 0 replace;

[0109] R 2 For-OR A or -alkylene-R B; wherein the alkylene group is optionally replaced by one or more R 0 replace;

[0110] R A is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0111] R B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0112] R C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently replaced by one or more R d replace;

[0113] Each R d 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 17 、-(CR a R b ) vCycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl, -(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;

[0114] 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;

[0115] X 1 CR 4a or N;

[0116] X 2 CR 4b or N;

[0117] X 3 CR 4c or N;

[0118] X 4 CR 4d or N;

[0119] B 1 CR 5a or N;

[0120] B 2 CR 5b or N;

[0121] B 3 CR 5c or N;

[0122] 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 Rb ) 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0123] or R 4b and R 4c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0124] or R 4c and R 4d Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0125] or R 5a and R 5bTogether with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0126] or R 5b and R 5c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0127] R 6 Selected from hydrogen atom, -NHR 7 and -NHC(O)R 7 ;

[0128] 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;

[0129] L is selected from CR 8 R 9 、C(O),O、NR 10 , S, S(O) and S(O)2;

[0130] 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;

[0131] or R 8 and R 9 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0132] 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;

[0133] R 11 、R 12 、R 13 、R 14 、R x and R yare 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0134] or R 11 、R 12 、R 13 、R 14 、R x and R y Any two carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally replaced by one or more R 0 replace;

[0135] or R 11 and R 12 Together they form =O;

[0136] or R 13 and R 14 Together they form =O;

[0137] or R on the same carbon atom x and R y Together they form =O;

[0138] R 15is 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;

[0139] Or, R 11 、R 12 、R 13 、R 14 、R x and R y Any one and R 15 Together with the atoms to which they are attached, they form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 replace;

[0140] W is selected from -C(O)R 16 、-S(O)2R 16 and -CN;

[0141] R 16 selected from alkenyl, alkynyl and alkenyl oxide; wherein the alkenyl, alkynyl and alkenyl oxide are each independently optionally selected from oxo, 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 is substituted by one or more substituents in a heteroaryl group;

[0142] R 0 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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;

[0143] R 17 、R 18 、R 19 and R 20 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace;

[0144] or R 18 and R 19 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 01 replace;

[0145] R 01 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, 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;

[0146] 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;

[0147] q is an integer from 0 to 25;

[0148] m is 0, 1, 2, 3 or 4;

[0149] n is 0, 1, 2, or 3;

[0150] v is 0, 1, 2, or 3.

[0151] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0152] in:

[0153] G is

[0154] Ring A is selected from polycyclic aryl, polycyclic heteroaryl, polycyclic cycloalkyl and polycyclic heterocyclyl;

[0155] Ring B is a monocyclic aryl group or a monocyclic heteroaryl group;

[0156] Each R 1 and each R 2a 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 17 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) vAryl, -(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;

[0157] Or, two R 1 Together with the ring atoms to which it is attached, it forms a cycloalkyl or heterocyclyl group; wherein said cycloalkyl or heterocyclyl group is optionally substituted by one or more R 0 replace;

[0158] R 2 For-OR A or -alkylene-R B ; wherein the alkylene group is optionally replaced by one or more R 0 replace;

[0159] R A is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0160] R B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0161] 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;

[0162] X 1 CR 4a or N;

[0163] X 2 CR 4b or N;

[0164] X 3 CR 4c or N;

[0165] X 4 CR 4d or N;

[0166] B 1 CR 5a or N;

[0167] B 2 CR 5b or N;

[0168] B 3 CR 5c or N;

[0169] 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0170] or R 4b and R 4c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0171] or R 4c and R 4d Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0172] or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0173] or R 5b and R 5c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace;

[0174] R 6 Selected from hydrogen atom, -NHR 7 and -NHC(O)R 7 ;

[0175] 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;

[0176] L is selected from CR 8 R 9 、C(O),O、NR 10 , S, S(O) and S(O)2;

[0177] 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;

[0178] or R 8 and R 9Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0179] 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;

[0180] 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0181] or R 11 、R 12 、R 13 、R 14 、R x and R y Any two carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally replaced by one or more R 0 replace;

[0182] or R 11 and R 12 Together they form =O;

[0183] or R 13 and R 14 Together they form =O;

[0184] or R on the same carbon atom x and R y Together they form =O;

[0185] 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;

[0186] Or, R 11 、R 12 、R 13 、R 14 、R x and R y Any one and R 15 Together with the atoms to which they are attached, they form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 replace;

[0187] W is selected from -C(O)R 16 、-S(O)2R 16 and -CN;

[0188] R 16 selected from alkenyl, alkynyl and alkenyl oxide; wherein the alkenyl, alkynyl and alkenyl oxide are each independently optionally selected from oxo, 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 、-NR20 C(O)OR 17 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 is substituted by one or more substituents in a heteroaryl group;

[0189] R 0 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, halogen, alkenyl, alkynyl, cyano, nitro, hydroxy, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 17 、-(CR a Rb ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v heteroaryl;

[0190] R 17 、R 18 、R 19 and R 20 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 Heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace;

[0191] or R 18 and R 19 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 01 replace;

[0192] R 01 are the same or different at each occurrence and are each independently selected from the group consisting of oxo, 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;

[0193] R a and R bis 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;

[0194] q is an integer from 0 to 25;

[0195] m is 0, 1, 2, 3 or 4;

[0196] n is 0, 1, 2, or 3;

[0197] v is 0, 1, 2, or 3.

[0198] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0199] in:

[0200] Ring D is a nitrogen-containing heterocyclic group;

[0201] p is 0, 1, 2, or 3;

[0202] G, R 3 、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 As defined in general formula (I).

[0203] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof:

[0204] in:

[0205] Ring C is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

[0206] R 1e R 1 ;

[0207] c is 0, 1, 2, 3, 4, or 5;

[0208] R 1 、R 3 、X 1、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、R 6 , L, 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); provided that, X 1 、X 2 、X 3 and X 4 At least one of them is N.

[0209] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein W is -C(O)R 16 ; R 16 As defined in formula (I); in some embodiments, W is -C(O)-CH=CH2.

[0210] In some embodiments of the present disclosure, in the compound represented by formula (I), formula (I-1) or formula (VI) or a pharmaceutically acceptable salt thereof, L is O.

[0211] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 1 is N.

[0212] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 2 CR 5b ; R 5b As defined in formula (I); in some embodiments, B 2 For CH.

[0213] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5a A hydrogen atom.

[0214] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5b A hydrogen atom.

[0215] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 1 N; B 2 CR 5b ; B 3 CR 5c or N; R 5b and R 5c As defined in formula (I); in some embodiments, B 1 N; B 2 CH; B 3 is CH or N; in some embodiments, B 1 N; B 2 CH; B 3 is N.

[0216] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein X 1 CR 4a ;X 2 CR 4b ;X 3 CR 4c ;X 4 CR 4d ; R 4a 、R 4b 、R 4c and R 4d As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 N or CR 4b ;X 3 CR 4c ;X 4 CR 4d ; R 4a 、R 4b 、R 4c and R 4d As defined in formula (I); in some embodiments, in some embodiments, X 1 CR 4a ;X 2 is N or CH; X 3 CR4c ;X 4 CH; R 4a and R 4c As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 CH; X 3 CR 4c ;X 4 CH; R 4a and R 4c As defined in formula (I); in some embodiments, X 1 CR 4a ; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; X 2 is N or CH; X 3 CR 4c ; R 4c is a hydrogen atom or a halogen; X 4 is CH; in some embodiments, X 1 CR 4a ; R 4a C 1-6 Alkyl; X 2 CH; X 3 CR 4c ; R 4c is a halogen; X 4 is CH; in some embodiments, X 1 CR 4a ; R 4a is methyl or hydroxymethyl; X 2 CH; X 3 CR 4c ; R 4c is a hydrogen atom or F; X 4 is CH; in some embodiments, X 1 CR 4a ; R 4a is methyl; X 2 CH; X 3 CR 4c ; R 4c F; X 4 For CH.

[0217] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl or a 6-membered heteroaryl; in some embodiments, ring C is phenyl or pyridyl; in some embodiments, ring C is phenyl.

[0218] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (VI) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI-1) or a pharmaceutically acceptable salt thereof:

[0219] in:

[0220] R 1e ,c,R 3 、X 1 、X 2 、X 3 、X 4 、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 formula (VI); provided that, X 1 、X 2 、X 3 and X 4 At least one of them is N.

[0221] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein X 1 N; X 2 CR 4b ;X 3 CR 4c ;X 4 CR 4d ; R 4b 、R 4c and R 4d As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 N; X 3 CR 4c ;X 4 CR 4d ; R 4a 、R 4c and R 4d As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 N; X 3 CR 4c ;X 4 CR4d ; R 4a 、R 4c and R 4d are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogen and C 1-6 Hydroxyalkyl; in some embodiments, X 1 CR 4a ;X 2 CR 4b ;X 3 N; X 4 CR 4d ; R 4a 、R 4b and R 4d As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 CR 4b ;X 3 CR 4c ;X 4 N; R 4a 、R 4b and R 4c As defined in formula (I); in some embodiments, X 1 CR 4a ;X 2 N; X 3 CH; X 4 CH; R 4a As defined in the general formula (I) (R 4a In some embodiments, C 1-6 Hydroxyalkyl; R 4a In some embodiments, hydroxymethyl).

[0222] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0223] in:

[0224] G, R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、Rx 、R y and n are as defined in the general formula (I).

[0225] 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 is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:

[0226] in:

[0227] p is 0, 1, 2, or 3;

[0228] x is 1, 2, 3, or 4;

[0229] G, R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 16 、R 0 、R x 、R y and n are as defined in the general formula (I).

[0230] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is optionally replaced by one or more R G substituted polycyclic aromatic groups or optionally substituted with one or more R G substituted heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted 8- to 14-membered polycyclic aromatic group or optionally substituted by one or more R G substituted 5- to 14-membered heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted 8- to 14-membered polycyclic aromatic group or optionally substituted by one or more R G substituted 8- to 14-membered polycyclic heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted 8- to 14-membered polycyclic aromatic group; in some embodiments, G is optionally substituted with one or more R G substituted 5- to 14-membered heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted 8- to 14-membered polycyclic heteroaryl; in some embodiments, G is optionally substituted with one or more R G Substituted phenyl; above R G As defined in general formula (I).

[0231] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein each R G are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyloxy, and cyano; in some embodiments, each R G are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, each R G The same or different, and each independently halogen or C 1-6 alkyl; in some embodiments, each R G are the same or different and are each independently halogen; in some embodiments, each R G are the same or different and are each independently methyl or F; in some embodiments, R G is F; in some embodiments, each R G are the same or different and are each independently halogen or 3 to 6 membered cycloalkyl; in some embodiments, each R G are the same or different and are each independently F or cyclopropyl; in some embodiments, each R G are the same or different and are each independently halogen or optionally replaced by a C 1-6 alkyl-substituted 3- to 6-membered cycloalkyl; in some embodiments, each R G The same or different, and each independently is F or

[0232] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is Ring A, R 1 and q are as defined in formula (I); in some embodiments, G is R 1 As defined in formula (I); in some embodiments, G is

[0233] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is In some embodiments, G is

[0234] In the above schemes: Q 1 , Q 2 , Q 3 and Q 4 One of them is C, connected to C(O); the other three are the same or different, and each is independently N or CR 1a ; A 1 and A 2 are the same or different and are each independently selected from a bond, C(O), O, NR, S, S(O), S(O)2 and (CR 1b R 1c ) j ; R 1a 、R 1b 、R 1c 、R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or R 1 ; or, R e and R f Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replace; or, R j and R k Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replace; or, R f and R jTogether with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replacement; or R 1b and R 1c Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 substituted; j is 0, 1, 2 or 3; r is 0 or 1; q1 is 0, 1, 2 or 3; R is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 1 As defined in general formula (I).

[0235] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is R 1 As defined in formula (I); in some embodiments, G is R 1 As defined in formula (I); in some embodiments, G is In some embodiments, G is

[0236] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G is selected from In some embodiments, G is selected from

[0237] In some embodiments, G is selected from

[0238] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is Ring B, R 2 、R 2a and m are as defined in the general formula (I).

[0239] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G is Ring B, R C 、R 2a and m are as defined in formula (I); in some embodiments, G is R C 、R 2a and m are as defined in formula (I); in some embodiments, G is R C and R 2a As defined in formula (I); in some embodiments, G is b is 1, 2, 3, 4, or 5 (in some embodiments, 1); y is 1, 2, or 3 (in some embodiments, 1); R d 、R 2a and m are as defined in formula (I); in some embodiments, G is y is 1, 2, or 3 (in some embodiments, 1); R d 、R 2a and m are as defined in formula (I); in some embodiments, G is R 2a and R d As defined in formula (I); in some embodiments, G is R 2a and R d As defined in formula (I); in some embodiments, G is

[0240] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is a 7- to 10-membered fused heterocyclic group; in some embodiments, ring A is an 8- or 9-membered fused heterocyclic group.

[0241] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is an 11- to 14-membered tricyclic aryl group or a 12- to 19-membered tetracyclic aryl group; in some embodiments, ring A is an 11- or 12-membered tricyclic aryl group or a 13-membered tetracyclic aryl group; in some embodiments, ring A is an 11- to 14-membered tricyclic aryl group; in some embodiments, ring A is an 11- or 12-membered tricyclic aryl group; in some embodiments, ring A is an 11-membered tricyclic aryl group; in some embodiments, ring A is a 12- to 19-membered tetracyclic aryl group; in some embodiments, ring A is a 13-membered tetracyclic aryl group; in some embodiments, ring A is an 8- to 14-membered polycyclic aryl group or an 8- to 14-membered polycyclic heteroaryl group; in some embodiments, Ring A is an 8- to 14-membered polycyclic aromatic group or a 5- to 14-membered heteroaryl group; in some embodiments, ring A is an 8- to 14-membered polycyclic aromatic group; in some embodiments, ring A is a 5- to 14-membered heteroaryl group; in some embodiments, ring A is a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a 5-membered heteroaryl group.

[0242] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from j is 0, 1, 2, or 3; r is 0 or 1; t is 1, 2, 3, or 4; z is 1, 2, 3, or 4; f is 1, 2, 3, or 4; in some embodiments, Ring A is selected from j is 0, 1, 2, or 3; r is 0 or 1; t is 1, 2, 3, or 4; z is 1, 2, 3, or 4; f is 1, 2, 3, or 4; In some embodiments, Ring A is j is 0, 1, 2, or 3; t is 1, 2, 3, or 4; z is 1, 2, 3, or 4; in some embodiments, Ring A is j is 0, 1, 2 or 3; t is 1, 2, 3 or 4; in some embodiments, Ring A is j is 0, 1, 2, or 3; t is 1, 2, 3, or 4; z is 1, 2, 3, or 4; in some embodiments, Ring A is j is 0, 1, 2 or 3; t is 1, 2, 3 or 4; in some embodiments, ring A is selected from In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is

[0243] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In the above schemes: Q 1 , Q 2 , Q 3 and Q 4 One of them is C, connected to C(O); the other three are the same or different, and each is independently N or CR 1a ; A 1 and A 2are the same or different and are each independently selected from a bond, C(O), O, NR, S, S(O), S(O)2 and (CR 1b R 1c ) j ; R 1a 、R 1b 、R 1c 、R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or R 1 ; or, R e and R f Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replace; or, R j and R k Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replace; or, R f and R j Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 Replacement; or R 1b and R 1c Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 substituted; j is 0, 1, 2 or 3; r is 0 or 1; q1 is 0, 1, 2 or 3; R is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 1 As defined in general formula (I).

[0244] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In the above schemes: j is 0, 1, 2 or 3; t is 1, 2, 3 or 4; z is 1, 2, 3 or 4; q1 is 0, 1, 2 or 3; R 1 As defined in general formula (I).

[0245] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 1 As defined in formula (I); in some embodiments, Selected from In some embodiments, for In some embodiments, for

[0246] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or R 1 ; or, R e and R f Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; or, R j and R k Together with the carbon atom to which it is attached, it forms a cycloalkyl group or a heterocyclic group; 1 is selected from a bond, CH2, O and NR; R is selected from a hydrogen atom, an alkyl group and a cycloalkyl group; R 1 As defined in formula (I); in some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for R 1 As defined in formula (I); in some embodiments, for In some embodiments, for

[0247] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein G or Selected from R 1 ' is a hydrogen atom or R 1 ; q1 is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6; R 1 As defined in formula (I); in some embodiments, G or Selected from q2 is 0, 1, 2, 3, or 4; R 1 ” is R 1 ; R 1 As defined in formula (I); in some embodiments, G or Selected from

[0248] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or a 5- or 6-membered heteroaryl group; in some embodiments, ring B is phenyl or a 6-membered heteroaryl group; in some embodiments, ring B is phenyl.

[0249] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for R 2 、R 2a and m are as defined in formula (I); in some embodiments, for R 2 and R 2a As defined in general formula (I).

[0250] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for R C 、R 2a and m are as defined in formula (I); in some embodiments, for R C and R 2a As defined in formula (I); in some embodiments, for b is 1, 2, 3, 4, or 5 (in some embodiments, 1); y is 1, 2, or 3 (in some embodiments, 1); R d 、R 2a and m are as defined in formula (I); in some embodiments, for y is 1, 2, or 3 (in some embodiments, 1); R d 、R 2a and m are as defined in formula (I); in some embodiments, for R d and R 2a As defined in formula (I); in some embodiments, for R 2a and R d As defined in formula (I); in some embodiments, for

[0251] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for R 2a is halogen; m is 1; y is 1, 2, or 3 (in some embodiments, 1); each R d are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; in some embodiments, for R 2a is halogen; R d C 1-6 Alkyl; in some embodiments, for R 2a is halogen; R d C 1-6 Alkyl; in some embodiments, for

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0253] in:

[0254] A 1 and A 2 are the same or different and are each independently selected from a bond, C(O), O, NR, S, S(O), S(O)2 and (CR 1b R 1c ) j ;

[0255] R 1b 、R 1c 、R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or R 1 ;

[0256] Or, R e and R f Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 replace;

[0257] Or, R j and R k Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 replace;

[0258] Or, R f and R j Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 replace;

[0259] Or, R 1band R 1c Together with the attached carbon atom, it forms a cycloalkyl or heterocyclyl group; said cycloalkyl or heterocyclyl group is optionally substituted with 1, 2, 3 or 4 (in some embodiments, 1 or 2, in some embodiments, 1) R 1 replace;

[0260] R 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, an aminoalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0261] j is 0, 1, 2, or 3;

[0262] q1 is 0, 1, 2, or 3;

[0263] r is 0 or 1;

[0264] R 1 、R 3 、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 the general formula (I).

[0265] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0266] in:

[0267] R 2a 、R 2 、R 3 、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 , m and n are as defined in the general formula (I).

[0268] 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 (V) or a pharmaceutically acceptable salt thereof:

[0269] in:

[0270] y is 1, 2, or 3; in some embodiments, 1;

[0271] b is 1, 2, 3, 4, or 5; in some embodiments, is 1;

[0272] R 2a 、R d 、R 3 、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 , m and n are as defined in the general formula (I).

[0273] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or a pharmaceutically acceptable salt thereof, wherein for A 1 、A 2 、R 1 、R e 、R f 、R j and R k As defined in formula (III); for A 1 、A 2 、R 1 、R e 、R f 、R j and R k As defined in formula (III); in some embodiments, for A 1 、A 2 、R 1 、R e、R f 、 R j and R k As defined in formula (III); in some embodiments, for A 1 、R 1 、R e 、R f 、R j and R k As defined in formula (III); in some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In the above schemes: j is 0, 1, 2 or 3; t is 1, 2, 3 or 4; z is 1, 2, 3 or 4; q1 is 0, 1, 2 or 3; R 1 As defined in general formula (I).

[0274] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from R 1 As defined in formula (I); in some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, Selected from

[0275] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyloxy, and cyano; in some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, each R 1 are the same or different and are each independently halogen or 3 to 6 membered cycloalkyl; in some embodiments, each R 1 are the same or different and are each independently F or cyclopropyl; in some embodiments, each R 1 The same or different, and each independently halogen or C 1-6 alkyl; in some embodiments, each R 1 are the same or different and are each independently halogen; each R 1 The same or different, and each independently is C 1-6 alkyl; in some embodiments, each R 1 are the same or different and are each independently methyl or F; in some embodiments, R 1 is methyl; in some embodiments, R 1 For F.

[0276] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 'Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 1 'Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1 ' is a hydrogen atom or a halogen; in some embodiments, R 1 ' is halogen; in some embodiments, R 1 'For F.

[0277] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 " are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 1 " is halogen or C 1-6 Alkyl; in some embodiments, R 1 " is C 1-6 Alkyl; in some embodiments, R 1 " is a methyl group.

[0278] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein q2 is 0, 1, 2 or 3; in some embodiments, q2 is 0, 1 or 2; in some embodiments, q2 is 2.

[0279] 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 (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 " is C 1-6 alkyl; q2 is 2; in some embodiments, R 1 " is a methyl group; q2 is 2.

[0280] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (VI) or general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein each R 1e are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally selected from halogen, C 1-6 Alkyl, C1-6 Haloalkyl, hydroxyl and C 1-6 In some embodiments, each R 1e are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 hydroxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 1e are the same or different and are each independently halogen or 3 to 6 membered cycloalkyl; in some embodiments, each R 1e are the same or different and are each independently halogen or cyclopropyl; in some embodiments, each R 1e are the same or different and are each independently F or cyclopropyl.

[0281] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or the general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein c is 1, 2 or 3; in some embodiments, c is 2.

[0282] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein for R 1e and c are as defined in Formula (VI); in some embodiments, for R 1f is a hydrogen atom or R 1e ; R 1g is a hydrogen atom or R 1e ; R 1e As defined in formula (VI); in some embodiments, for

[0283] In some embodiments of the present disclosure, the compound represented by the general formula (VI), the general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein for R 1f is a hydrogen atom or R 1e ; R 1g is a hydrogen atom or R 1e ; R 1e As defined in formula (VI-1); in some embodiments, for

[0284] In some embodiments of the present disclosure, wherein R 1f Selected from hydrogen atoms, halogens, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 1f is a hydrogen atom or a halogen; in some embodiments, R 1f is halogen; in some embodiments, R 1f For F.

[0285] In some embodiments of the present disclosure, wherein R 1g Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl and C 1-6 In some embodiments, R 1g is a 3 to 6-membered cycloalkyl group; wherein the 3 to 6-membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl and C 1-6 In some embodiments, R 1g is a 3- to 6-membered cycloalkyl group; in some embodiments, R 1g It is cyclopropyl.

[0286] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, wherein q is an integer from 0 to 20 (i.e., q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); in some embodiments, q is an integer from 0 to 10 (i.e., q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); in some embodiments, q is 0, 1, 2, 3, 4, 5 or 6; in some embodiments, q is 0, 1, 2, 3 or 4; in some embodiments, q is 1, 2 or 3; in some embodiments, q is 0, 1, 2 or 3; in some embodiments, q is 1 or 3; in some embodiments, q is 0 or 1; in some embodiments, q is 1; in some embodiments, q is 3.

[0287] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein q1 is 0, 1 or 2; in some embodiments, q1 is 0 or 1; in some embodiments, q1 is 1; in some embodiments, q1 is 0.

[0288] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R A is a 3- to 6-membered cycloalkyl group or a C 1-6 Alkyl; in some embodiments, R A is cyclopropyl or isopropyl; in some embodiments, R A is a 3- to 6-membered cycloalkyl group; in some embodiments, R A is cyclopropyl; in some embodiments, R A C 1-6 Alkyl; in some embodiments, R A It is isopropyl.

[0289] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R B is a 3- to 6-membered cycloalkyl group; in some embodiments, R B It is cyclopropyl.

[0290] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 For-OR A or 3 to 6 membered cycloalkyl C 1-6 Alkyl; R A As defined in formula (I); in some embodiments, R 2 is selected from isopropyloxy, cyclopropyloxy and cyclopropylmethyl.

[0291] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (V) or a pharmaceutically acceptable salt thereof, wherein for y is 1, 2, or 3 (in some embodiments, 1); R d 、R 2a and m are as defined in formula (I); in some embodiments, for R2a and R d As defined in formula (I); in some embodiments, for R 2a and R d As defined in formula (I); in some embodiments, for

[0292] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (V) or a pharmaceutically acceptable salt thereof, wherein R C is a 3- to 6-membered cycloalkyl group; wherein the 3- to 6-membered cycloalkyl group is replaced by one or more R d Replacement; R d As defined in formula (I); in some embodiments, R C is a cyclopropyl group; wherein the cyclopropyl group is replaced by one or more R d Replacement; R d As defined in formula (I); in some embodiments, R C is a cyclopropyl group; wherein the cyclopropyl group is replaced by a C 1-6 Alkyl substituted; in some embodiments, R C for b is 1, 2, 3, 4, or 5 (in some embodiments, 1); y is 1, 2, or 3 (in some embodiments, 1); R d As defined in formula (I); in some embodiments, R C for y is 1, 2, or 3 (in some embodiments, 1); R d As defined in formula (I); in some embodiments, R C for R d As defined in formula (I); in some embodiments, R C for R d As defined in formula (I); in some embodiments, R C for

[0293] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (V) or a pharmaceutically acceptable salt thereof, wherein each R d are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, each R d The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, each R d are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; in some embodiments, each R d are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R d The same or different, and each independently selected from C 1-6 Alkyl, C 1- 6 haloalkyl and C 1-6 Alkoxy; in some embodiments, each R d The same or different, and each independently is C 1-6 alkyl or halogen; in some embodiments, each R d The same or different, and each independently is C 1- 6 alkyl; in some embodiments, R d It is a methyl group.

[0294] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (IV) or general formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, each R 2a are the same or different and are each independently halogen; in some embodiments, R 2a For F.

[0295] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; in some embodiments, m is 0 or 1; in some embodiments, m is 1.

[0296] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 4a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; in some embodiments, R 4a C 1- 6 alkyl; in some embodiments, R 4a is methyl; in some embodiments, R 4a C 1-6 Hydroxyalkyl; in some embodiments, R 4a is methyl or hydroxymethyl; in some embodiments, R 4a It is hydroxymethyl.

[0297] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 4b A hydrogen atom.

[0298] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 4c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 4c is a hydrogen atom or a halogen; in some embodiments, R 4c is halogen; in some embodiments, R 4c is a hydrogen atom or F; in some embodiments, R4c is a hydrogen atom; in some embodiments, R 4c For F.

[0299] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 4d Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 4d A hydrogen atom.

[0300] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) 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 hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or a halogen; R 4d is a hydrogen atom; in some embodiments, R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; in some embodiments, R 4a is methyl or hydroxymethyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or F; R 4d is a hydrogen atom; in some embodiments, R 4a is methyl; R 4b is a hydrogen atom; R 4c F; R 4d A hydrogen atom.

[0301] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, C 1-6 alkyl and cyclopropyl; in some embodiments, R 3 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 3 A hydrogen atom.

[0302] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 5c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5c A hydrogen atom.

[0303] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein B 3 is CH or N; in some embodiments, B 3 is N.

[0304] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 6 NHR 7 ; R 7 As defined in formula (I); in some embodiments, R 6 In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 7 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 7 A hydrogen atom.

[0305] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; in some embodiments, n is 0.

[0306] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) 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 hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 11 、R 12 、R 13 and R 14 The same or different, and each independently a hydrogen atom or a C 1- 6 alkyl; 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 a deuterium atom; in some embodiments, R 11 、R 12 、R 13 and R 14 A hydrogen atom.

[0307] In some embodiments of the present disclosure, the compound represented by the general formula (I-1) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 11 and R 12 are the same or different and are each independently a hydrogen atom or a deuterium atom; in some embodiments, R 11 and R 12 The same or different, and each independently a hydrogen atom or C 1-6 Alkyl; in some embodiments, R 11 and R 12 is a deuterium atom; in some embodiments, R 11 and R 12 A hydrogen atom.

[0308] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 11 、R 12 、R 13 and R 14 is a hydrogen atom; and / or n is 0.

[0309] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R x and R y are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R x and R y The same or different, and each independently a hydrogen atom or C 1-6 Alkyl; in some embodiments, R x and R y A hydrogen atom.

[0310] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 15 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 haloalkyl; in some embodiments, R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 deuterated alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 15 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 15 C 1-6 alkyl or 3 to 6 membered cycloalkyl; in some embodiments, R 15 C 1-6 Alkyl or C 1-6 deuterated alkyl; in some embodiments, R15 C 1-6 Alkyl; in some embodiments, R 15 is methyl or -CD3; in some embodiments, R 15 is methyl or cyclopropyl; in some embodiments, R 15 is methyl; in some embodiments, R 15 is -CD3; in some embodiments, R 15 is cyclopropyl; in some embodiments, R 15 is selected from the group consisting of methyl, -CD3, ethyl and -CH2CH2F.

[0311] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 14 and R 15 Together with the atoms to which they are attached, they form a 4- to 7-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 0 Replacement; R 0 As defined in formula (I); in some embodiments, R 14 and R 15 Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 0 Replacement; R 0 The same or different, and each independently halogen or C 1-6 Alkoxy.

[0312] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 13 is a hydrogen atom; R 14 and R 15 Together with the atoms to which they are attached, they 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 Replacement; R 0 As defined in formula (I); in some embodiments, R 13 is a hydrogen atom; R 14 and R 15 Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocyclic group; wherein the 5-membered nitrogen-containing heterocyclic group is optionally replaced by one or more R 0 Replacement; R 0 As defined in formula (I); in some embodiments, R 13 is a hydrogen atom; R 14and R 15 Together with their respective atoms to which they are attached, they form a pyrrolidinyl group, wherein said pyrrolidinyl group is optionally substituted by one or more R 0 Replacement; R 0 As defined in formula (I); in some embodiments, R 13 is a hydrogen atom; R 14 and R 15 Together with the atoms to which they are attached form a pyrrolidinyl group.

[0313] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) 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 hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 15 Selected from hydrogen atoms, C 1-6 alkyl and 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 hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 13 is a hydrogen atom; R 14 and R 15 Together with the atoms to which they are attached, they 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 Replacement; R 0 As defined in formula (I);

[0314] In some embodiments, R 11 、R 12 、R 13 、R 14 、R x and R y The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; R 15 C 1-6 Alkyl or 3 to 6 membered cycloalkyl; or R 11 、R 12 、R x and R y The same or different, and each independently a hydrogen atom or a C1-6 Alkyl; R 13 is a hydrogen atom; R 14 and R 15 Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocyclic group; wherein the 5-membered nitrogen-containing heterocyclic group is optionally replaced by one or more R 0 Replacement; R 0 As defined in formula (I);

[0315] In some embodiments, R 11 、R 12 、R 13 、R 14 、R x and R y is a hydrogen atom; R 15 C 1-6 Alkyl or 3 to 6 membered cycloalkyl; or R 11 、R 12 、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 attached, they form a 5-membered nitrogen-containing heterocyclic group;

[0316] In some embodiments, R 11 、R 12 、R 13 、R 14 、R x and R y is a hydrogen atom; R 15 C 1-6 Alkyl; or R 11 、R 12 、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 attached form a pyrrolidinyl group.

[0317] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom or a deuterium atom; R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1- 6 haloalkyl; or, R14 and R 15 Together with the atoms to which they are attached, they form a 4- to 7-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 0 Replacement; R 0 The same or different, and each independently halogen or C 1-6 Alkoxy; in some embodiments, R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl or C 1-6 deuterated alkyl; in some embodiments, R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl; in some embodiments, R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 It is a methyl group.

[0318] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 16 C 2-6 alkenyl; wherein said 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 each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 16 C 2-6 alkenyl; in some embodiments, R 16 It is -CH=CH2.

[0319] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 0are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 0 are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 0 is the same or different at each occurrence and is independently halogen or C 1-6 Alkoxy; in some embodiments, R 0 is the same or different at each occurrence and is independently F or methoxy.

[0320] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 01 are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; in some embodiments, R 01 are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0321] In some embodiments of the present disclosure, the compound represented by the general formula (I-1) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; in some embodiments, p is 0; in some embodiments, p is 1.

[0322] In some embodiments of the present disclosure, the compound represented by the general 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 a pyrrolidinyl group.

[0323] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein x is 2 or 3; in some embodiments, x is 2.

[0324] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0; in some embodiments, r is 1.

[0325] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1.

[0326] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein z is 1.

[0327] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein f is 1 or 2; in some embodiments, f is 1.

[0328] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; in some embodiments, j is 0 or 1; in some embodiments, j is 1 or 2; in some embodiments, j is 1; in some embodiments, j is 0.

[0329] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1b and R 1c are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R 1b and R 1c A hydrogen atom.

[0330] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein A 1 A is selected from a bond, O and CH2; 2 Selected from bond, O and CR 1b R 1c ; R 1b and R 1c is a hydrogen atom; or R 1b and R 1cTogether with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, A 1 A is selected from a bond, O and CH2; 2 Selected from bond, O and CR 1b R 1c ; R 1b and R 1c is a hydrogen atom; or R 1b and R 1c Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, A 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; in some embodiments, A 1 CH2 or O, A 2 is a bond; in some embodiments, A 1 For CH2, A 2 is a bond; in some embodiments, A 1 for O,A 2 is a bond; in some embodiments, A 1 for O,A 2 is O; in some embodiments, A 1 is the key, A 2 is CH2 or O; in some embodiments, A 1 is the key, A 2 is O; in some embodiments, A 1 is the key, A 2 is CH2; in some embodiments, A 1 is O or CH2; A 2 is a key; or, A 2 is O or CH2; A 1 is the key.

[0331] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein A 2 Selected from bond, O and CR 1b R 1c ; R 1b and R 1c is a hydrogen atom; or R 1b and R 1c Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, A 2 is a bond or O; in some embodiments, A 2 is a bond; in some embodiments, A 2 is CH2 or O;

[0332] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein in some embodiments, A 1 is O; in some embodiments, A 1 is a bond; in some embodiments, A 1 is CH2 or O.

[0333] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R e 、R f 、R j and R k are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R f and R j Together with the attached carbon atom, they form a 4- to 6-membered cycloalkyl group; in some embodiments, R e 、R f 、R j and R k is a hydrogen atom; or, R e and R f Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R f and R j Together with the attached carbon atom, they form a cyclobutyl group; in some embodiments, R e 、R f 、R j and R k A hydrogen atom or C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R e 、R f 、R j and R k is a hydrogen atom or a methyl group; or, R e and Rf Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R j and R k Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R e and R f C 1-6 Alkyl; or R e and R f Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; R j and R k is a hydrogen atom; in some embodiments, R j and R k C 1-6 Alkyl; or R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; R e and R f A hydrogen atom.

[0334] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1; R e and R f Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, R j and R k is a hydrogen atom; or r is 1; R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, R e and R f is a hydrogen atom; or r is 1, R f and R j Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, R e and R k is a hydrogen atom; in some embodiments, r is 0 or 1, R e and R f Together with the attached carbon atom, it forms a cyclopropyl group, R j and R k is a hydrogen atom; or r is 1, R j and R k Together with the attached carbon atom, it forms a cyclopropyl group, R e and R f is a hydrogen atom; or r is 1, R f and R j Together with the attached carbon atom, it forms a cyclobutyl group, R e and R k is a hydrogen atom; in some embodiments, r is 1, R jand R k Together with the attached carbon atom, it forms a cyclopropyl group, R e and R f A hydrogen atom.

[0335] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R e and R f are each independently a hydrogen atom or a C 1-6 Alkyl; or R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R e and R f Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R e and R f Together with the attached carbon atoms, In some embodiments, R e and R f Each independently is C 1-6 Alkyl; in some embodiments, R e and R f is methyl; in some embodiments, R e and R f A hydrogen atom.

[0336] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R j and R k are each independently a hydrogen atom or a C 1-6 Alkyl; or R j and R k Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R j and R k Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R j and R k Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R j and R k Together with the attached carbon atoms, In some embodiments, R j and R k Each independently is C1-6 Alkyl; in some embodiments, R j and R k is methyl; in some embodiments, R j and R k A hydrogen atom.

[0337] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R e 、R f 、R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or, R e and R f Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a cyclopropyl group; r is 0 or 1; A 1 A is selected from a bond, O and CH2; 2 Selected from bond, O and CR 1b R 1c ; R 1b and R 1c is a hydrogen atom; or R 1b and R 1c Together with the attached carbon atom it forms a cyclopropyl group.

[0338] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R 17 、R 18 、R 19 and R 20 is the same or different at each occurrence and is independently a hydrogen atom or a C 1- 6 alkyl.

[0339] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1; in some embodiments, v is 0.

[0340] In some embodiments of the present disclosure, the compound represented by formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R a and R b A hydrogen atom.

[0341] In some embodiments of the present disclosure, wherein G is optionally substituted with one or more R G substituted 5 or 6 membered heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted 5-membered heteroaryl; in some embodiments, G is optionally substituted with one or more R G substituted thienyl; in some embodiments, G is optionally substituted with one or more R G Replaced In some embodiments, G is

[0342] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G is selected from R 1 'Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; q1 is 0 or 1; q is 0, 1, 2, 3 or 4; R 3 is a hydrogen atom; X 1 CR 4a ; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; X 2 is N or CH; X 3 CR 4c ; R 4c is a hydrogen atom or a halogen; X 4 CH; B 1 N; B 2 CH; B3 is N; L is O; R 6 is amino; n is 0; R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom or a deuterium atom; R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 haloalkyl; or, R 14 and R 15 Together with the atoms to which they are attached, they form a 4- to 7-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 0 Replacement; R 0 The same or different, and each independently halogen or C 1-6 Alkoxy; W is -C(O)-CH=CH2.

[0343] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is selected from R 1 is halogen; R 1 " is C 1-6 Alkyl; q2 is 0, 1, 2 or 3; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or a halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; n is 0; R 11 、R 12 、R 13 and R 14 are each independently a hydrogen atom or a deuterium atom; R 15 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 haloalkyl; or, R 14 and R 15 Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 0 Replacement; R 0 The same or different, and each independently halogen or C 1-6 Alkoxy; R 16 It is -CH=CH2.

[0344] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G is r is 1; q1 is 1; R 1 A is a halogen; 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; R e 、R f 、R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; R 3 is a hydrogen atom; X 1 CR 4a ; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; X 2 is N or CH; X 3 CR 4c ; R 4c is a hydrogen atom or a halogen; X 4 CH; B 1 N; B 2 CH; B 3 N; R 6 is amino; L is O; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl or C 1-6 Deuterated alkyl; n is 0; W is -C(O)-CH=CH2.

[0345] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein G is R 1 is halogen; R 3 is a hydrogen atom; X 1 CR 4a ; R 4a C 1- 6 alkyl; X 2 CH; X 3 CR 4c ; R 4c is a halogen; X 4 CH; B1 N; B 2 CH; B 3 N; R 6 is amino; L is O; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl; n is 0; W is -C(O)-CH=CH2.

[0346] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is R 1 is halogen; R e 、R f 、R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or a halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl or C 1-6 Deuterated alkyl; n is 0; R 16 It is -CH=CH2.

[0347] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4bis a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 is methyl or -CD3; n is 0; R 16 It is -CH=CH2.

[0348] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; q1 is 1; A 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; r is 1; R e 、R f 、R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl or C 1-6 Hydroxyalkyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or a halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl or C 1-6 Deuterated alkyl; n is 0; R 16 It is -CH=CH2.

[0349] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; q1 is 1; A 1 is O or CH2; A 2 is a key; or, A 2 is O or CH2; A 1is a key; r is 1; R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or a methyl group; or, R e and R f Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R j and R k Together with the attached carbon atom, it forms a cyclopropyl group; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; R 15 C 1-6 Alkyl; n is 0; R 16 It is -CH=CH2.

[0350] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is for q1 is 1; R 1 is halogen; j is 1; t is 1; z is 1; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 CH or N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 16 C 2-6 Alkenyl.

[0351] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is Ring A is selected from Each R 1are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyloxy, and cyano; q is 0, 1, 2, or 3; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 CH or N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 16 C 2-6 Alkenyl.

[0352] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is for R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0353] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1; R e and R f Together with the attached carbon atom, it forms a cyclopropyl group, R j and R k is a hydrogen atom; or r is 1, R j and Rk Together with the attached carbon atom, it forms a cyclopropyl group, R e and R f is a hydrogen atom; or r is 1, R f and R j Together with the attached carbon atom, it forms a cyclobutyl group, R e and R k A is a hydrogen atom; 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; q1 is 1; R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 CH or N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 6-membered cycloalkyl; R 16 C 2-6 Alkenyl.

[0354] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 1; R j and R k Together with the attached carbon atom, it forms a cyclopropyl group; R e and R f A is a hydrogen atom; 1 CH2; A 2 is a key; q1 is 1; R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0355] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1; A 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; R e 、R f 、R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; q1 is 0 or 1; R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0356] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 1; A 1 CH2 or O, A 2 is a key; R e 、R f 、R j and R k are the same or different and are each independently a hydrogen atom or a methyl group; or, R e and R f Together with the carbon atom to which it is attached, it forms a cyclopropyl group; or, R j and R k Together with the carbon atom to which it is attached, it forms a cyclopropyl group; q1 is 1; R 1 is halogen; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0357] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein R 2a is halogen; m is 1; b is 1; y is 1; R d Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; R 3 is a hydrogen atom; R 4a C 1-6 Alkyl; R 4b is a hydrogen atom; R 4c is halogen; R 4d is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R 12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0358] In some embodiments of the present disclosure, the compound represented by the general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein for R 1g is a 3- to 6-membered cycloalkyl group; R 1f is a halogen; X 1 CR 4a ;X 2 N; X 3 CR 4c ;X 4 CR 4d ; R 4a 、R 4c and R 4d are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, halogen and C 1-6 Hydroxyalkyl; R 3 is a hydrogen atom; B 3 N; R 6 is amino; R 11 、R12 、R 13 and R 14 is a hydrogen atom; n is 0; R 15 C 1-6 Alkyl; R 16 It is -CH=CH2.

[0359] Table A Typical compounds of the present disclosure include, but are not limited to:

[0360] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

[0361] in:

[0362] G, R 3 、X 1 、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、R 6 , L, R 11 、R 12 、R 13 、R 14 、R 15 、R x 、 R y and n are as defined in the general formula (I).

[0363] Another aspect of the present disclosure relates to a compound represented by general formula (I-1A) or a salt thereof:

[0364] in:

[0365] G, R 3 、X 1 、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、R 6 , L, R 11 、R 12 、R x 、R y ,n,ring D,R 0and p are as defined in the general formula (I-1).

[0366] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof:

[0367] in:

[0368] G, R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R x 、R y and n are as defined in general formula (II).

[0369] Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof:

[0370] in:

[0371] G, R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R x 、R y ,n,R 0 , p and x are as defined in the general formula (II-1).

[0372] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof:

[0373] in:

[0374] A 1 、A 2 、R e 、R f 、R j 、R k , r, R 1 ,q1,R 3 、R 4a 、R 4b 、R 4c 、R 4d、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R x 、R y and n are as defined in general formula (III).

[0375] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof:

[0376] in:

[0377] R 2 、R 2a ,m,R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R x 、R y and n are as defined in general formula (IV).

[0378] Another aspect of the present disclosure relates to a compound represented by general formula (VA) or a salt thereof:

[0379] in:

[0380] R d ,y,b,R 2a ,m,R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14 、R 15 、R x 、R y and n are as defined in formula (V).

[0381] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0382] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0383] The compound represented by general formula (IA) or its salt undergoes a condensation reaction with the compound represented by general formula (IB) or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

[0384] in:

[0385] X is a halogen, in some embodiments Cl;

[0386] W is -C(O)R 16 or -S(O)2R 16 ;

[0387] G, R 3 、X 1 、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、R 6 , L, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R x 、R y and n are as defined in the general formula (I).

[0388] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0389] The compound represented by the general formula (I-1A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0390] in:

[0391] X is a halogen, in some embodiments Cl;

[0392] W is -C(O)R 16 or -S(O)2R 16 ;

[0393] G, R 3 、X 1 、X 2 、X 3 、X 4 、B 1 、B 2 、B 3 、R 6 , L, R 11 、R 12 、R 16 、R x 、R y ,n,ring D,R 0 and p are as defined in the general formula (I-1).

[0394] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0395] The compound represented by general formula (IIA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0396] in:

[0397] X is a halogen, in some embodiments Cl;

[0398] G, R 3 、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 (II).

[0399] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0400] The compound represented by general formula (II-1A) or a salt thereof undergoes a condensation reaction with the compound represented by general formula (IIB) or a salt thereof to obtain the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0401] in:

[0402] X is a halogen, in some embodiments Cl;

[0403] G, R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 16 、R x 、R y ,n,R 0 , p and x are as defined in the general formula (II-1).

[0404] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0405] The compound represented by general formula (IIIA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0406] in:

[0407] X is a halogen, in some embodiments Cl;

[0408] A 1 、A 2 、R e 、R f 、R j 、R k , r, R 1 ,q1,R 3 、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 (III).

[0409] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0410] The compound represented by general formula (IVA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0411] in:

[0412] X is a halogen, in some embodiments Cl;

[0413] R 2 、R 2a ,m,R 3 、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 (IV).

[0414] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0415] The compound represented by general formula (VA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (V) or its pharmaceutically acceptable salt;

[0416] in:

[0417] X is a halogen, in some embodiments Cl;

[0418] R d ,y,b,R 2a ,m,R 3 、R 4a 、R 4b 、R 4c 、R 4d 、B 3 、R 6 、R 11 、R 12 、R 13 、R 14、R 15 、R x 、R y , n and R 16 As defined in general formula (V).

[0419] In some embodiments of the present disclosure, in the preparation method of the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VI-1), the condensation reaction is carried out under alkaline conditions; the reagents providing alkaline conditions include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; in some embodiments, the reagent providing alkaline conditions is N,N-diisopropylethylamine.

[0420] In some embodiments of the present disclosure, the preparation method of the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III), general formula (IV), general formula (V), general formula (VI) or general formula (VI-1), the condensation reaction is carried out in a solvent, and the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

[0421] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VI-1) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0422] The present disclosure further relates to the use of compounds of Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VI-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by BTK.

[0423] The present disclosure further relates to the use of compounds of formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of BTK inhibitors.

[0424] The present disclosure further relates to the use of compounds of Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VI-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions; the diseases or conditions are selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine dysfunction, and neurological disorders; in some embodiments, the diseases or conditions are selected from autoimmune diseases, inflammatory diseases, and cancer; in some embodiments, the diseases or conditions are autoimmune diseases or inflammatory diseases;In some embodiments, the disease or disorder is selected from the group consisting of B-cell malignancies, multiple myeloma, leukemias (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), malignant lymphomas (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's lymphoma, B-cell non-Hodgkin's lymphoma, B-cell lymphoma, and follicular lymphoma), Waldenstrom's macroglobulin Leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom's 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 1 diabetes, type 2 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 (e.g., chronic spontaneous urticaria, chronic induced urticaria, chronic autoimmune urticaria), hepatic insufficiency, allergies (e.g., atopic dermatitis, atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic 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, gram-negative bacteria, Reves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic disease, myocardial infarction, angina pectoris, stroke, ischemic conditions, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications due to organ transplantation, allograft, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection.

[0425] The present disclosure further relates to a method for inhibiting BTK, comprising administering to a patient in need thereof a compound of Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VI-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0426] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by BTK, comprising administering to a patient in need thereof a compound of Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VI-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0427] The present disclosure further relates to a method for treating and / or preventing a disease or condition, comprising administering to a patient in need thereof a compound of Formula (I), Formula (I-1), Formula (II), Formula (II-1), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VI-1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the disease or condition is selected from cancer, autoimmune disease, inflammatory disease, allergic disease, allergic reaction, respiratory disease, cardiovascular disease, viral infection, transplant rejection, metabolic / endocrine dysfunction, and neurological disorder; in some embodiments, the disease or condition is selected from autoimmune disease, inflammatory disease, and cancer; in some embodiments, the disease or condition is an autoimmune disease or an inflammatory disease;In some embodiments, the disease or disorder is selected from the group consisting of B-cell malignancies, multiple myeloma, leukemias (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), malignant lymphomas (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's lymphoma, B-cell non-Hodgkin's lymphoma, B-cell lymphoma, and follicular lymphoma), Waldenstrom's macroglobulin Leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom's 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 1 diabetes, type 2 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 (e.g., chronic spontaneous urticaria, chronic induced urticaria, chronic autoimmune urticaria), hepatic insufficiency, allergies (e.g., atopic dermatitis, atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic 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, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, 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.

[0428] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug.

[0429] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a BTK inhibitor.

[0430] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing diseases or conditions mediated by BTK.

[0431] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI) or formula (VI-1) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or condition; the disease or condition is selected from cancer, autoimmune disease, inflammatory disease, allergic disease, allergic reaction, respiratory disease, cardiovascular disease, viral infection, transplant rejection, metabolic / endocrine dysfunction and neurological disorder; in some embodiments, the disease or condition is selected from autoimmune disease, inflammatory disease and cancer; in some embodiments, the disease or condition is an autoimmune disease or inflammatory disease;In some embodiments, the disease or disorder is selected from the group consisting of B-cell malignancies, multiple myeloma, leukemias (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), malignant lymphomas (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's lymphoma, B-cell non-Hodgkin's lymphoma, B-cell lymphoma, and follicular lymphoma), Waldenstrom's macroglobulin Leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom's 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 1 diabetes, type 2 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 (e.g., chronic spontaneous urticaria, chronic induced urticaria, chronic autoimmune urticaria), hepatic insufficiency, allergies (e.g., atopic dermatitis, atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic 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, gram-negative bacteria, Reves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolic disease, myocardial infarction, angina pectoris, stroke, ischemic conditions, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications due to organ transplantation, allograft, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection.

[0432] In some embodiments, the arthritis described herein is rheumatoid arthritis.

[0433] In some embodiments, the diabetes described herein is type 1 diabetes.

[0434] In some embodiments, the urticaria described in the present disclosure is chronic urticaria or acute urticaria; in some embodiments, the urticaria described in the present disclosure is chronic urticaria.

[0435] In some embodiments, the urticaria described in the present disclosure is chronic spontaneous urticaria (CSU) or chronic inducible urticaria; in some embodiments, the urticaria described in the present disclosure is chronic spontaneous urticaria.

[0436] In some embodiments, the dermatitis described herein is atopic dermatitis.

[0437] In some embodiments, the multiple sclerosis described herein is relapsing multiple sclerosis (RMS).

[0438] In some embodiments, the allergy described herein is a food allergy.

[0439] In some embodiments, the diseases or conditions described herein or the diseases or conditions mediated by BTK are selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, allergic reactions, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine dysfunction and neurological disorders; in some embodiments, the diseases or conditions described herein or the diseases or conditions mediated by BTK are selected from cancer, autoimmune diseases and inflammatory diseases; the diseases or conditions described herein or the diseases or conditions mediated by BTK are autoimmune diseases or inflammatory diseases; in some embodiments, the diseases or conditions described herein or the diseases or conditions mediated by BTK are selected from B cell malignancies. , B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma (e.g., ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, 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 (burkitt lymphoma / leukemia) 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, Sjögren'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 syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosisgranulomatosis), psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity reaction, 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 Inflammation, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, 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 (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhotic liver disease, alcohol-induced liver fibrosis, bile duct damage, bile duct fibrosis, cholestasis or cholangiopathy, liver or liver fibrosis (including but not limited to liver fibrosis associated with alcoholism), viral infection (e.g., hepatitis C, B, or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), renal disease associated with injury / fibrosis (e.g., chronic diabetes mellitus renal disease (e.g., diabetic nephropathy), lupus, nephroderma, 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 damage, renal disease associated with HIV, or fibrosis associated with exposure to toxins, irritants, or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; inflammatory diseases of the foregut (e.g., Barrett's esophagus)fibrosis associated with inflammatory bowel diseases (e.g., inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease), age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma;

[0440] In some embodiments, the disease or condition described herein or the disease or condition mediated by BTK is selected from B-cell malignancies, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic myeloid 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's lymphoma, B-cell non-Hodgkin's lymphoma, B-cell lymphoma, leukemia (e.g., rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA)), multiple sclerosis (e.g., relapsing multiple sclerosis), amyotrophic lateral sclerosis (ALS), osteoporosis, diabetes (e.g., type 1 diabetes, type 2 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 (e.g., chronic spontaneous urticaria, chronic induced urticaria, chronic autoimmune urticaria), hepatic insufficiency, allergies (e.g., atopic dermatitis, atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic 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, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications due to organ transplantation, allograft, antibody-mediated transplant rejection (AMR), graft-versus-host disease, B-cell-mediated hyperacute, acute, and chronic transplant rejection;

[0441] In some embodiments, the diseases or conditions described herein or the diseases or conditions mediated by BTK are 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, urticaria, liver insufficiency, allergy, ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, These include: arthritis, 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, essential thrombocytopenic purpura, hidradenitis suppurativa, and myasthenia gravis.

[0442] In some embodiments, the cancer of the present disclosure is a hematological malignancy; in some embodiments, the cancer is selected from leukemia, multiple myeloma, and malignant lymphoma; in some embodiments, the cancer is selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute granulocytic leukemia, chronic myeloid 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's lymphoma, B-cell non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, and multiple myeloma.

[0443] In some embodiments, the cancer described herein is selected from the group consisting of:

[0444] Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0445] Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma;

[0446] Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0447] Genitourinary tract: Kidney (adenocarcinoma, Wilms tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma);

[0448] Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0449] Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;

[0450] Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0451] Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors, glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[0452] Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma);

[0453] Hematological: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0454] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform mole, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0455] and adrenal glands: neuroblastoma.

[0456] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compound 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 capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0457] As a general guide, the active compound is, in some embodiments, in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0458] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0459] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0460] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0461] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0462] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0463] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0464] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0465] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0466] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0467] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0468] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0469] The disclosed compounds 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 temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0470] 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.

[0471] 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.

[0472] Terminology

[0473] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0474] 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 The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 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 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 chain isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0475] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 1-20The alkylene group is, in some embodiments, an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments an alkylene group having 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. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0476] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group, in some embodiments, is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0477] The term "alkylene oxide" refers to a branched or unbranched hydrocarbon group containing an epoxy group and having 2 to 12 carbon atoms, in some embodiments C 2-6 Alkyl oxide. Representative examples of “alkylene oxide” include ethylene oxide, propenyl 1,2-oxide, butenyl 1,2-oxide, and the like.

[0478] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group, in some embodiments, is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are, in some embodiments, selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0479] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituents being selected, in some embodiments, from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0480] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a polycyclic ring 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 group is, in some embodiments, a cycloalkyl group having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), in some embodiments, a cycloalkyl group having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), in some embodiments, a cycloalkyl group having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl), or a cycloalkyl group having 5 or 6 ring atoms (i.e., 5 or 6-membered cycloalkyl), or a cycloalkyl group having 5 ring atoms (i.e., 5-membered cycloalkyl).

[0481] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0482] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0483] The term "spiroalkyl" refers to a polycyclic ring system that shares a carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and 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 spiroalkyl). The spiroalkyl group is, in some embodiments, a spiroalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl group), and in some embodiments, a spiroalkyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl group). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), in some embodiments monospirocycloalkyl or bispirocycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples include:

[0484] Its connection point can be at any position; wait.

[0485] The term "fused cycloalkyl" refers to a polycyclic ring system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring and 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., 5-20 membered fused cycloalkyl). The fused cycloalkyl, in some embodiments, is a fused cycloalkyl having 6 to 14 ring atoms (i.e., 6-14 membered fused cycloalkyl), and in some embodiments, is a fused cycloalkyl having 7 to 10 ring atoms (i.e., 7-10 membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), in some embodiments bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0486] , whose connection points can be at any position;

[0487] wait.

[0488] The term "bridged cycloalkyl" refers to a full-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 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 is, in some embodiments, a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0489] Its connection point can be at any position.

[0490] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0491] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and 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., a 3- to 20-membered heterocyclyl). The heterocyclyl group is, in some embodiments, a heterocyclyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl group) or a heterocyclyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group) or a heterocyclyl group having 5 ring atoms (i.e., a 5-membered heterocyclyl group).

[0492] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, dihydropyrrolyl, dihydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0493] The polycyclic heterocyclic group includes spiroheterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups. The term "spiroheterocyclic group" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, 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 spiroheterocyclic group). The spiroheterocyclyl group is, in some embodiments, a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroheterocyclyl group); in some embodiments, a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroheterocyclyl group); in some embodiments, a spiroheterocyclyl group having 7 to 9 ring atoms (i.e., a 7- to 9-membered spiroheterocyclyl group); in some embodiments, a spiroheterocyclyl group having 7 or 8 ring atoms (i.e., a 7- or 8-membered spiroheterocyclyl group). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), in some embodiments a monospiro heterocyclic radical or a bispiro heterocyclic radical, in some embodiments a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiro heterocyclic radical. Non-limiting examples include:

[0494] wait.

[0495] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and 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 heterocyclyl). The fused heterocyclyl is, in some embodiments, a fused heterocyclyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl), in some embodiments, a fused heterocyclyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused heterocyclyl); in some embodiments, a fused heterocyclyl having 7 to 9 ring atoms (i.e., a 7- to 9-membered fused heterocyclyl); in some embodiments, a fused heterocyclyl having 8 or 9 ring atoms (i.e., an 8- or 9-membered fused heterocyclyl). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), in some embodiments, bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, in some embodiments, 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples include:

[0496] wait.

[0497] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), and 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 heterocyclyl). In some embodiments, the bridged heterocyclyl is a bridged heterocyclyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl), and in some embodiments, a bridged heterocyclyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), and in some embodiments, it is a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0498] wait.

[0499] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0500] 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) with a conjugated π electron system having 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). In some embodiments, the aryl group is an aryl group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aryl group) or an aryl group having 10 to 15 ring atoms (i.e., a 10- to 15-membered aryl group); in some embodiments, the aryl group is an aryl group having 11 to 14 ring atoms (i.e., an 11- to 14-membered aryl group); in some embodiments, the aryl group is an aryl group having 8 to 14 ring atoms (i.e., an 8- to 14-membered aryl group); in some embodiments, the aryl group is an aryl group having 11 or 12 ring atoms (i.e., an 11- or 12-membered aryl group); in some embodiments, the aryl group is an aryl group having 11 ring atoms (i.e., an 11-membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system (in some embodiments, a bicyclic aromatic group or a tricyclic aromatic group), non-limiting examples include:

[0501] wait.

[0502] Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0503] The number of rings in the "tricyclic aryl" ring system is 3, and the connection point is on the phenyl group. In some embodiments, the "tricyclic aryl" is a tricyclic aryl having 11 to 14 ring atoms (i.e., an 11- to 14-membered tricyclic aryl); in some embodiments, it is a tricyclic aryl having 11 or 12 ring atoms (i.e., an 11- or 12-membered tricyclic aryl); in some embodiments, it is a tricyclic aryl having 11 ring atoms (i.e., an 11-membered tricyclic aryl). Taking Ring A in the general formula (I) of the present disclosure as an example, non-limiting examples of "tricyclic aryl" include wait.

[0504] The number of rings in the "tetracyclic aryl" ring system is 4, and the connection point is on the phenyl group. In some embodiments, the "tetracyclic aryl" is a tetracyclic aryl having 12 to 19 ring atoms (i.e., a 12- to 19-membered tetracyclic aryl); in some embodiments, it is a tetracyclic aryl having 12 to 14 ring atoms (i.e., a 12- to 14-membered tetracyclic aryl); in some embodiments, it is a tetracyclic aryl having 13 ring atoms (i.e., a 13-membered tetracyclic aryl). Taking Ring A in the general formula (I) of the present disclosure as an example, non-limiting examples of "tetracyclic aryl" include wait.

[0505] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and 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., a 5- to 22-membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl group); in some embodiments, a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group); in some embodiments, a heteroaryl group having 9 to 14 ring atoms (i.e., a 9- to 14-membered heteroaryl group); in some embodiments, a heteroaryl group having 8 to 14 ring atoms (i.e., an 8- to 14-membered heteroaryl group); in some embodiments, a heteroaryl group having 11 or 12 ring atoms (i.e., an 11- or 12-membered heteroaryl group); in some embodiments, a heteroaryl group having 10 ring atoms (i.e., a 10-membered heteroaryl group); in some embodiments, a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group), and in some embodiments, a heteroaryl group having 5 ring atoms (i.e., a 5-membered heteroaryl group).

[0506] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0507] The polycyclic heteroaryl (in some embodiments, a 9- to 14-membered heteroaryl; in some embodiments, an 8- to 14-membered heteroaryl), non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein 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 heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system (in some embodiments, a bicyclic heteroaryl or a tricyclic heteroaryl). Non-limiting examples include:

[0508] wait.

[0509] The number of rings in the "tricyclic heteroaryl" ring system is 3, and the point of attachment is on the monocyclic heteroaryl ring. "Tricyclic heteroaryl" is, in some embodiments, a tricyclic heteroaryl having 9 to 14 ring atoms (i.e., a 9- to 14-membered tricyclic heteroaryl); in some embodiments, a tricyclic heteroaryl having 10 to 12 ring atoms (i.e., a 10- to 12-membered tricyclic heteroaryl); and in some embodiments, a tricyclic heteroaryl having 10 ring atoms (i.e., a 10-membered tricyclic heteroaryl).

[0510] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl group.

[0511] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0512] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0513] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0514] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0515] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0516] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0517] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above; for example, -CH2Ph.

[0518] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above.

[0519] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0520] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above; for example, -OCF3.

[0521] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above; for example, -CH2OH.

[0522] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; for example, -CH2OCH3.

[0523] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above; for example, -CH2NH2.

[0524] The term "methylidene" refers to =CH2.

[0525] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0526] The term "hydroxy" refers to -OH.

[0527] The term "mercapto" refers to -SH.

[0528] The term "amino" refers to -NH2.

[0529] The term "cyano" refers to -CN.

[0530] The term "nitro" refers to -NO2.

[0531] The term "oxo" or "oxo" refers to "=0".

[0532] The term "carbonyl" refers to C=O.

[0533] The term "carboxy" refers to -C(O)OH.

[0534] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0535] In the general formula (III) of the present disclosure, when j is 0, it is equivalent to A 1 or A 2 is the key.

[0536] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these 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 compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0537] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0538] 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 a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc.

[0539] For example, a compound should be understood to include either or both tautomers of the following structures:

[0540] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0541] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. 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, and iodine, for example, 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., in some embodiments, deuterium.

[0542] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0543] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for 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 abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0544] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0545] "Substitution" or "substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0546] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0547] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately 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.

[0548] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0549] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0550] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments, within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0551] Figure 1. The degree of skin swelling in mice.

[0552] Figure 2. Percent inhibition of mouse skin swelling by compound 3. DETAILED DESCRIPTION

[0553] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0554] Example

[0555] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0556] MS was determined using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS);

[0557] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector);

[0558] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).

[0559] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0560] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0561] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0562] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0563] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0564] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0565] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0566] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0567] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0568] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0569] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0570] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0571] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0572] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0573] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0574] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0575] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0576] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0577] Example 1

[0578] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1

[0579] first step

[0580] 6-Fluoro-1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 1b

[0581] 5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-one 1a (500 mg, 2.18 mmol, Bidler) was dissolved in N,N-dimethylformamide (5 mL, Sinopharm) and methanol (2.5 mL, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (160 mg, 0.22 mmol, Adamas) and N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) were added. The atmosphere was replaced with carbon monoxide three times, and the mixture was reacted at 80°C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 1b (170 mg, yield: 37.4%).

[0582] Step 2

[0583] 6-Fluoro-1-methylidene-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 1c

[0584] Compound 1b (170 mg, 0.82 mmol) was dissolved in tetrahydrofuran (5 mL, Anaiji), and methyltriphenylphosphonium bromide (584 mg, 1.63 mmol, Shaoyuan) and potassium tert-butoxide (184 mg, 1.64 mmol, Adamas) were added. The mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to obtain the title compound 1c (90 mg, 53.4% ​​yield).

[0585] MS m / z(ESI):207.3[M+1]

[0586] Step 3

[0587] 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxylic acid methyl ester 1d

[0588] Diethylzinc (1 M, 1.75 mL, 1.75 mmol, Adamas) was dissolved in dichloromethane (1 mL, Anergy) under nitrogen protection. Trifluoroacetic acid (200 mg, 1.75 mmol, Adamas) was added dropwise at 0°C and reacted at 0°C for 1 hour. Diiodomethane (468 mg, 1.75 mmol, Anergy) was added dropwise and reacted at 0°C for 0.5 hour. A solution of compound 1c (90 mg, 0.44 mmol) in dichloromethane (1 mL, Anergy) was added dropwise and reacted at room temperature for 3 hours. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent System B to obtain the title compound 1d (78 mg, yield: 81.1%).

[0589] MS m / z(ESI):221.3[M+1]

[0590] Step 4

[0591] 6'-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1e

[0592] Compound 1d (39 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1 mL, Anaiji) and 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (49 mg, 0.20 mmol, prepared using the method disclosed for intermediate INT3 on page 31 of the specification of patent application WO2015079417A1) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.13 mL, 0.13 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 2 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent System B to obtain the title compound 1e (30 mg, 38.6% yield).

[0593] MS m / z(ESI):440.5[M+1]

[0594] Step 5

[0595] Tert-butyl (2-((4-amino-6-(5-fluoro-3-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate

[0596] The crude compound 1e (30 mg, 0.07 mmol) was dissolved in ethylene glycol dimethyl ether (1 mL, Sinopharm) and water (0.3 mL, Sinopharm), and bis(triphenylphosphine)palladium chloride (4.8 mg, 0.01 mmol, Adamas), tert-butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)methyl)carbamate (25 mg, 0.08 mmol prepared by the method disclosed in intermediate INT8 on page 39 of the specification of patent application WO2015079417A1) and sodium carbonate (15 mg, 0.14 mmol, Sinopharm) were added, and the mixture was replaced with nitrogen three times and reacted in a microwave at 110 ° C for 1 hour. 3 mL of water was added, and the mixture was extracted with ethyl acetate (3 mL×3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent System A to give the title compound 1f (30 mg, yield: 75.8%).

[0597] MS m / z(ESI):580.2[M+1]

[0598] Step 6

[0599] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1g

[0600] Crude compound 1f (30 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL, Sinopharm), and trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g (24.8 mg) of the crude title compound. The product was directly used in the next reaction without purification.

[0601] MS m / z(ESI):480.6[M+1]

[0602] Step 7

[0603] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1

[0604] The crude compound 1g (24.8 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL, Sinopharm), and N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) was added. Acryloyl chloride (4.7 mg, 0.05 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 3 mL of water was added, and the mixture was extracted with dichloromethane (3 mL x 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to obtain the title compound 1 (12 mg, yield: 43.5%).

[0605] MS m / z(ESI):534.5[M+1]

[0606] 1 H NMR (500MHz, DMSO-d6): δ9.75-9.57(m,1H),8.21-8.18(m,1H),7.71-7.50(m,2H),7.23-6.98(m,3H),6.78-6.65(m,2H),6.06-6.03(m,1H),5.6 0-5.58(m,1H),3.58-3.47(m,4H),3.04-3.02(m,2H),2.80(s,3H),2.17 -2.14(m,2H),2.01-1.96(m,3H),1.24-1.22(m,2H),1.03-1.02(m,2H).

[0607] Example 2

[0608] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide

[0609] first step

[0610] 1-Bromo-2-fluoro-4-(prop-1-en-2-yl)benzene 2b

[0611] 1-(4-Bromo-3-fluorophenyl)ethan-1-one 2a (1 g, 4.61 mmol, Shaoyuan) was dissolved in tetrahydrofuran (20 mL, Anaiji), and methyltriphenylphosphonium bromide (3.3 g, 9.24 mmol, Shaoyuan) and potassium tert-butoxide (1.04 g, 9.27 mmol, Adamas) were added. The mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent System B to obtain the title compound 2b (780 mg, yield: 78.7%).

[0612] Step 2

[0613] 1-Bromo-2-fluoro-4-(1-methylcyclopropyl)benzene 2c

[0614] Diethylzinc (1M, 6.52mL, 6.52mmol, Adamas) was dissolved in dichloromethane (3mL, Anergy) under nitrogen protection. Trifluoroacetic acid (743mg, 6.52mmol, Adamas) was added dropwise at 0°C and reacted at 0°C for 1 hour. Diiodomethane (1.75g, 6.54mmol, Anergy) was added dropwise and reacted at 0°C for 0.5 hour. A solution of compound 2b (350mg, 1.63mmol) in dichloromethane (3mL, Anergy) was added dropwise and reacted at room temperature for 3 hours. 15mL of water was added and the mixture was extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with 15mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 2c (240mg, yield: 64.4%).

[0615] Step 3

[0616] Methyl 2-fluoro-4-(1-methylcyclopropyl)benzoate 2d

[0617] Compound 2c (240 mg, 1.05 mmol) was dissolved in N,N-dimethylacetamide (3 mL, Sinopharm) and methanol (3 mL, Sinopharm), and 1,3-bis(diphenylphosphino)propane (87 mg, 0.21 mmol, Shaoyuan), N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas), and palladium acetate (48 mg, 0.21 mmol, Adamas) were added. The carbon monoxide gas was replaced three times, and the reaction was carried out at 80°C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 2d (140 mg, yield: 64.2%).

[0618] Step 4

[0619] 2-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(1-methylcyclopropyl)benzamide 2e

[0620] Compound 2d (140 mg, 0.67 mmol) was dissolved in tetrahydrofuran (3 mL, Anaiji) and 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (186 mg, 0.74 mmol, prepared using the method disclosed for intermediate INT3 on page 31 of the specification of patent application WO2015079417A1) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2M, 0.51 mL, 1.02 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent System B to obtain the title compound 2e (85 mg, yield: 29.6%).

[0621] MS m / z(ESI):428.3[M+1]

[0622] Step 5

[0623] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(2-fluoro-4-(1-methylcyclopropyl)benzamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 2f

[0624] Compound 2e (85 mg, 0.20 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL, Sinopharm), water (0.8 mL, Sinopharm), and bis(triphenylphosphine)palladium chloride (14 mg, 0.02 mmol, Adamas), tert-butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate (73 mg, 0.24 mmol prepared by the method disclosed in intermediate INT8 on page 39 of the specification of patent application WO2015079417A1), sodium carbonate (43 mg, 0.41 mmol, Sinopharm), and the mixture was replaced with nitrogen three times and reacted in a microwave at 110 ° C for 1 hour. Add 10 mL of water, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with 10 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by column chromatography with eluent System A to give the title compound 2f (110 mg, yield: 97.4%).

[0625] MS m / z(ESI):568.6[M+1]

[0626] Step 6

[0627] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide 2g

[0628] Compound 2f (110 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), and trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 2g (90 mg, 99.3% yield). The product was directly used in the next step without purification.

[0629] MS m / z(ESI):468.4[M+1]

[0630] Step 7

[0631] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide

[0632] The crude compound 2g (90mg, 0.19mmol) was dissolved in dichloromethane (2mL, Sinopharm), and N,N-diisopropylethylamine (125mg, 0.97mmol, Adamas) was added. Acryloyl chloride (18mg, 0.20mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 10mL of water was added, and the mixture was extracted with dichloromethane (10mL x 3). The organic phases were combined, washed with 10mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to obtain the title compound 2 (18mg, yield: 17.9%).

[0633] MS m / z(ESI):522.5[M+1]

[0634] 1H NMR (500MHz, DMSO-d6): δ9.81-9.59(m,1H),8.21-8.18(m,1H),7.78-7.56(m,2H),7.21-6.97(m,4H),6.67-6.57(m,2H),6.1 0-6.02(m,1H),5.61-5.58(m,1H),3.59-3.45(m,4H),2.53(s,3H),2.02-1.97(m,3H),1.44-1.43(m,3H),0.99-0.86(m,4H).

[0635] Example 3

[0636] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3

[0637] first step

[0638] 3-Bromo-4-fluorophenyl acetate 3b

[0639] 3-Bromo-4-fluorophenol 3a (5 g, 26.18 mmol, Adamas) was dissolved in dichloromethane (100 mL, Sinopharm), triethylamine (5.3 g, 52.38 mmol, Sinopharm) was added, and acetyl chloride (2.88 g, 36.69 mmol, Sinopharm) was added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 3b (5.52 g, yield: 90.5%).

[0640] Step 2

[0641] 1-(4-Bromo-5-fluoro-2-hydroxyphenyl)ethan-1-one 3c

[0642] Compound 3b (5.52 g, 23.69 mmol) and aluminum chloride (6.32 g, 47.40 mmol, TCI) were added to a reaction flask and reacted at 165°C for 3 hours. The mixture was cooled to room temperature, and 50 mL of glacial dilute hydrochloric acid was added. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 3c (5.12 g, 92.8% yield).

[0643] MS m / z(ESI):231.0[M-1]

[0644] Step 3

[0645] 2-Bromo-1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethan-1-one 3d

[0646] Compound 3c (4 g, 17.16 mmol) was dissolved in methanol (40 mL, Sinopharm), and a solution of tetrabutylammonium tribromide (9.11 g, 18.89 mmol, Shaoyuan) in dichloromethane (40 mL, Sinopharm) was added dropwise. The mixture was reacted at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 3d (5.3 g, yield: 99.0%).

[0647] MS m / z(ESI):310.9[M-1]

[0648] Step 4

[0649] 6-Bromo-5-fluorobenzofuran-3(2H)-one 3e

[0650] Compound 3d (5.3 g, 16.99 mmol) was dissolved in ethanol (120 mL, Sinopharm), and sodium acetate (4.18 g, 50.95 mmol) was added. The mixture was stirred at room temperature for 1 hour. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 3e (1.6 g, 40.8% yield).

[0651] Step 5

[0652] 6-Bromo-5-fluoro-3-methylidene-2,3-dihydrobenzofuran 3f

[0653] Compound 3e (1.6 g, 6.93 mmol) was dissolved in tetrahydrofuran (30 mL, Adamas), and methyltriphenylphosphonium bromide (4.95 g, 13.86 mmol, Shaoyuan) was added. The atmosphere was purged with nitrogen three times, and potassium tert-butoxide (1M, 13.9 mL, 13.9 mmol) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 6 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 3f (260 mg, 16.4% yield).

[0654] Step 6

[0655] 6-Bromo-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 3g

[0656] Diethylzinc (1M, 4.54mL, 4.54mmol, Adamas) was dissolved in dichloromethane (4mL, Anergy) under nitrogen protection. Trifluoroacetic acid (518mg, 4.54mmol, Adamas) was added dropwise at 0°C and reacted at 0°C for 1 hour. Diiodomethane (1.22g, 4.56mmol, Anergy) was added dropwise and reacted at 0°C for 0.5 hour. A solution of compound 3f (260mg, 1.14mmol) in dichloromethane (1mL, Anergy) was added dropwise and reacted at room temperature for 3 hours. 15mL of water was added and the mixture was extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with 15mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 3g (150mg, yield: 54.4%).

[0657] Step 7

[0658] 5-Fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxylic acid methyl ester 3h

[0659] Compound 3g (150 mg, 0.62 mmol) was dissolved in N,N-dimethylacetamide (2 mL, Sinopharm) and methanol (2 mL, Sinopharm), and palladium acetate (28 mg, 0.12 mmol, Adamas), N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas), 1,3-bis(diphenylphosphino)propane (51 mg, 0.12 mmol, Adamas) were added. The carbon monoxide gas was replaced three times, and the reaction was carried out at 80°C overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 3h (100 mg, yield: 72.9%).

[0660] MS m / z(ESI):223.1[M+1]

[0661] Step 8

[0662] 5-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3j

[0663] Compound 3h (50 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2 mL, Anaiji) and 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 3i (63 mg, 0.25 mmol, prepared using the method disclosed for intermediate INT3 on page 31 of the specification of patent application WO2015079417A1) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.17 mL, 0.34 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent System B to obtain the title compound 3j (60 mg, yield: 60.4%).

[0664] MS m / z(ESI):442.3[M+1]

[0665] Step 9

[0666] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 3l

[0667] The crude compound 3j (60 mg, 0.14 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL, Sinopharm) and water (0.6 mL, Sinopharm), and bis(triphenylphosphine)palladium chloride (9.6 mg, 0.02 mmol, Adamas), tert-butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)methyl)carbamate 3k (50 mg, 0.17 mmol, prepared by the method disclosed for intermediate INT8 on page 39 of the specification of patent application WO2015079417A1), sodium carbonate (29 mg, 0.27 mmol, Sinopharm), and the mixture was replaced with nitrogen three times and reacted in a microwave at 110 ° C for 1 hour. Add 5 mL of water, extract with ethyl acetate (5 mL×3), combine the organic phases, wash with 5 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by column chromatography with eluent System A to give the title compound 31 (79 mg, yield: 99.9%).

[0668] MS m / z(ESI):582.5[M+1]

[0669] Step 10

[0670] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3m

[0671] Compound 3l (79 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL, Sinopharm), and trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 3m (65 mg, yield: 99.4%). The product was directly used in the next step without purification.

[0672] MS m / z(ESI):482.1[M+1]

[0673] Step 11

[0674] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-

[0675] 2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3

[0676] Crude compound 3m (65 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), and N,N-diisopropylethylamine (70 mg, 0.54 mmol, Adamas) was added. Acryloyl chloride (6.2 mg, 0.07 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 3 mL of water was added, and the mixture was extracted with dichloromethane (3 mL x 3). The combined organic phases were washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to obtain the title compound 3 (9 mg, yield: 12.4%).

[0677] MS m / z(ESI):536.5[M+1]

[0678] 1H NMR (500MHz, DMSO-d6): δ9.77-9.55(m,1H),8.21-8.18(m,1H),7.58-7.51(m,1H),7.20-6.91(m,4H),6.68-6.53(m,2H),6.10-6.0 2(m,1H),5.61-5.58(m,1H),4.56(s,2H),3.59-3.45(m,4H),2.55(s,3H),2.01-1.96(m,3H),1.24-1.22(m,2H),1.18-1.17(m,2H).

[0679] Example 4

[0680] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0681] first step

[0682] Methyl 2-fluoro-3-((2-methylallyl)oxy)benzoate 4b

[0683] Methyl 2-fluoro-3-hydroxybenzoate 4a (2.0 g, 11.75 mmol, Bidex) was dissolved in acetonitrile (2 mL). Potassium carbonate (1.95 g, 14.11 mmol, Sinopharm) and 3-bromo-2-methylpropene (1.91 g, 14.11 mmol, Adamas) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 4b (1.92 g, 72.8% yield).

[0684] MS m / z(ESI):225.1[M+1].

[0685] Step 2

[0686] Methyl 2-fluoro-3-hydroxy-4-(2-methylallyl)benzoate 4c

[0687] Compound 4b (1.7 g, 7.58 mmol) was dissolved in biphenyl-biphenyl ether (15 mL), and the reaction mixture was heated to 200°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and directly purified by silica gel column chromatography using eluent System A to obtain the title compound 4c (570 mg, yield: 33.5%).

[0688] MS m / z(ESI):225.1[M+1].

[0689] Step 3

[0690] 7-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 4d

[0691] Compound 4c (445 mg, 1.98 mmol) was dissolved in formic acid (15 mL), and the reaction mixture was heated to 110°C and stirred for 30 minutes. The reaction mixture was cooled to room temperature, and saturated sodium chloride solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4d (440 mg, yield: 98.9%).

[0692] MS m / z(ESI):225.1[M+1].

[0693] Step 4

[0694] 7-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 4e

[0695] Compound 4d (200 mg, 0.89 mmol) and compound 3i (246 mg, 0.98 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was cooled to 0°C, and sodium bis(trimethylsilyl)amide (245 mg, 1.34 mmol, Adamas) was added. The reaction solution was then warmed to room temperature and stirred for 2 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 4e (310 mg, 78.4% yield).

[0696] MS m / z(ESI):444.1[M+1].

[0697] Step 5

[0698] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 4f

[0699] Compound 4e (310 mg, 0.70 mmol), compound 3k (211 mg, 0.70 mmol), tetrakistriphenylphosphine palladium (80 mg, 0.07 mmol, Bid), and potassium carbonate (193 mg, 1.40 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The atmosphere was purged with nitrogen three times and microwaved at 110°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to provide the title compound 4f (380 mg, 93.1% yield).

[0700] MS m / z(ESI):584.3[M+1].

[0701] Step 6

[0702] 4 g of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0703] Compound 4f (380 mg, 0.65 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 4 g, which was used directly in the next step without further purification.

[0704] MS m / z(ESI):484.3[M+1].

[0705] Step 7

[0706] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0707] Compound 4g (314 mg, 0.65 mmol) and N,N-diisopropylethylamine (420 mg, 3.25 mmol, Adamas) were dissolved in dichloromethane (5 mL). The reaction solution was cooled to -40°C, and acryloyl chloride (59 mg, 0.65 mmol, Adamas) was added. The mixture was stirred at -40°C for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 4 (140 mg, 40.1% yield).

[0708] MS m / z(ESI):538.2[M+1].

[0709] 1 H NMR(500MHz,DMSO-d6)δ9.89-9.68(m,1H),8.22(d,1H),7.52(dd,1H),7.34-7.05 (m,4H),7.00(td,1H),6.61(dt,1H),6.06(ddd,1H),5.59(td,1H),3.52(ddt,4H), 3.16(s,2H),2.81-2.52(m,3H),2.00(d,3H),1.49(s,6H).

[0710] Example 5

[0711] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5

[0712] first step

[0713] 3-Bromo-2-fluorophenyl acetate 5b

[0714] 3-Bromo-2-fluorophenol 5a (5 g, 26.18 mmol, Bidex) was dissolved in dichloromethane (100 mL, Sinopharm), triethylamine (5.3 g, 52.38 mmol, Sinopharm) was added, and acetyl chloride (2.88 g, 36.69 mmol, Sinopharm) was added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent system B to give the title compound 5b (4.37 g, yield: 71.6%).

[0715] Step 2

[0716] 1-(4-Bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one 5c

[0717] Compound 5b (4.37 g, 18.75 mmol) and aluminum chloride (5 g, 37.50 mmol, Sinopharm) were added to a reaction flask and reacted at 165°C for 3 hours. The mixture was cooled to room temperature, and 50 mL of glacial dilute hydrochloric acid was added. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography using eluent System B to afford the title compound 5c (3.9 g, 89.24% yield).

[0718] MS m / z(ESI):231.0[M-1]

[0719] Step 3

[0720] 2-Bromo-1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one 5d

[0721] Compound 5c (3.7 g, 15.87 mmol) was dissolved in ethyl acetate (50 mL, Sinopharm), and copper bromide (7.1 g, 31.78 mmol, Sinopharm) was added. The mixture was reacted overnight at 80°C. The reaction mixture was filtered and the filtrate was concentrated to obtain the title compound 5d (4.95 g, yield: 99.94%).

[0722] MS m / z(ESI):310.9[M-1]

[0723] Step 4

[0724] 6-Bromo-7-fluorobenzofuran-3(2H)-one 5e

[0725] Compound 5d (4.95 g, 15.86 mmol) was dissolved in ethanol (50 mL, Sinopharm), and sodium acetate (3.92 g, 47.78 mmol) was added. The mixture was stirred at room temperature for 1 hour. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent System B to afford the title compound 5e (1.59 g, 43.37% yield).

[0726] Step 5

[0727] 6-Bromo-7-fluoro-3-methylidene-2,3-dihydrobenzofuran 5f

[0728] Compound 5e (1.59 g, 6.88 mmol) was dissolved in tetrahydrofuran (30 mL, Adamas), and methyltriphenylphosphonium bromide (4.93 g, 13.80 mmol, Shaoyuan) was added. The atmosphere was purged with nitrogen three times, and potassium tert-butoxide (1M, 13.9 mL, 13.9 mmol) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography using eluent System B to afford the title compound 5f (190 mg, 12.05% yield).

[0729] Step 6

[0730] 6-Bromo-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 5g

[0731] Diethylzinc (1 M, 3.32 mL, 3.32 mmol, Adamas) was dissolved in dichloromethane (2 mL, Anergy) under nitrogen protection. Trifluoroacetic acid (379 mg, 3.32 mmol, Adamas) was added dropwise at 0°C and reacted at 0°C for 1 hour. Diiodomethane (889 mg, 3.32 mmol, Anergy) was added dropwise and reacted at 0°C for 0.5 hour. A solution of compound 5f (190 mg, 0.83 mmol) in dichloromethane (1 mL, Anergy) was added dropwise and reacted at room temperature for 3 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent System B to give the title compound 5g (140 mg, yield: 69.43%).

[0732] Step 7

[0733] 7-Fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxylic acid methyl ester 5h

[0734] Compound 5g (140 mg, 0.57 mmol) was dissolved in N,N-dimethylacetamide (2 mL, Sinopharm) and methanol (2 mL, Sinopharm), and palladium acetate (26 mg, 0.116 mmol, Adamas), N,N-diisopropylethylamine (149 mg, 1.15 mmol, Adamas), and 1,3-bis(diphenylphosphino)propane (48 mg, 0.116 mmol, Adamas) were added. The mixture was replaced with carbon monoxide gas three times, and the reaction was carried out at 80°C overnight. The mixture was concentrated under reduced pressure and purified by column chromatography with eluent system B to give the title compound 5h (100 mg, yield: 78.13%).

[0735] MS m / z(ESI):223.1[M+1]

[0736] Step 8

[0737] 7-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5i

[0738] Compound 5h (50 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2 mL, Anaiji), and compound 3i (63 mg, 0.25 mmol) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.17 mL, 0.34 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent System B to give the title compound 5i (65 mg, yield: 65.46%).

[0739] MS m / z(ESI):442.3[M+1]

[0740] Step 9

[0741] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 5j

[0742] Crude compound 5i (65 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL, Sinopharm) and water (0.6 mL, Sinopharm). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol, Bidex), compound 3k (54 mg, 0.18 mmol), and potassium carbonate (61 mg, 0.44 mmol, Sinopharm) were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 90°C for 2 hours. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent System A to afford the title compound 5j (60 mg, 70% yield).

[0743] MS m / z(ESI):582.5[M+1]

[0744] Step 10

[0745] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5k

[0746] Crude compound 5j (60 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL, Sinopharm), and trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 5k (49 mg, yield: 98.64%). The product was directly used in the next step without purification.

[0747] MS m / z(ESI):482.1[M+1]

[0748] Step 11

[0749] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5

[0750] Crude compound 5k (49 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), and N,N-diisopropylethylamine (53 mg, 0.41 mmol, Adamas) was added. Acryloyl chloride (5.53 mg, 0.06 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 3 mL of water was added, and the mixture was extracted with dichloromethane (3 mL x 3). The combined organic phases were washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography with eluent System A to afford the title compound 5 (9 mg, 16.51% yield).

[0751] MS m / z(ESI):536.5[M+1]

[0752] 1 H NMR (500MHz, DMSO-d6): δ9.85-9.64(m,1H),8.21-8.18(m,1H),7.56-7.54(m,1H),7.28-6.97(m,4H),6.81-6.67(m,1H),6.64-6.58(m,1 H),6.09-6.03(m,1H),5.62-5.58(m,1H),4.67-4.64(m,2H),3.59-3.45(m,3H),2.80-2.78(m,1H),2.03-1.97(m,3H),1.24-1.14(m,7H).

[0753] Example 6

[0754] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6

[0755] first step

[0756] 2-Chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde 6b

[0757] 3,3-Dimethylcyclopentan-1-one 6a (700 mg, 6.24 mmol, Bidex) was dissolved in dichloromethane (40 mL). N,N-dimethylformamide (1.14 g, 15.6 mmol, Sinopharm) was added at room temperature. The reaction solution was heated to 40°C, followed by phosphorus oxychloride (2.0 g, 13.1 mmol, Sinopharm) and stirred at 40°C for 16 hours. The reaction solution was cooled to room temperature and quenched with aqueous potassium phosphate (2 mL, 4 M). The reaction solution was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6b, which was used directly in the next step without further purification.

[0758] Step 2

[0759] 5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid ethyl ester 6c

[0760] Compound 6b (500 mg, 3.15 mmol) was dissolved in dichloromethane (5 mL), and ethyl mercaptoacetate (416 mg, 3.46 mmol, Adamas) and triethylamine (988 mg, 9.77 mmol, Sinopharm) were added. The mixture was stirred at 40°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 6c (340 mg, 48.1% yield).

[0761] MS m / z(ESI):225.1[M+1].

[0762] Step 3

[0763] 5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid 6d

[0764] Compound 6c (200 mg, 0.89 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and an aqueous lithium hydroxide solution (60 mg, 1.35 mmol, 2 mL) was added. The mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to adjust the pH of the reaction solution to 1, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6d (170 mg, yield: 97.1%).

[0765] MS m / z(ESI):197.2[M+1].

[0766] Step 4

[0767] 3-Fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid 6e

[0768] Compound 6d (83 mg, 0.42 mmol) was dissolved in tetrahydrofuran (3 mL). The reaction solution was cooled to -78°C and n-butyllithium (68 mg, 1.06 mmol, Adamas) was added dropwise. The mixture was stirred at -78°C for 2 hours. N-Fluorobisbenzenesulfonamide (333 mg, 1.06 mmol, Shaoyuan) was then added. The reaction solution was allowed to warm to room temperature and stirred for 1 hour. Saturated ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound 6e, which was used directly in the next step without further purification.

[0769] MS m / z(ESI):215.1[M+1].

[0770] Step 5

[0771] 3-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6f

[0772] Compound 6e (85 mg, 0.4 mmol) and compound 3i (100 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (3 mL). 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.6 mmol, Adamas) and N,N-diisopropylethylamine (129 mg, 1.0 mmol, Adamas) were added. The reaction mixture was then heated to 70°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 6f (70 mg, 39.1% yield).

[0773] MS m / z(ESI):448.2[M+1].

[0774] Step 6

[0775] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 6g

[0776] Compound 6f (70 mg, 0.15 mmol), compound 3k (50 mg, 0.16 mmol), tetrakistriphenylphosphine palladium (18 mg, 0.015 mmol, Bidex), and potassium carbonate (43 mg, 0.31 mmol, Sinopharm) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). The atmosphere was purged with nitrogen three times and microwaved at 110°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 6g (80 mg, 87.0% yield).

[0777] MS m / z(ESI):588.5[M+1].

[0778] Step 7

[0779] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6h

[0780] Compound 6g (80 mg, 0.14 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 6h, which was used directly in the next step without further purification.

[0781] MS m / z(ESI):488.5[M+1].

[0782] Step 8

[0783] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6

[0784] Compound 6h (66 mg, 0.13 mmol) and N,N-diisopropylethylamine (87 mg, 0.67 mmol, Adamas) were dissolved in dichloromethane (3 mL). The reaction solution was cooled to -40°C, and acryloyl chloride (12 mg, 0.13 mmol, Adamas) was added. The mixture was stirred at -40°C for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 6 (12 mg, 16.3% yield).

[0785] MS m / z(ESI):542.3[M+1].

[0786] 1 H NMR(500MHz,DMSO)δ9.17-8.95(m,1H),8.21-8.18(m,1H),7.64-7.60(m,1H),7.22-6.94(m,3H),6.64(ddd,1H),6.07(ddd, 1H),5.59(ddd,1H),3.61-3.43(m,4H),2.78-2.77(m,3H),2.60-2.59(m,2H),2.43(s,2H),1.99-1.91(m,3H),1.23(s,6H).

[0787] Example 7

[0788] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0789] first step

[0790] Methyl 4-bromo-2-fluoro-3-hydroxybenzoate 7b

[0791] Methyl 2-fluoro-3-hydroxybenzoate 7a (500 mg, 2.94 mmol, Shaoyuan) was dissolved in chloroform (5 mL). A solution of bromine (564 mg, 3.53 mmol, Sinopharm) in acetic acid (5 mL, Sinopharm) was added dropwise at 0°C and allowed to react at room temperature for 12 hours. 20 mL of sodium thiosulfate solution was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 7b (730 mg, 99.7% yield).

[0792] MS m / z(ESI):247.0[M-1]

[0793] Step 2

[0794] Methyl 4-bromo-2-fluoro-3-((2-methylallyl)oxy)benzoate 7c

[0795] Compound 7b (730 mg, 2.93 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (608 mg, 4.40 mmol, Sinopharm) was added, and 3-bromo-2-methylprop-1-ene (475 mg, 3.52 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at room temperature for 12 hours, 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 7c (780 mg, yield: 87.8%).

[0796] Step 3

[0797] 7-Fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 7d

[0798] Compound 7c (780 mg, 2.57 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tetraethylammonium chloride (470 mg, 2.84 mmol, J&K), sodium formate (193 mg, 2.84 mmol, Shaoyuan), palladium acetate (58 mg, 0.26 mmol, Adamas), and anhydrous sodium acetate (634 mg, 7.73 mmol, Sinopharm) were added. The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 7d (40 mg, yield: 6.9%).

[0799] Step 4

[0800] 7-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 7e

[0801] Compound 7d (40 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), and compound 3i (50 mg, 0.20 mmol) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.14 mL, 0.28 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 7e (53 mg, 67.0% yield).

[0802] MS m / z(ESI):444.3[M+1]

[0803] Step 5

[0804] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 7f

[0805] Compound 7e (53 mg, 0.12 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.6 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17.5 mg, 0.02 mmol, Bis(II)), compound 3k (43.5 mg, 0.14 mmol), and potassium carbonate (34 mg, 0.25 mmol, Sinopharm) were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 90°C for 2 hours. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography with eluent System A afforded the title compound 7f (69 mg, 98.9% yield).

[0806] MS m / z(ESI):584.4[M+1]

[0807] Step 6

[0808] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 7 g

[0809] Compound 7f (69 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added. The reaction was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7g (57 mg, yield: 99.7%). The product was directly used in the next reaction without purification.

[0810] MS m / z(ESI):484.5[M+1]

[0811] Step 7

[0812] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0813] Crude compound 7g (57 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (61 mg, 0.47 mmol, Adamas) was added. Acryloyl chloride (9 mg, 0.10 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to obtain the title compound 7 (9 mg, yield: 14.2%).

[0814] MS m / z(ESI):538.3[M+1]

[0815] 1 H NMR (500MHz, DMSO-d6): δ9.92-9.72(m,1H),8.21-8.18(m,1H),7.55-7.48(m,1H),7.33-6.97(m,5H),6.65-6.58(m,1H),6.0 9-6.03(m,1H),5.62-5.57(m,1H),4.42-4.41(m,2H),3.59-3.45(m,4H),2.53(s,3H),2.03-1.98(m,3H),1.36-1.24(m,6H).

[0816] Example 8

[0817] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8

[0818] first step

[0819] Methyl 4-bromo-2-fluoro-5-hydroxybenzoate 8b

[0820] Methyl 2-fluoro-5-hydroxybenzoate 8a (1 g, 2.94 mmol, Bidex) was dissolved in chloroform (10 mL). A solution of bromine (1.41 g, 8.82 mmol, Sinopharm) in acetic acid (10 mL, Sinopharm) was added dropwise at 0°C and allowed to react at room temperature for 12 hours. 40 mL of sodium thiosulfate solution was added, and the mixture was extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with 40 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 8b (290 mg, 19.8% yield).

[0821] MS m / z(ESI):246.8[M-1]

[0822] Step 2

[0823] Methyl 4-bromo-2-fluoro-5-((2-methylallyl)oxy)benzoate 8c

[0824] Compound 8b (290 mg, 1.16 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (242 mg, 1.75 mmol, Sinopharm) was added, and 3-bromo-2-methylprop-1-ene (475 mg, 3.52 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at room temperature for 12 hours, and 15 mL of water was added. The mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 8c (320 mg, yield: 90.7%).

[0825] Step 3

[0826] 5-Fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 8d

[0827] Compound 8c (170 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (8 mL), and tetraethylammonium chloride (102 mg, 0.62 mmol, J&K), sodium formate (42 mg, 0.62 mmol, Shaoyuan), palladium acetate (12.6 mg, 0.06 mmol, Adamas), and anhydrous sodium acetate (138 mg, 1.68 mmol, Sinopharm) were added. The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 8d (65 mg, yield: 52.0%).

[0828] Step 4

[0829] 5-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8e

[0830] Compound 8d (65 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and compound 3i (81 mg, 0.32 mmol) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.22 mL, 0.44 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 8e (90 mg, 70.0% yield).

[0831] MS m / z(ESI):444.3[M+1]

[0832] Step 5

[0833] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 8f

[0834] Compound 8e (90 mg, 0.20 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.6 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol, Bis(II)), compound 3k (74 mg, 0.24 mmol), and potassium carbonate (57 mg, 0.41 mmol, Sinopharm) were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 90°C for 2 hours. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to afford the title compound 8f (110 mg, 92.8% yield).

[0835] MS m / z(ESI):584.6[M+1]

[0836] Step 6

[0837] 8 g of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide

[0838] Compound 8f (110 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added. The reaction was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8g (91 mg, 99.9% yield). The product was directly used in the next step without purification.

[0839] MS m / z(ESI):484.3[M+1]

[0840] Step 7

[0841] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8

[0842] The crude product compound 8g (91 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (98 mg, 0.76 mmol, Adamas) was added. Acryloyl chloride (10.3 mg, 0.11 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to obtain the title compound 8 (22 mg, yield: 21.7%).

[0843] MS m / z(ESI):538.4[M+1]

[0844] 1 H NMR (500MHz, DMSO-d6): δ9.85-9.64(m,1H),8.21-8.18(m,1H),7.63-7.50(m,1H),7.33-6.96(m,5H),6.67-6.58(m,1H),6.0 9-6.03(m,1H),5.62-5.57(m,1H),4.30-4.29(m,2H),3.59-3.45(m,4H),2.53(s,3H),2.03-1.98(m,3H),1.34-1.24(m,6H).

[0845] Example 9

[0846] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxamide 9

[0847] first step

[0848] 5-Bromo-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-1-one 9b

[0849] In a dry flask, 5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one 9a (1 g, 4.37 mmol, Bidex) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (418 mg, 10.91 mmol, 60% purity, Sinopharm) was added with stirring at room temperature. The mixture was stirred for 10 minutes, followed by iodomethane (4.3 g, 30.56 mmol, Adamas), and stirred for 12 hours. The reaction mixture was slowly added dropwise to 50 mL of ice water with stirring, and extracted with diethyl ether (50 mL x 2). The organic phases were combined, washed with 50 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 9b (800 mg, 71.27% yield).

[0850] Step 2

[0851] 4-Fluoro-2,2-dimethyl-1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 9c

[0852] Compound 9b (800 mg, 3.11 mmol), triethylamine (944.6 mg, 9.33 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (341.5 mg, 0.47 mmol, Bidex) were dissolved in N,N-dimethylformamide (8 mL) and methanol (24 mL). The atmosphere was replaced with nitrogen twice, and then carbon monoxide gas was introduced at 3 atmospheres. The reaction was allowed to react at 100°C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to obtain the title compound 9c (85 mg, 11.56% yield).

[0853] Step 3

[0854] 4-Fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester 9d

[0855] In a dry flask, compound 9c (70 mg, 0.30 mmol) was dissolved in trifluoroacetic acid (2 mL, Sinopharm). Triethylsilane (172.3 mg, 1.48 mmol, Shaoyuan) was added with stirring at room temperature and stirred for 7 hours. 10 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 9d (65 mg, 98.7% yield).

[0856] Step 4

[0857] 4-Fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxamide 9e

[0858] Compound 9d (70 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL), and compound 3i (87 mg, 0.35 mmol) was added. The atmosphere was purged with nitrogen three times, and sodium bis(trimethylsilyl)amide (2 M, 0.24 mL, 0.47 mmol, Adamas) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 9e (43.7 mg, 31.44% yield).

[0859] MS m / z(ESI):442.3[M+1]

[0860] Step 5

[0861] tert-Butyl (2-((4-amino-6-(5-fluoro-3-(4-fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxamido)-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 9f

[0862] Compound 9e (43.73 mg, 0.1 mmol) was dissolved in ethylene glycol dimethyl ether (1.4 mL) and water (0.5 mL). Bis(triphenylphosphine)palladium chloride (3.5 mg, 0.005 mmol, Adamas), compound 3k (30 mg, 0.1 mmol), and sodium carbonate (31.5 mg, 0.3 mmol, Sinopharm) were added. The mixture was purged with nitrogen for 10 minutes and microwaved at 110°C for 40 minutes. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to afford the title compound 9f (44 mg, 76.34% yield).

[0863] MS m / z(ESI):582.4[M+1]

[0864] Step 6

[0865] N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxamide 9 g

[0866] Compound 9f (44 mg, 0.08 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.07 g, 9.42 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 5 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9g (36 mg, yield: 98.8%). The product was directly used in the next step without purification.

[0867] MS m / z(ESI):482.4[M+1]

[0868] Step 7

[0869] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxamide 9

[0870] Crude compound 9g (36 mg, 0.07 mmol) was dissolved in dichloromethane (1.5 mL). N,N-diisopropylethylamine (48.3 mg, 0.37 mmol, Adamas) was added, and acryloyl chloride (6.8 mg, 0.07 mmol, Sinopharm) was added dropwise at -20°C. The mixture was allowed to react for 10 minutes at -20°C. 5 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Welch Ultimate PFP, 5 μm 30 x 150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 30%-95%) to obtain the title compound 9 (3.5 mg, yield: 8.74%).

[0871] MS m / z(ESI):536.3[M+1]

[0872] 1H NMR (500MHz, CDCl3): δ8.65-8.59(m,1H),8.43-8.36(m,1H),8.17-8.10(m,1H) ,8.03-8.00(m,1H),7.16-7.14(m,1H),7.00-6.97(m,1H),6.61-6.53(m,1H),6 .40-6.34(m,1H),5.89(s,2H),5.73-5.71(m,1H),3.64-3.55(m,4H),2.99(s,3 H),2.89-2.85(m,3H),2.26-2.16(m,3H),2.04-2.02(m,1H),1.28-1.23(m,6H).

[0873] Example 10

[0874] N-(4-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-3-(hydroxymethyl)pyridin-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10

[0875] first step

[0876] 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxylic acid 10a

[0877] Compound 1d (560 mg, 2.54 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide (1.07 g, 25.50 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 2 hours. 1 M hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 10a (524 mg, yield: 99.9%). MS m / z (ESI): 207.1 [M+1]

[0878] Step 2

[0879] 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10b

[0880] Compound 10a (524 mg, 2.54 mmol) was dissolved in N,N-dimethylformamide (7 mL). Ammonium chloride (164 mg, 3.06 mmol, Sinopharm), N,N-diisopropylethylamine (1.32 g, 10.21 mmol, Adamas), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.45 g, 3.81 mmol, Adamas) were added and reacted at room temperature for 16 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 10b (450 mg, 86.3% yield). MS m / z (ESI): 206.1 [M+1]

[0881] Step 3

[0882] N-(4-chloro-3-formylpyridin-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10c

[0883] Compound 10b (200 mg, 0.97 mmol), 2-bromo-4-chloropyridine-3-carboxaldehyde (257 mg, 1.16 mmol, Bidler), tris(dibenzylideneacetone)dipalladium (89 mg, 0.09 mmol, Bidler), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (113 mg, 0.19 mmol, Shaoyuan), and cesium carbonate (635 mg, 1.95 mmol, Adamas) were dissolved in 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 10c (85 mg, 25.3% yield).

[0884] MS m / z(ESI):345.2[M+1].

[0885] Step 4

[0886] tert-Butyl (2-((4-acetamido-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 10d

[0887] Compound 3k (3 g, 9.91 mmol) was dissolved in dichloromethane (60 mL), and pyridine (3.13 g, 39.57 mmol, Sinopharm) and acetic anhydride (2.02 g, 19.79 mmol, Sinopharm) were added. The mixture was allowed to react at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 10d (2.57 g, 75.2% yield).

[0888] MS m / z(ESI):345.3[M+1]

[0889] Step 5

[0890] tert-Butyl (2-((4-acetamido-6-(trimethyltinyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 10e

[0891] Compound 10d (200 mg, 0.58 mmol) was dissolved in toluene (10 mL). Triphenylarsine (36 mg, 0.12 mmol, Inochem), tetrakistriphenylphosphine palladium (67 mg, 0.06 mmol, Bidler), and hexamethyltin (380 mg, 1.16 mmol, Adamas) were added. The atmosphere was purged with nitrogen three times and the mixture was reacted at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound 10e. The crude product was used directly in the next step without purification.

[0892] MS m / z(ESI):475.2[M+2].

[0893] Step 6

[0894] Tert-butyl (2-((4-amino-6-(2-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-formamido)-3-formylpyridin-4-yl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 10f

[0895] Compound 10e (236 mg, 0.50 mmol) was dissolved in 1,4-dioxane (10 mL). Compound 10c (85 mg, 0.25 mmol), cuprous iodide (95 mg, 0.50 mmol, Leyan), and bis(triphenylphosphine)palladium chloride (70 mg, 0.10 mmol, Adamas) were added. The atmosphere was purged with nitrogen three times and the mixture was reacted at 90°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 10f (115 mg, 40.0% yield).

[0896] MS m / z(ESI):577.5[M+1].

[0897] Step 7

[0898] Tert-butyl (2-((4-amino-6-(2-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)-3-(hydroxymethyl)pyridin-4-yl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 10g

[0899] Compound 10f (115 mg, 0.20 mmol) was dissolved in methanol (5 mL), and sodium borohydride (8 mg, 0.21 mmol, Chinese medicine) was added. The reaction was allowed to react at room temperature for 30 minutes. 1N hydrochloric acid (1 mL) was added to quench the reaction, and 10 mL of water was added. The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10 g of the title compound (58 mg, yield: 50.4%). MS m / z (ESI): 579.2 [M+1]

[0900] Step 8

[0901] N-(4-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-3-(hydroxymethyl)pyridin-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10h

[0902] Compound 10g (58 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (924 mg, 8.10 mmol, Adamas) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10h (47 mg, yield: 98.1%). The product was directly used in the next step without purification.

[0903] MS m / z(ESI):479.2[M+1]

[0904] Step 9

[0905] N-(4-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-3-(hydroxymethyl)pyridin-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10

[0906] Crude compound 10h (47 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) was added. Acryloyl chloride (9.5 mg, 0.10 mmol, Sinopharm) was added dropwise at -20°C, and the mixture was allowed to react for 1 hour at -20°C. 3 mL of water was added, and the mixture was extracted with dichloromethane (3 mL x 3). The organic phases were combined, washed with 3 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to afford the title compound 10 (1.8 mg, 3.4% yield).

[0907] MS m / z(ESI):533.2[M+1]

[0908] 1 H NMR(500MHz,DMSO-d6)δ10.64-10.37(m,1H),8.58-8.41(m,2H),8.09(s,2H),7.57(t,1H),7.31(dd,1H),6.76(d,1H),6.62(ddd ,1H),6.07(ddd,1H),5.61(ddd,1H),4.46(d,2H),3.62-3.48(m,4H),3.02(t,2H),2.82-2.48(m,3H),2.15(t,2H),1.02(d,4H).

[0909] Example 11

[0910] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11

[0911] first step

[0912] N-(3-Bromo-5-fluoro-2-formylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11a

[0913] Compound 10b (300 mg, 1.46 mmol), 2,6-dibromo-4-fluorobenzaldehyde (825 mg, 2.92 mmol, Bidex), tris(dibenzylideneacetone)dipalladium (135 mg, 0.15 mmol, Bidex), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (85 mg, 0.15 mmol, Shaoyuan), and cesium carbonate (715 mg, 2.19 mmol, Adamas) were dissolved in 1,4-dioxane (15 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 11a (330 mg, 55.6% yield).

[0914] MS m / z(ESI):407.9[M+2].

[0915] Step 2

[0916] N-(3-Bromo-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11b

[0917] Compound 11a (330 mg, 0.81 mmol) was dissolved in methanol (10 mL), and sodium borohydride (31 mg, 0.82 mmol, Chinese medicine) was added. The reaction was allowed to react at room temperature for 30 minutes. 1N hydrochloric acid (1 mL) was added to quench the reaction, and 15 mL of water was added. The mixture was extracted with dichloromethane (15 mL x 2). The organic phases were combined, washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 11b (330 mg, yield: 99.5%). MS m / z (ESI): 406.2 [M-2]

[0918] Step 3

[0919] Benzyl 2-bromo-4-fluoro-6-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)acetate 11c

[0920] Compound 11b (330 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (82 mg, 0.81 mmol, Sinopharm) and 4-dimethylaminopyridine (10 mg, 0.08 mmol, Shaoyuan) were added. Acetic anhydride (83 mg, 0.81 mmol, Sinopharm) was added dropwise at 0°C and allowed to react at room temperature for 1 hour. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System B to afford the title compound 11c (225 mg, 61.8% yield).

[0921] MS m / z(ESI):451.9[M+2]

[0922] Step 4

[0923] Benzyl 4-fluoro-2-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetate 11d

[0924] Compound 11c (225 mg, 0.50 mmol) was dissolved in 1,4-dioxane (5 mL). [1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (42 mg, 0.05 mmol, Bidex), pinacol diboron (318 mg, 1.25 mmol, Shaoyuan), and potassium acetate (147 mg, 1.5 mmol, Adamas) were added. The atmosphere was purged with nitrogen three times and the mixture was reacted at 90°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 11d (150 mg, 60.3% yield).

[0925] 1 H NMR(500MHz, CDCl3)δ9.27(d,1H),8.05(dd,1H),7.94(d,1H),7.35(dd,1H),6.45(d,1H),5.48(s ,2H),3.08(t,2H),2.21(t,2H),2.08(s,3H),1.28(s,12H),1.09-1.06(m,2H),1.00-0.96(m,2H).

[0926] Step 5

[0927] Benzyl 2-(6-amino-5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)pyrimidin-4-yl)-4-fluoro-6-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)acetate 11e

[0928] Compound 11d (150 mg, 0.30 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). Compound 3k (92 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol, Bidex), and potassium carbonate (85 mg, 0.61 mmol, Sinopharm) were added. The atmosphere was purged with nitrogen three times and the reaction was microwaved at 110°C for 30 minutes. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent System A to afford the title compound 11e (191 mg, 99.3% yield).

[0929] MS m / z(ESI):638.3[M+1]

[0930] Step 6

[0931] Tert-butyl (2-((4-amino-6-(5-fluoro-3-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamido)-2-(hydroxymethyl)phenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate 11f

[0932] Compound 11e (191 mg, 0.30 mmol) was dissolved in tetrahydrofuran (1.5 mL) and water (1.5 mL). Lithium hydroxide (36 mg, 1.50 mmol, Adamas) was added and allowed to react at room temperature for 30 minutes. 1 M hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 11f (178 mg, yield: 99.7...

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: G is selected from Ring A is selected from polycyclic aromatic groups, heteroaromatic groups, cycloalkyl groups and heterocyclic groups; Ring B is a monocyclic aryl group or a monocyclic heteroaryl group; Each R 1 and each R 2a are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a deuterated alkoxy group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 and =CR p R q 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 Together with the ring 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 0 replace; R 2 For-OR A or -alkylene-R B ; wherein the alkylene group is optionally replaced by one or more R 0 replace; R A is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; R B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; R C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently replaced by one or more R d replace; Each R d are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 and =CR p R q wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl 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, a deuterated 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 a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, a -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace; or R 4c and R 4d Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace; or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more R 0 replace; or R 5b and R 5c Together with the carbon atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is 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 deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy 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 , S, S(O) and S(O)2; R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a halogen alkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, amino, cycloalkyl, and cycloalkylalkyl; or R 8 and R 9 Together with the attached carbon atom, it forms 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 deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy 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 a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a -(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 carbon atoms connected thereto together form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted 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, deuterated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl 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 one of them and R 15 Together with the atoms to which they are attached, they form a nitrogen-containing heterocyclic group; wherein the nitrogen-containing heterocyclic group is optionally substituted by one or more R 0 replace; W is selected from -C(O)R 16 、-S(O)2R 16 and -CN; R 16 selected from alkenyl, alkynyl and alkene oxide; wherein the alkenyl, alkynyl and alkene oxide are each independently optionally selected from oxo, =S, =CR p R q , deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, 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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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 is substituted by one or more substituents in a heteroaryl group; R 0 are the same or different at each occurrence and are independently selected from oxo, =S, =CR p R q , deuterium atom, halogen, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, aminoalkyl, -(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 、-SR 17 、-S(O)R 17 、-S(O)2R 17 、-S(O)2NR 18 R 19 、-NR 20 S(O)2R 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; R 17 , R 18 , R 19 and R 20 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 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R 01 replace; R 01 are the same or different at each occurrence and are independently selected from oxo, =S, =CR p R q , a deuterium atom, a halogen, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, an amino group, a -NH alkyl group, a -N(alkyl)2 group, a -C(O)O alkyl group, a -C(O)OH group, a -C(O)NH2 group, a -C(O)halogen group, a -C(O)alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, an aryloxy group, a heteroaryl group, a heteroarylalkyl group, and a heteroaryloxy group; R a and R b is the same or different at each occurrence and is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group; R p and R q is the same or different at each occurrence and is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyl group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group; q is an integer from 0 to 25; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; v is 0, 1, 2, or 3.

2. 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 (II) or a pharmaceutically acceptable salt thereof: in: G.R 3 , 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 is as defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein G is selected from R 1 ' is a hydrogen atom or R 1 ; q1 is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6; R 1 As defined in claim 1; preferably, G is selected from 4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof: in: A 1 and A 2 are the same or different and are each independently selected from a bond, C(O), O, NR, S, S(O), S(O)2 and (CR 1b R 1c ) j ; R 1b , R 1c , R e , R f , R j and R k are the same or different and are each independently a hydrogen atom or R 1 ; Or, R e and R f Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by 1, 2, 3 or 4 R 1 replace; Or, R j and R k Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by 1, 2, 3 or 4 R 1 replace; Or, R f and R j Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by 1, 2, 3 or 4 R 1 replace; Or, R 1b and R 1c Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by 1, 2, 3 or 4 R 1 replace; R 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, an aminoalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; j is 0, 1, 2, or 3; q1 is 0, 1, 2, or 3; r is 0 or 1; R 1 , R 3 , 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 is as defined in claim 1.

5. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein 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, each R 1 The same or different, and each independently is halogen; More preferably, R 1 For F.

6. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 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 or C 1-6 Hydroxyalkyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or a halogen; R 4d is a hydrogen atom; more preferably, R 4a is methyl or hydroxymethyl; R 4b is a hydrogen atom; R 4c is a hydrogen atom or F; R 4d A hydrogen atom.

7. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein B 3 is CH or N; preferably, B 3 N; and / or R 6 It is amino.

8. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 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, C 1-6 deuterated alkyl and 3 to 6 membered cycloalkyl; preferably, R 15 It is methyl or -CD3.

9. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein 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.

10. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 9, wherein A 1 and A 2 are the same or different and are each independently selected from a bond, O and CH2; preferably, A 1 CH2 or O, A 2 is the key.

11. A compound represented by general formula (I) according to any one of claims 4 to 10 or a pharmaceutically acceptable salt thereof, wherein R e , R f , R j and R k are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; or, R e and R f Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; or, R j and R k Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; or, R f and R j Together with the attached carbon atom, it forms a 4- to 6-membered cycloalkyl group.

12. The compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

13. A compound represented by the general formula (IA) or a salt thereof: in: G.R 3 , X 1 , X 2 , X 3 , X 4 , B 1 , B 2 , B 3 , R 6 , L, R 11 , R 12 , R 13 , R 14 , R 15 , R x , R y and n is as defined in claim 1.

14. A compound or a salt thereof, which is selected from any one of the following compounds:

15. A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; in: X is a halogen, preferably Cl; W is -C(O)R 16 or -S(O)2R 16 ; G.R 3 , X 1 , X 2 , X 3 , X 4 , B 1 , B 2 , B 3 , R 6 , L, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R x , R y and n is as defined in claim 1.

16. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by BTK.

18. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing a disease or condition selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, Preferably, the disease or condition is selected from the group consisting of autoimmune diseases, inflammatory diseases and cancer; More preferably, the disease or condition is selected from the group consisting of 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, Sjögren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria, liver insufficiency, allergies, ankylosing spondylitis, skin 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, stroke, ischemic disorders, pulmonary embolism, gout, pemphigus vulgaris , idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, 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.

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